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  • 1.
    Alikhani, Nyosha
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Guo, Lan
    Yan, Shiqiang
    Du, Heng
    Pinho, Catarina Moreira
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Chen, John Xi
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yan, Shirley ShiDu
    Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria2011In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 27, no 1, p. 75-87Article in journal (Refereed)
    Abstract [en]

    Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD.

  • 2.
    Atti, Anna Rita
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Forlani, Claudia
    de Ronchi, Diana
    Palmer, Katie
    Casadio, Paola
    Dalmonte, Edoardo
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Cognitive Impairment after Age 60: clinical and Social Correlates in the "Faenza Project"2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 21, no 4, p. 1325-1334Article in journal (Refereed)
    Abstract [en]

    A total of 7,389 dementia-free elderly (60–102 years old) enrolled in the "Faenza Project" (Northern Italy) were clinically evaluated by nurses and physicians with the aim of detecting the independent and combined association of medical and social factors with cognitive status. Cognitive Impairment No Dementia (CIND) was defined for MMSE scores ⩽ 2 standard deviations than the age- and education-corrected mean score obtained by the non-demented persons of the Faenza cohort. Logistic Regression analysis was used to estimate Odds Ratios and 95% Confidence Intervals (OR, 95%CI) for CIND. The diagnostic procedure identified 402 (5.4%) CIND cases. Diabetes (OR, 95%CI=1.6, 1.2–2.2), stroke (OR, 95%CI=1.9, 1.4–2.6), and depressive symptoms (OR, 95%CI=1.9, 1.4–2.7) emerged as the most relevant medical comorbidities of CIND. Low education (OR, 95%CI=1.8, 1.1–2.9), low Socio Economic Status (SES) (OR, 95%CI=1.5, 1.1–2.1), and unmarried status (OR, 95%CI=1.7, 1.2–2.5) were associated with CIND. Medical and social factors were independently related to CIND occurrence. In comparison to subjects without any of the above mentioned conditions, subjects with one medical and one social factor had an OR, 95%CI for CIND equal to 6.0, 2.9–12.4. The strength of the association increased when more of those conditions occurred in combination, suggesting a synergistic effect. Despite some methodological limitations, data from this cross-sectional population-based Italian study show that low education, low SES, unmarried status together with diabetes, stroke, and depressive symptoms are related to cognitive impairment in the general population. The interaction of medical and social factors further increases the probability of CIND.

  • 3. Barbera, Mariagnese
    et al.
    Mangialasche, Francesca
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Jongstra, Susan
    Guillemont, Juliette
    Ngandu, Tiia
    Beishuizen, Cathrien
    Coley, Nicola
    Brayne, Carol
    Andrieu, Sandrine
    Richard, Edo
    Soininen, Hilkka
    Kivipelto, Miia
    Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 62, no 2, p. 649-663Article in journal (Refereed)
    Abstract [en]

    Background: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. Objective: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. Methods: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. Results: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. Conclusion: Despite differences inCVRmanagement within the countries considered, itwas possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.

  • 4.
    Caracciolo, Barbara
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Gatz, Margaret
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Marengoni, Alessandra
    Pedersen, Nancy L.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Relationship of Subjective Cognitive Impairment and Cognitive Impairment No Dementia to Chronic Disease and Multimorbidity in a Nation-Wide Twin Study2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 36, no 2, p. 275-284Article in journal (Refereed)
    Abstract [en]

    We investigated the relation of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND) to common chronic diseases of the elderly and multimorbidity, and assessed the contribution of genetic background and shared familial environment to these associations. Subjects were 11,379 dementia-free twin individuals aged >= 65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. In unmatched, fully-adjusted regression models, mental, musculoskeletal, respiratory, and urological diseases were all significantly associated with increased odds ratios (ORs) of SCI and CIND. Circulatory and gastrointestinal diseases were related to SCI only, while endocrine diseases were associated with CIND. The adjusted ORs of multimorbidity were 2.1 [95% confidence intervals (95% CI): 1.8-2.3] for SCI and 1.5 for CIND (95% CI: 1.3-1.8). A dose-dependent relationship was observed between number of chronic diseases and ORs for SCI but not for CIND. In co-twin control analyses, the chronic diseases-SCI association was largely unchanged. On the other hand, the chronic diseases-CIND association was no longer statistically significant, except for cancer, where an increased OR was observed. In conclusion, chronic morbidity is associated with both SCI and CIND but disease profiles do not always overlap between the two cognitive syndromes. The association is stronger when diseases co-occur, especially for SCI. Genetic and early-life environmental factors may partially explain the association of CIND but not that of SCI with chronic diseases.

  • 5.
    Caracciolo, Barbara
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Gatz, Margaret
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Pedersen, Nancy L
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Differential distribution of subjective and objective cognitive impairment in the population: a nation-wide twin-study2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 29, no 2, p. 393-403Article in journal (Refereed)
    Abstract [en]

    We report the prevalence of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND), their socio-demographic profile, and the contribution of genetic background and shared familial environment to SCI and CIND. Subjects were 11,926 dementia-free twin individuals aged ≥65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. Overall prevalence rates of SCI and CIND were 39% (95% CI 38-39%) and 25% (95% CI 24-25%). In multivariate GEE models, both SCI and CIND were older compared with people without any cognitive impairment. CIND were also less educated, more likely to be unmarried and to have lower socioeconomic status (SES). SCI individuals differed from persons with CIND as they were older, more educated, more likely to be married, and to have higher SES. Co-twin control analysis, which corrects for common genetic and shared environmental background, confirmed the association of low education with CIND. Probandwise concordance for SCI and CIND was 63% and 52% in monozygotic twins, 63% and 50% in dizygotic same-sex twins, and 42% and 29% in dizygotic unlike-sex twins. Tetrachoric correlations showed no significant differences between monozygotic and dizygotic same-sex twins. We conclude that subjective and objective cognitive impairment are both highly prevalent among nondemented elderly yet have distinct sociodemographic profiles. Shared environmental influences rather than genetic background play a role in the occurrence of SCI and CIND.

  • 6. Cermakova, Pavla
    et al.
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Garcia-Ptacek, Sara
    Lund, Lars H.
    Winblad, Bengt
    Eriksdotter, Maria
    Religa, Dorota
    Cardiovascular Diseases in similar to 30,000 Patients in the Swedish Dementia Registry2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 48, no 4, p. 949-958Article in journal (Refereed)
    Abstract [en]

    Background: Cardiovascular diseases are leading causes of death and patients with dementia are often affected by them. Objective: Investigate associations of cardiovascular diseases with different dementia disorders and determine their impact on mortality. Methods: This study included 29,630 patients from the Swedish Dementia Registry (mean age 79 years, 59% women) diagnosed with Alzheimer's disease (AD), mixed dementia, vascular dementia, dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), frontotemporal dementia (FTD), or unspecified dementia. Records of cardiovascular diseases come from the Swedish National Patient Register. Multinomial logistic regression and cox proportional hazard models were applied. Results: Compared to AD, we found a higher burden of all cardiovascular diseases in mixed and vascular dementia. Cerebrovascular diseases were more associated with DLB than with AD. Diabetes mellitus was less associated with PDD and DLB than with AD. Ischemic heart disease was less associated with PDD and FTD than AD. All cardiovascular diseases predicted death in patients with AD, mixed, and vascular dementia. Only ischemic heart disease significantly predicted death in DLB patients (HR = 1.72; 95% CI = 1.16-2.55). In PDD patients, heart failure and diabetes mellitus were associated with a higher risk of death (HR = 3.06; 95% CI = 1.74-5.41 and HR = 3.44; 95% CI = 1.31-9.03). In FTD patients, ischemic heart disease and atrial fibrillation or flutter significantly predicted death (HR = 2.11; 95% CI = 1.08-4.14 and HR= 3.15; 95% CI = 1.60-6.22, respectively). Conclusion: Our study highlights differences in the occurrence and prognostic significance of cardiovascular diseases in several dementia disorders. This has implications for the care and treatment of the different dementia disorders.

  • 7. Choo, Il Han
    et al.
    Ni, Ruiqing
    Scholl, Michael
    Wall, Anders
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Nordberg, Agneta
    Combination of f 18 fdg pet and cerebrospinal fluid biomarkers as a better predictor of the progression to alzheimer's disease in mild cognitive impairment patients2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 33, no 4, p. 929-939Article in journal (Refereed)
    Abstract [en]

    The biomarker-based new diagnostic criteria have been proposed for Alzheimer's disease (AD) spectrum. However, any biomarker alone has not been known to have satisfactory AD predictability. We explored the best combination model with baseline demography, neuropsychology, F-18-fluorodeoxyglucose positron emission tomography (FDG-PET), cerebrospinal fluid (CSF) biomarkers, and apolipoprotein E (APOE) genotype evaluation to predict progression to AD in mild cognitive impairment (MCI) patients. Alongitudinal clinical follow-up (mean, 44 months; range, 1.6-161.7 months) of MCI patients was done. Among 83 MCI patients, 26 progressed to AD (MCI-AD) and 51 did not deteriorate (MCI-Stable). We applied that univariate and multivariate logistic regression analyses, and multistep model selection for AD predictors including biomarkers. In univariate logistic analysis, we selected age, Rey Auditory Verbal Retention Test, parietal glucose metabolic rate, CSF total tau, and presence or not of at least one APOE epsilon 4 allele as predictors. Through multivariate stepwise logistic analysis and model selection, we found the combination of parietal glucose metabolic rate and total tau representing the best model for AD prediction. In conclusion, our findings highlight that the combination of regional glucose metabolic assessment by PET and CSF biomarkers evaluation can significantly improve AD predictive diagnostic accuracy of each respective method.

  • 8. Eketjäll, Susanna
    et al.
    Jeppsson, Fredrik
    CNS and Pain iMed, AstraZeneca, Södertälje, Sweden; Operations Global Quality, AstraZeneca, Södertälje, Sweden.
    Cebers, Gvido
    AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 50, no 4, p. 1109-1123Article in journal (Refereed)
    Abstract [en]

    A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-beta peptide (A beta) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-beta protein precursor (A beta PP) to A beta peptides, with the soluble N terminal fragment of A beta PP (sA beta PP beta) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of A beta. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose-and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of A beta(40), A beta(42), and sA beta PP beta. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of A beta. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

  • 9. Ferrari, Camilla
    et al.
    Lombardi, Gemma
    Polito, Cristina
    Lucidi, Giulia
    Bagnoli, Silvia
    Piaceri, Irene
    Nacmias, Benedetta
    Berti, Valentina
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Centrum, Sweden.
    Sorbi, Sandro
    Alzheimer's Disease Progression: Factors Influencing Cognitive Decline2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 2, p. 785-791Article in journal (Refereed)
    Abstract [en]

    Background:

    Alzheimer's disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors.

    Objective:

    The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients.

    Methods:

    We retrospectively selected 160 AD patients diagnosed at the Neurology Unit of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period.

    Results:

    Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) epsilon 4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated epsilon 4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non epsilon 4-carriers.

    Conclusion:

    At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches.

  • 10. Garcia-Ptacek, Sara
    et al.
    Farahmand, Bahman
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Jönköping University, Sweden.
    Religa, Dorota
    Luz Cuadrado, Maria
    Eriksdotter, Maria
    Mortality Risk after Dementia Diagnosis by Dementia Type and Underlying Factors: A Cohort of 15,209 Patients based on the Swedish Dementia Registry2014In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 41, no 2, p. 467-477Article in journal (Refereed)
    Abstract [en]

    Background: Knowledge on survival in dementia is crucial for patients and public health planning. Most studies comparing mortality risk included few different dementia diagnoses. Objectives: To compare mortality risk in the most frequent dementia disorders in a large cohort of patients with an incident diagnosis, adjusting for potential confounding factors. Methods: 15,209 patients with dementia from the national quality database, Swedish Dementia Registry (SveDem), diagnosed in memory clinics from 2008 to 2011, were included in this study. The impact of age, gender, dementia diagnosis, baseline Mini-Mental State Examination (MMSE), institutionalization, coresidency, and medication on survival after diagnosis were examined using adjusted hazard ratios (HR) with 95% confidence intervals (CI). Results: During a mean follow-up of 2.5 years, 4,287 deaths occurred, with 114 (95% CI 111-117) deaths/1,000 person-years. Adjusted HR of death for men was 1.56 (95% CI 1.46-1.66) compared to women. Low MMSE, institutionalization, and higher number of medications were associated with higher HR of death. All dementia diagnoses demonstrated higher HR compared to Alzheimer's disease, with vascular dementia presenting the highest crude HR. After adjusting, frontotemporal dementia had the highest risk with a HR of 1.91 (95% CI 1.52-2.39), followed by Lewy body dementia (HR 1.64; 95% CI 1.39-1.95), vascular dementia (HR 1.55; 95% CI 1.42-1.69), Parkinson's disease dementia (HR 1.47; 95% CI 1.17-1.84), and mixed Alzheimer's disease and vascular dementia (HR 1.32; 95% CI 1.22-1.44). Conclusion: Worse cognition, male gender, higher number of medications, institutionalization, and age were associated with increased death risk after dementia diagnosis. Adjusted risk was lowest in Alzheimer's disease patients and highest in frontotemporal dementia subjects.

  • 11. Gil-Bea, Francisco J
    et al.
    Solas, Maite
    Solomon, Alina
    Mugueta, Carmen
    Winblad, Bengt
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Ramirez, Maria J
    Cedazo-Mínguez, Angel
    Insulin levels are decreased in the cerebrospinal fluid of women with prodomal Alzheimer's disease2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 22, no 2, p. 405-413Article in journal (Refereed)
    Abstract [en]

    Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1-42 (Aβ1-42) levels and cognitive score. Furthermore, total-tau/(Aβ1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1-42 ratio for early AD diagnosis in women.

  • 12. Handels, Ron L. H.
    et al.
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Caracciolo, Barbara
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Wang, Rui
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Verhey, Frans R. J.
    Severens, Johan L.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Joore, Manuela A.
    Wimo, Anders
    Natural Progression Model of Cognition and Physical Functioning among People with Mild Cognitive Impairment and Alzheimer's Disease2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 37, no 2, p. 357-365Article in journal (Refereed)
    Abstract [en]

    Background: Empirical models of the natural history of Alzheimer's disease (AD) may help to evaluate new interventions for AD. Objective: We aimed to estimate AD-free survival time in people with mild cognitive impairment (MCI) and decline of cognitive and physical function in AD cases. Methods: Within the Kungsholmen project, 153 incident MCI and 323 incident AD cases (international criteria) were identified during 9 years of follow-up in a cognitively healthy cohort of elderly people aged >= 75 at baseline (n = 1,082). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily life function was evaluated with the Katz index of activities of daily living (ADL) at each follow-up examination. Data were analyzed using parametric survival analysis and mixed effect models. Results: Median AD-free survival time of 153 participants with incident MCI was 3.5 years. Among 323 incident AD cases, the cognitive decline was 1.84 MMSE points per year, which was significantly associated with age. Physical functioning declined by 0.38 ADL points per year and was significantly associated with age, education, and MMSE, but not with gender. Conclusion: Elderly people with MCI may develop AD in approximately 3.5 years. Both cognitive and physical function may decline gradually after AD onset. The empirical models can be used to evaluate long-term disease progression of new interventions for AD.

  • 13. Hartikainen, Päivi
    et al.
    Räsänen, Janne
    Julkunen, Valtteri
    Niskanen, Eini
    Hallikainen, Merja
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Vanninen, Ritva
    Remes, Anne M
    Soininen, Hilkka
    Cortical thickness in frontotemporal dementia, mild cognitive impairment, and Alzheimer's disease2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 30, no 4, p. 857-874Article in journal (Refereed)
    Abstract [en]

    Cortical thickness analysis has been proposed as a potential diagnostic measure in memory disorders. In this retrospective study, we compared the cortical thickness values of 24 patients with frontotemporal dementia (FTD) to those of 25 healthy controls, 45 symptomatic subjects with stable mild cognitive impairment (S-MCI), 15 subjects with progressive mild cognitive impairment (P-MCI), and 36 patients with Alzheimer's disease (AD). The patterns of regions of thinning in FTD when compared to controls and also S-MCI patients showed similar trends; thinning of the bilateral frontal poles and bilateral medial temporal lobe structures, especially the anterior part of the gingulum, the uncus, and parahippocampal gyri. Cortical thinning in FTD was also found on the boundary regions of parietal and occipital lobes. In the P-MCI group compared to FTD, the trend of thinning in small distinct areas of the parietal and occipital lobes was observed. The FTD and AD groups did not differ statistically, but we found trends toward thinning in FTD of the left cingulate gyrus, and the left occipitotemporal gyri, and in AD of the inferior parietal, occipitoparietal, and the pericalcarine regions, more in the right hemisphere. In FTD, increased slowness in the executive test (Trail-Making A) correlated with the thinner cortex, whereas the language tests showed the lower scores, the thinner cortex in the left hemisphere. Cortical thickness might be a tool for detecting subtle changes in brain atrophy in screening of dementia prior to the development of diffuse or lobar atrophies.

  • 14. Hedskog, Louise
    et al.
    Brohede, Jesper
    Wiehager, Birgitta
    Pinho, Catarina Moreira
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Revathikumar, Priya
    Lilius, Lena
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Graff, Caroline
    Karlstrom, Helena
    Ankarcrona, Maria
    Biochemical studies of poly t variants in the alzheimer's disease associated tomm40 gene2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 3, p. 527-536Article in journal (Refereed)
    Abstract [en]

    The apolipoprotein E (APOE) gene remains the most strongly established risk factor for late onset Alzheimer's disease (LOAD). Recently the gene, TOMM40, which is in linkage disequilibrium with APOE, was identified to be associated with LOAD in genome-wide association studies. One of the identified polymorphisms in TOMM40 is rs10524523, which is located in intron 6 and composed of thymidine repeats varying between 14 to 36 base-pairs in length. Reported results are contradictory in regard to the very long poly-T variant that has been associated with both increased and decreased risk of LOAD. Our study aimed to elucidate the functional implication of rs10524523 in an in vitro model of human fibroblast cells obtained from cognitively healthy APOE epsilon 3/epsilon 4 carriers harboring very long or short poly-T variants coupled to their APOE epsilon 3 allele. We have studied (i) expression levels of TOM40 protein and mRNA, (ii) TOM40 mRNA splicing, and (iii) mitochondrial function and morphology; and we have found no significant differences in regards to very long or short poly-T variant.

  • 15.
    Håkansson, Krister
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Ledreux, Aurelie
    Daffner, Kirk
    Terjestam, Yvonne
    Bergman, Patrick
    Carlsson, Roger
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Granholm, Ann-Charlotte
    Mohammed, Abdul Kadir H.
    BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 55, no 2, p. 645-657Article in journal (Refereed)
    Abstract [en]

    Brain-derived neurotrophic factor (BDNF) has a central role in brain plasticity by mediating changes in cortical thickness and synaptic density in response to physical activity and environmental enrichment. Previous studies suggest that physical exercise can augment BDNF levels, both in serum and the brain, but no other study has examined how different types of activities compare with physical exercise in their ability to affect BDNF levels. By using a balanced cross over experimental design, we exposed nineteen healthy older adults to 35-minute sessions of physical exercise, cognitive training, and mindfulness practice, and compared the resulting changes in mature BDNF levels between the three activities. We show that a single bout of physical exercise has significantly larger impact on serum BDNF levels than either cognitive training or mindfulness practice in the same persons. This is the first study on immediate BDNF effects of physical activity in older healthy humans and also the first study to demonstrate an association between serum BDNF responsivity to acute physical exercise and working memory function. We conclude that the BDNF increase we found after physical exercise more probably has a peripheral than a central origin, but that the association between post-intervention BDNF levels and cognitive function could have implications for BDNF responsivity in serum as a potential marker of cognitive health.

  • 16. Iaccarino, Leonardo
    et al.
    Chiotis, Konstantinos
    Alongi, Pierpaolo
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden; Karolinska University Hospital Huddinge, Sweden.
    Wall, Anders
    Cerami, Chiara
    Bettinardi, Valentino
    Gianolli, Luigi
    Nordbereg, Agneta
    Perani, Daniela
    A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 59, no 2, p. 603-614Article in journal (Refereed)
    Abstract [en]

    Assessments of brain glucose metabolism (F-18-FDG-PET) and cerebral amyloid burden (C-11-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of F-18-FDGPET and C-11-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for F-18-FDG-PET and of standardized uptake value ratio semiquantification for C-11-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57 +/- 7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, F-18-FDG-PET and C-11-PiB-PET. F-18-FDG-PET, compared to C-11-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both F-18-FDG-PET and C-11-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

  • 17. Imtiaz, Bushra
    et al.
    Tolppanen, Anna Maija
    Solomon, Alina
    Soininen, Hilkka
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland, Finland; National Institute for Health and Welfare, Finland .
    Estradiol and Cognition in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Cohort Study2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 56, no 2, p. 453-458Article in journal (Refereed)
    Abstract [en]

    Cardiovascular Risk factors, Aging and Dementia (CAIDE) is a Finnish population-based study. 731 cognitively normal women had self-reported hormone therapy (HT) data in 1998 as: no use, use <= 5 years, and >5 years. Information on type of HT was only available from 1995-1998 (Prescription Register). Cognition was assessed in 1998 and 2005-2008. Longterm (>5 years) HT use, especially use of estradiol alone among women having hysterectomy with bilateral oophorectomy, was associated with better episodic memory in 1998, but not in 2005-2008. Although a strong evidence for protective effect of estradiol on cognition was not observed in our study, improved global cognition among long-term users suggests that long-term postmenopausal HT may be beneficial for some cognitive domains.

  • 18. Imtiaz, Bushra
    et al.
    Tuppurainen, Marjo
    Tiihonen, Miia
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland, Finland.
    Soininen, Hilkka
    Hartikainen, Sirpa
    Tolppanen, Anna-Maija
    Oophorectomy, Hysterectomy, and Risk of Alzheimer's Disease: A Nationwide Case-Control Study2014In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 42, no 2, p. 575-581Article in journal (Refereed)
    Abstract [en]

    Background: Association between oophorectomy and/or hysterectomy and dementia in context of hormone therapy (HT) use is ambiguous. Objective: To assess whether oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy are related to risk of Alzheimer's disease (AD), whether the possible indication for surgery plays a role, and if the associations are modified by HT. Methods: Our nationwide register based case-control (1 : 1) study included all women with clinically-verified AD diagnoses, residing in Finland on December 31, 2005 (n of cases = 19,043, n of controls = 19,043). AD cases, diagnosed according to NINCS-ADRDA and the DSM-IV criteria, were identified from Special Reimbursement Register. Information on HT use was collected from national prescription register, and data on surgery and uterine/ovarian/cervical cancer were obtained from the hospital discharge register. Most of the women (91.8%) were over 51 years of age when the surgery was performed. Results: Oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy were associated with lower risk of AD (OR/95% CI: 0.85/0.75-0.97, 0.89/0.81-0.97 and 0.85/0.75-0.98, respectively) among women without the history of uterine/ovarian/cervical cancer, although the absolute risk difference was small. The association was not evident in women with uterine/ovarian/cervical cancer history (3.00 /0.20-44.87 for all surgeries). The associations were not modified by HT use, which was independently associated with AD risk, with longer use showing protective association. Conclusion: Our findings indicate that oophorectomy with or without hysterectomy after commencement of natural menopause is not an important determinant of AD risk in older age and support the critical window hypothesis for HT use.

  • 19. Julkunen, Valtteri
    et al.
    Niskanen, Eini
    Koikkalainen, Juha
    Herukka, Sanna-Kaisa
    Pihlajamäki, Maija
    Hallikainen, Merja
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Muehlboeck, Sebastian
    Evans, Alan C
    Vanninen, Ritva
    Soininen, Hilkka
    Differences in cortical thickness in healthy controls, subjects with mild cognitive impairment, and Alzheimer's disease patients: a longitudinal study2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 21, no 4, p. 1141-1151Article in journal (Refereed)
    Abstract [en]

    In this study, we analyzed differences in cortical thickness (CTH) between healthy controls (HC), subjects with stable mild cognitive impairment (S-MCI), progressive MCI (P-MCI), and Alzheimer's disease (AD), and assessed correlations between CHT and clinical disease severity, education, and apolipoprotein E4 (APOE) genotype. Automated CTH analysis was applied to baseline high-resolution structural MR images of 145 subjects with a maximum followup time of 7.4 years pooled from population-based study databases held in the University of Kuopio. Statistical differences in CTH between study groups and significant correlations between CTH and clinical and demographic factors were assessed and displayed on a cortical surface model. Compared to HC group (n = 26), the AD (n = 21) group displayed significantly reduced CTH in several areas of frontal and temporal cortices of the right hemisphere. Higher education and lower MMSE scores were correlated with reduced CTH in the AD group, whereas no significant correlation was found between CDR-SB scores or APOE genotype and CTH. The P-MCI group demonstrated significantly reduced CTH compared to S-MCI in frontal, temporal and parietal cortices even after statistically adjusting for all confounding variables. Ultimately, analysis of CTH can be used to detect cortical thinning in subjects with progressive MCI several years before conversion and clinical diagnosis of AD dementia, irrespective of their cognitive performance, education level, or APOE genotype.

  • 20.
    Keller, Lina
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Graff, Caroline
    The Obesity Related Gene, FTO, Interacts with APOE and is Associated with Alzheimer's Disease Risk: A Prospective Cohort Study2011In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 23, no 3, p. 461-469Article in journal (Refereed)
    Abstract [en]

    The FTO gene has been shown to have a small but robust effect on body mass index (BMI) and to increase the risk for diabetes. Both high BMI and diabetes are vascular risk factors that might play a role in the development of Alzheimer's disease (AD) and dementia. Thus, our aim was to explore the impact of FTO on AD and dementia risk. Nine years of follow-up data was gathered from the Kungsholmen project, a prospective population-based study on 1,003 persons without dementia. Cox-regression models were used to assess the relative risks of developing AD and dementia (DSM-III-R criteria) according to FTO genotypes (rs9939609), taking into account APOE, physical inactivity, BMI, diabetes, and cardiovascular disease (CVD). Compared to carriers of the FTO TT-genotype, AA-carriers had a higher risk for AD (RR 1.58, 95% CI: 1.11-2.24) and for dementia (RR 1.48, 95% CI: 1.09-2.02) after adjustment for age, gender, education, and APOE genotype. This effect remained after additional adjustment for physical inactivity, BMI, diabetes, and CVD. An interaction between FTO and APOE was found, with increased risk for dementia for those carrying both FTO AA and APOE epsilon 4. Importantly, the effect of the AA-genotype on dementia/AD risk seems to act mostly through the interaction with APOE epsilon 4. Our findings suggest that the FTO AA-genotype increases the risk for dementia, and in particular AD, independently of physical inactivity, BMI, diabetes, and CVD measured at baseline. Our results are in line with the recently reported association between FTO and reduced brain volume in cognitively healthy subjects.

  • 21. Leoni, Valerio
    et al.
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Lövgren-Sandblom, Anita
    Minthon, Lennart
    Blennow, Kaj
    Hansson, Oskar
    Wahlund, Lars-Olof
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Björkhem, Ingemar
    Diagnostic Power of 24S-Hydroxycholesterol in Cerebrospinal Fluid: Candidate Marker of Brain Health2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 36, no 4, p. 739-747Article in journal (Refereed)
    Abstract [en]

    We evaluated the diagnostic potential of 24S-hydroxycholesterol (24OHC) in cerebrospinal fluid. At a memory clinic, we investigated subjects with subjective cognitive impairment (SCI, n = 33), mild cognitive impairment (MCI) patients (n = 27), MCI patients with later progression into Alzheimer dementia at follow up (n = 10), and patients with AD (n = 24). We also had a control group of healthy volunteers who did not later develop cognitive problems (n = 13). The fraction of the population with pathological levels of 24OHC was 8% in controls, 34% in SCI, 37% in MCI, 80% in MCI with progression, and 42% in AD. The corresponding fractions for T-tau, P-tau, and A beta(42) were lower in the case of SCI and MCI but higher in the case of controls and AD. In case of MCI with progression, the fraction of pathological levels of 24OHC and A beta(42) were 80% and 63% respectively. We also studied a population of old healthy subjects age 75-99 years (n = 25). The fraction of individuals in this population with pathological levels of 24OHC was 0% whereas the fraction of individuals with pathological level of at least one of the other three biomarkers was 40%. The diagnostic power of 24OHC in cerebrospinal fluid seems to be similar to or lower than that of the established biomarkers T-tau, P-tau, and A beta(42) in the diagnosis of established AD. Our data suggest that 24OHC may be more sensitive than the classical biomarkers in an early phase of the neurodegenerative process and a better marker for brain health in old age.

  • 22. Leuzy, Antoine
    et al.
    Carter, Stephen F.
    Chiotis, Konstantinos
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Wall, Anders
    Nordberg, Agneta
    Concordance and Diagnostic Accuracy of [C-11]PIB PET and Cerebrospinal Fluid Biomarkers in a Sample of Patients with Mild Cognitive Impairment and Alzheimer's Disease2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 45, no 4, p. 1077-1088Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer's disease (AD) pathology can be quantified in vivo using cerebrospinal fluid (CSF) levels of amyloid-beta(1-42) (A beta(1-42)), total-tau (t-tau), and phosphorylated tau (p- tau(181p)), as well as with positron emission tomography (PET) using [C-11]Pittsburgh compound-B ([C-11]PIB). Studies assessing concordance between these measures, however, have provided conflicting results. Moreover, it has been proposed that [C-11]PIB PET may be of greater clinical utility in terms of identifying patients with mild cognitive impairment (MCI) who will progress to the dementia phase of AD. Objective: To determine concordance and classification accuracy of CSF biomarkers and [C-11]PIB PET in a cohort of patients with MCI and AD. Methods: 68 patients (MCI, n = 33; AD, n = 35) underwent [C-11]PIB PET and CSF sampling. Cutoffs of >1.41 ([C-11]PIB), <450 pg/mL-and a more lenient cutoff of 550 pg/mL-(A beta(1-42)), <6.5 (A beta(1-42)/p-tau181p), and 1.14 (A beta(1- 42)/t-tau), were used to determine concordance. Logistic regression was used to determine classification accuracy with respect to stable MCI (sMCI) versus MCI who progressed to AD (pMCI). Results: Concordance between [C-11]PIB and A beta(1-42) was highest for sMCI (67%), followed by AD (60%) and pMCI (33%). Agreement was increased across groups using A beta(1-42) < 550 pg/mL, or A beta(1-42) to tau ratios. Logistic regression showed that classification accuracy of [11C] PIB, between sMCI and pMCI, was superior to A beta(1-42) (73% versus 58%), A beta(1-42)/t-tau (63%), and A beta(1-42)/p-tau181p (65%). Conclusion: In the present study, [C-11]PIB proved a better predictor of progression to AD in patients with MCI, relative to CSF measures of A beta(1-42) or A beta(1-42)/tau. Discordance between PET and CSF markers for A beta(1-42) suggests they cannot be used interchangeably, as is currently the case.

  • 23. Li, Xiaozhen
    et al.
    Westman, Eric
    Thordardottir, Steinunn
    Ståhlbom, Anne Kinhult
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Blennow, Kaj
    Wahlund, Lars-Olof
    Graff, Caroline
    The Effects of Gene Mutations on Default Mode Network in Familial Alzheimer’s Disease2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 56, no 1, p. 327-334Article in journal (Refereed)
    Abstract [en]

    Familial Alzheimer’s disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel’s time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.

  • 24.
    Mangialasche, Francesca
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Perugia, Italy.
    Baglioni, Mauro
    Cecchetti, Roberta
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Ruggiero, Carmelinda
    Piobbico, Danilo
    Kussmaul, Lothar
    Monastero, Roberto
    Brancorsini, Stefano
    Mecocci, Patrizia
    Lymphocytic Mitochondrial Aconitase Activity is Reduced in Alzheimer's Disease and Mild Cognitive Impairment2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 44, no 2, p. 649-660Article in journal (Refereed)
    Abstract [en]

    Background: Specific mechanisms behind the role of oxidative/nitrosative stress and mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis remain elusive. Mitochondrial aconitase (ACO2) is a Krebs cycle enzyme sensitive to free radicalmediated damage. Objective: We assessed activity and expression of ACO2 extracted from blood lymphocytes of subjects with AD, mild cognitive impairment (MCI), older adults with normal cognition (OCN, age >= 65 years), and younger adults with normal cognition (YCN, age < 65 years). Plasma levels and activities of antioxidants were also measured. Methods: Blood samples were collected from 28 subjects with AD, 22 with MCI, 21 OCN, and 19 YCN. ACO2 activity was evaluated in a subsample before and after in vitro exposure to free radicals. Results: ACO2 activity was significantly lower in AD and MCI cases than controls: ACO2 median activity was 0.64 +/- 0.21 U/mg protein for AD, 0.93 +/- 0.28 U/mg protein for MCI, 1.17 +/- 0.78 U/mg protein for OCN subjects, and 1.23 +/- 0.43 U/mg protein for YCN individuals. In subjects with AD and MCI, ACO2 expression was lower than OCN subjects, and ACO2 activity correlated with vitamin E plasma levels (rho: 0.64, p < 0.001) and Mini- Mental State Examination total score (rho: 0.82, p < 0.001). Furthermore, free radicals exposure reduced ACO2 activity more in individuals with AD than in OCN subjects. Conclusion: Our results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with AD and MCI and correlates with antioxidant protection. Further studies are warranted to verify the role of ACO2 in AD pathogenesis and its importance as a marker of AD progression.

  • 25.
    Marengoni, Alessandra
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Bandinelli, Stefania
    Ferrucci, Luigi
    Socioeconomic Status During Lifetime and Cognitive Impairment No-Dementia in Late Life: The Population-Based Aging in the Chianti Area (InCHIANTI) Study2011In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 24, no 3, p. 559-568Article in journal (Refereed)
    Abstract [en]

    Thousand and twelve dementia-free elderly (60-98 years old) enrolled in the InChianti Study (Italy) were evaluated at baseline (1998-2000) and at 3-year follow-up (2001-2003) with the aim of analyzing the association of lifetime socioeconomic status (SES) with prevalent and incident cognitive impairment no-dementia (CIND). SES was defined from information on formal education, longest held occupation, and financial conditions through life. CIND was defined as age-adjusted Mini-Mental State Examination score one standard deviation below the baseline mean score of participants without dementia. Logistic regression and Cox proportional-hazards models were used to estimate the association of SES with CIND. Demographics, occupation characteristics (i.e., job stress and physical demand), cardiovascular diseases, diabetes, apolipoprotein E (APOE) genotype, smoking, alcohol consumption, depressive symptoms, and C-reactive protein were considered potential confounders. Prevalence of CIND was 17.7%. In the fully adjusted model, low education (OR = 2.1; 95% confidence intervals, CI = 1.4 to 3.2) was associated with prevalent CIND. Incidence rate of CIND was 66.0 per 1000 person-years. Low education (HR = 1.7; 95% CI = 1.04 to 2.6) and manual occupation (HR = 1.9; 95% CI = 1.0 to 3.6) were associated with incident CIND. Among covariates, high job-related physical demand was associated with both prevalent and incident CIND (OR = 1.6; 95% CI = 1.1 to 2.4 and HR = 1.5; 95% CI = 1.0 to 2.3). After stratification for education, manual occupation was still associated with CIND among participants with high education (HR = 2.2; 95% CI = 1.2 to 4.3 versus HR = 1.4; 95% CI = 0.2 to 10.4 among those with low education). Proxy markers of lifetime SES (low education, manual occupation and high physical demand) are cross-sectional correlates of CIND and predict incident CIND over a three-year follow-up.

  • 26.
    Marseglia, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Laukka, Erika J.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Santoni, Giola
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Pedersen, Nancy L.
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Early Cognitive Deficits in Type 2 Diabetes: A Population-Based Study2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 53, no 3, p. 1069-1078Article in journal (Refereed)
    Abstract [en]

    Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care-Kungsholmen, 2305 cognitively intact participants aged >= 60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (beta -1.10 [95% CI -1.98, -0.23]), category fluency (beta -1.27 [95% CI -2.52, -0.03]), and digit span forward (beta -0.35 [95% CI -0.54, -0.17]). Critically, these associations were present only among APOE epsilon 4 non-carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations.

  • 27. Miralbell, Julia
    et al.
    Spulber, Gabriela
    Hooshmand, Babak
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Besga, Ariadna
    Mataró, Maria
    Cedazo-Minguez, Angel
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wahlund, Lars-Olof
    Grey matter and cognitive patterns in cognitive impaired subjects using CSF biomarker cut-offs2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 29, no 4, p. 741-749Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate brain tissue volumes, grey matter (GM) distribution, and cognitive performance for cognitively impaired subjects using cerebrospinal fluid (CSF) biomarker cut-offs as grouping criteria. 41 subjects attending the Memory Clinic, Karolinska University Hospital, Huddinge, Sweden, were divided into groups based on normal or abnormal CSF levels of Aβ1-42, t-tau, and p-tau181. SIENAX algorithms were employed for brain tissue volumes estimation and voxel-based morphometry (VBM) for mapping the differences in GM patterns. VBM revealed significant lower GM volumes in temporo-parietal, occipital, and prefrontal cortices for those subjects belonging to abnormal CSF t-tau and p-tau181 groups. No differences were found between groups according to CSF Aβ1-42 cut-offs. Patients with abnormal CSF p-tau181 showed lower cognitive performance compared to those with normal levels. Patients with abnormal levels of CSF tau (but not Aβ1-42) showed an Alzheimer's disease-like pattern for both GM distribution and cognitive profile, compared to those with normal levels. These results support the hypothesis that CSF t-tau or p-tau181 levels may be of direct value for the evaluation of disease severity.

  • 28. Nordberg, Agneta
    et al.
    Kadir, Ahmadul
    Andreasen, Niels
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Wall, Anders
    Blennow, Kaj
    Langström, Bengt
    Zetterberg, Henrik
    Correlations between Alzheimer's Disease Cerebrospinal Fluid Biomarkers and Cerebral Glucose Metabolism after 12 Months of Phenserine Treatment2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 47, no 3, p. 691-704Article in journal (Refereed)
    Abstract [en]

    New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-beta (A beta) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-A beta compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for A beta and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF A beta(40) and alpha- and beta-secretase-cleaved soluble amyloid-beta protein precursor (sA beta PP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF A beta(40) and sA beta PP correlated positively with rCMRglc and cognition while CSF A beta(42) levels, the A beta(42/40) ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increased levels of CSF A beta(40), sA beta PP alpha, and sA beta PP beta, which positively correlated with improvements in rCMRglc and cognition. The study illustrates the value of using biomarkers in the CSF and brain for evaluation of drug effects.

  • 29.
    Paillard-Borg, Stephanie
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    An active lifestyle postpones dementia onset by more than one year in very old adults2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 4, p. 835-842Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to test the hypothesis that an active lifestyle delays age at dementia onset. This study included 388 incident dementia cases (DSM-III-R criteria) that developed over a 9-year follow-up period among 1,375 baseline dementia-free community dwellers with good cognitive function (MMSE > 23) (mean age = 81.2) from the Kungsholmen Project. An active lifestyle was defined as participation in mental, physical, or social activity. We used linear regression models to estimate influence of baseline active lifestyle on age at onset of incident dementia and general linear models to estimate mean age at dementia onset. Age at onset of dementia was significantly older in persons who had higher levels of participation in mental, physical, or social activity (beta: 0.18, 0.29 and 0.23 respectively, p < 0.001 for all the activities) independent of education, medical condition, functional status, and other confounders including APOE. When the three types of activities were integrated into an index, we found that the broader the spectrum of participation in the activities, the later the onset of disease (beta = 0.93, p = 0.01 for participating in two activities, and beta = 1.42, p < 0.001 for three activities). There were 17 months difference in mean age at dementia onset between the inactive group and the most active group. An active lifestyle operates as a protective factor for dementia by delaying the clinical onset of the disease. These findings highlight the relevance of encouraging old adults to have active lifestyles, which could have a great impact on public health.

  • 30.
    Payton, Nicola M.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kalpouzos, Gregoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Kivipelto, Miia
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Laukka, Erika J.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Combining Cognitive, Genetic, and Structural Neuroimaging Markers to Identify Individuals with Increased Dementia Risk2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 64, no 2, p. 533-542Article in journal (Refereed)
    Abstract [en]

    Background: Cognitive and biological markers have shown varying degrees of success in identifying persons who will develop dementia. Objective: To evaluate different combinations of cognitive and biological markers and identify prediction models with the highest accuracy for identifying persons with increased dementia risk. Methods: Neuropsychological assessment, genetic testing (apolipoprotein E - APOE), and structural magnetic resonance imaging (MRI) were performed for 418 older individuals without dementia (60-97 years) from a population-based study (SNAC-K). Participants were followed for six years. Results: Cognitive, genetic, and MRI markers were systematically combined to create prediction models for dementia at six years. The most predictive individual markers were perceptual speed or carrying at least one APOE epsilon 4 allele (AUC = 0.875). The most predictive model (AUC = 0.924) included variables from all three modalities (category fluency, general knowledge, any epsilon 4 allele, hippocampal volume, white matter-hyperintensity volume). Conclusion: This study shows that combining markers within and between modalities leads to increased predictivity for future dementia. However, minor increases in predictive value should be weighed against the cost of additional tests in larger-scale screening.

  • 31. Pimouguet, Clement
    et al.
    Le-Goff, Melanie
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Berr, Claudine
    Leffondre, Karen
    Peres, Karine
    Dartigues, Jean Francois
    Helmer, Catherine
    Effect of Early Referral to Specialist in Dementia on Institutionalization and Functional Decline: Findings from a Population-Based Study2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 49, no 3, p. 819-828Article in journal (Refereed)
    Abstract [en]

    Background: Although early diagnosis has been hypothesized to benefit both patients and caregivers, until nowstudies evaluating the effect of early dementia diagnosis are lacking. Objective: To investigate the influence of early specialist referral for dementia on the risk of institutionalization and functional decline in Activity of Daily Living (ADL). Methods: Incident dementia cases were screened in a prospective population-based cohort, the Three-City Study, and initial specialist consultation for cognitive complaint was assessed at dementia diagnosis. Proportional hazard regression and illness-death models were used to test the association between specialist referral and, respectively, institutionalization and functional decline. Results: Only one third of the incident individuals with dementia had consulted a specialist for cognitive problems early (36%). After adjustment on potential confounders (including cognitive and functional decline) and competing risk of death, participants who had consulted a specialist early in the disease course presented a higher rate of being institutionalized than those who did not (Hazard Ratio = 2.00, 95% Confidence Interval (CI): 1.09-3.64). But early specialist referral was not associated with further functional decline (HR = 1.09, 95% CI: 0.71-1.67). Conclusions: Early specialist referral in dementia is associated with increased risk of institutionalization but not with functional decline in ADL. These findings suggest that early care referral in dementia may be a marker of concern for patients and/or caregivers; subsequent medical and social care could be suboptimal or inappropriate to allow patients to stay longer at home.

  • 32.
    Pimouguet, Clement
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Lagergren, Mårten
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Influence of Incipient Dementia on Hospitalization for Primary Care Sensitive Conditions: A Population-Based Cohort Study2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 52, no 1, p. 213-222Article in journal (Refereed)
    Abstract [en]

    Background: Studies have reported that moderate/severe stages of dementia are linked to increased hospitalization rates, but little is known about the influence of incipient dementia on hospitalizations for primary care sensitive conditions (PCSCs). Objective: To examine the associations between incipient dementia and hospitalization outcomes, including all-cause and PCSC hospitalization. Methods: A total of 2,268 dementia-free participants in the Swedish National study on Aging and Care-Kungsholmen were interviewed and clinically examined at baseline. Participants aged >= 78 years were followed for 3 years, and those aged 60-72 years, for 6 years. Number of hospitalizations was retrieved from the National Patient Register. Dementia was diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Hospitalization outcomes were compared in participants who did and did not develop dementia. Zero-inflated Poisson regressions and logistic regressions were used in data analysis. Results: During the follow-up, 175 participants developed dementia. The unadjusted PCSC admission rate was 88.2 per 1000 person-years in those who developed dementia and 25.6 per 1000 person-years in those who did not. In the fully adjusted logistic regression model, incipient dementia was associated with an increased risk of hospitalization for PCSCs (OR = 2.3, 95% CI 1.3-3.9) but not with the number of hospitalizations or with all-cause hospitalization. Risks for hospitalization for diabetes, congestive heart failure, and pyelonephritis were higher in those who developed dementia than in those who did not. About 10% participants had a PCSC hospitalization attributable to incipient dementia. Conclusion: People with incipient dementia are more prone to hospitalization for PCSCs but not to all-cause hospitalization.

  • 33.
    Qiu, Chengxuan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Preventing Alzheimer's disease by targeting vascular risk factors: hope and gap2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 32, no 3, p. 721-731Article, review/survey (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is a major cause of functional dependence, poor quality of life, institutionalization, and mortality among elderly people. As a multifactorial disorder, AD has been frequently linked to vascular risk factors (e.g., smoking, hypertension, obesity, diabetes, hyperlipidemia, and inflammation) in numerous prospective cohort studies of the general population. Systematic reviews and meta-analyses of prospective studies have from the life-course perspective revealed an age-dependent association with the risk of AD for several vascular risk factors such as high blood pressure, obesity, and high total cholesterol, such that possessing these factors in mid-life, but not necessarily in late-life, is associated with an increased risk of AD. The biological plausibility for vascular risk factors to be involved in the pathogenesis and clinical manifestation of Alzheimer syndrome is partly supported by population-based neuroimaging and neuropathological studies. However, randomized controlled trials that target those major cardiovascular risk factors (e.g., antihypertensive, cholesterol-lowering, and anti-inflammatory therapies) have generally failed to prove as efficacious preventative approaches for AD. To bridge the gap, the multifactorial nature of AD and the proper time-window for intervention should be taken into account in the future when designing preventative interventions against this devastating disorder.

  • 34.
    Qiu, Chengxuan
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Shandong University, China.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden .
    Aging without Dementia is Achievable: Current Evidence from Epidemiological Research2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 62, no 3, p. 933-942Article, review/survey (Refereed)
    Abstract [en]

    Both the incidence and the prevalence of dementia increase exponentially with increasing age. This raises the question of whether dementia is an inevitable consequence of aging or whether aging without dementia is achievable. In this review article, we sought to summarize the current evidence from epidemiological and neuropathological studies that investigated this topic. Epidemiological studies have shown that dementia could be avoided even at extreme old ages (e.g., centenarians or supercentenarians). Furthermore, clinico-neuropathological studies found that nearly half of centenarians with dementia did not have sufficient brain pathology to explain their cognitive symptoms, while intermediate-to-high Alzheimer pathology was present in around one-third of very old people without dementia or cognitive impairment. This suggests that certain compensatory mechanisms (e.g., cognitive reserve or resilience) may play a role in helping people in extreme old ages escape dementia syndrome. Finally, evidence has been accumulating in recent years indicating that the incidence of dementia has declined in Europe and North America, which supports the view that the risk of dementia in late life is modifiable. Evidence has emerged that intervention strategies that promote general health, maintain vascular health, and increase cognitive reserve are likely to help preserve cognitive function till late life, thus achieving the goal of aging without dementia.

  • 35.
    Qiu, Chengxuan
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Vascular and Psychosocial Factors in Alzheimer's Disease: Epidemiological Evidence Toward Intervention2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 3, p. 689-697Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD), the most common cause of dementia, is posing serious threat to public health and health care system in both developed and developing nations due to a rapid increase in the aging population. Identification of etiological factors for AD and active implementation of interventions targeting those modifiable factors that may prevent or postpone clinical onset of the dementing disorder will provide an opportunity to cope with this challenge. Multidisciplinary research involving epidemiology, neuropathology, and neuroimaging has provided moderately strong evidence supporting the role of vascular factors and related disorders (e. g., midlife high blood pressure and obesity, diabetes, cerebral microvascular lesions, and smoking) as risk factors and the possible role of psychosocial factors (e.g., high educational achievements, mentally-stimulating activity, social engagement, and physical exercise) as protective factors in the development and clinical manifestation of the dementia syndrome, including AD. The implementation of long-term, multidomain interventions designed for the modification of multiple vascular risk factors and the maintenance of socially-integrated lifestyles and mentally-stimulating activities is expected to postpone the clinical onset of AD and dementia, and thus, substantially reduce the burden of the disease at both the individual and societal levels.

  • 36.
    Qiu, Chengxuan
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Vascular risk profiles for dementia and Alzheimer's disease in very old people: a population-based longitudinal study2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 1, p. 293-300Article in journal (Refereed)
    Abstract [en]

    Numerous studies have linked individual vascular factors to dementia including Alzheimer's disease (AD). We investigated different vascular risk profiles in relation to dementia and AD among very old people. A standardized follow-up procedure was applied three times to a dementia-free cohort (n=1270, age >or= 75) over a nine-year period to detect dementia and AD cases using the DSM-III-R criteria. We examined two vascular risk profiles, which were scored by counting the number of corresponding vascular factors: 1) atherosclerotic profile included systolic pressure >or= 160 mmHg, diabetes/prediabetes, and stroke; and 2) cerebral hypoperfusion profile constituted diastolic pressure < 70 mmHg, pulse pressure < 70 mmHg, and heart failure. Data were analyzed with Cox proportional-hazards models controlling for major potential confounders. During the 6406 person-years of follow-up, 428 subjects developed dementia, including 328 AD cases. All components of vascular profiles were significantly or marginally associated with increased dementia risk. The risk of dementias was increased with increasing score of both risk profiles (p for trend <or= 0.001); subjects with a score >or= 2 in either profile had an approximately twofold-increased risk for dementia and AD. These data suggest that aggregation of atherosclerotic- and hypoperfusion-related vascular factors increases the risk of dementia in very old people. Severe cerebral atherosclerosis and insufficient perfusion are involved in the development of dementia including AD.

  • 37.
    Rizzuto, Debora
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Feldman, Adina L.
    Karlsson, Ida K.
    Dahl Aslan, Anna K.
    Gatz, Margaret
    Pedersen, Nancy L.
    Detection of Dementia Cases in Two Swedish Health Registers: A Validation Study2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 4, p. 1301-1310Article in journal (Refereed)
    Abstract [en]

    Background: Population-based health registers are potential assets in epidemiological research; however, the quality of case ascertainment is crucial.

    Objective: To compare the case ascertainment of dementia, from the National Patient Register (NPR) and the Cause of Death Register (CDR) with dementia diagnoses from six Swedish population based studies.

    Methods: Sensitivity, specificity, and positive predictive value (PPV) of dementia identification in NPR and CDR were estimated by individual record linkage with six Swedish population based studies (n = 19,035). Time to detection in NPR was estimated using data on dementia incidence from longitudinal studies with more than two decades of follow-up.

    Results: Barely half of the dementia cases were ever detected by NPR or CDR. Using data from longitudinal studies we estimated that a record with a dementia diagnosis appears in the NPR on average 5.5 years after first diagnosis. Although the ability of the registers to detect dementia cases was moderate, the ability to detect non-dementia cases was almost perfect (99%). When registers indicate that there is a dementia diagnosis, there are very few instances in which the clinicians determined the person was not demented. Indeed, PPVs were close to 90%. However, misclassification between dementia subtype diagnoses is quite common, especially in NPR.

    Conclusions: Although the overall sensitivity is low, the specificity and the positive predictive value are very high. This suggests that hospital and death registers can be used to identify dementia cases in the community, but at the cost of missing a large proportion of the cases.

  • 38. Rusanen, Minna
    et al.
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Levälahti, Esko
    Laatikainen, Tiina
    Tuomilehto, Jaakko
    Soininen, Hilkka
    Ngandu, Tiia
    Heart diseases and long-term risk of dementia and Alzheimer's disease: a population-based CAIDE study.2014In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 42, no 1, p. 183-91Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Many cardiovascular risk factors are shown to increase the risk of dementia and Alzheimer's disease (AD), but the impact of heart disease on later development of dementia is still unclear.

    OBJECTIVE: The aim of the study was to investigate the long-term risk of dementia and Alzheimer's disease (AD) related to midlife and late-life atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) in a population-based study with a follow-up of over 25 years.

    METHODS: Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study includes 2000 participants who were randomly selected from four separate, population-based samples originally studied in midlife (1972, 1977, 1982, or 1987). Re-examinations were carried out in 1998 and 2005-2008. Altogether 1,510 (75.5%) persons participated in at least one re-examination, and 127 (8.4%) persons were diagnosed with dementia (of which 102 had AD).

    RESULTS: AF in late-life was an independent risk factor for dementia (HR 2.61, 95% CI 1.05-6.47; p = 0.039) and AD (HR 2.54, 95% CI 1.04-6.16; p = 0.040) in the fully adjusted analyses. The association was even stronger among the apolipoprotein E (APOE) ε4 non-carriers. Late-life HF, but not CAD, tended to increase the risks as well. Heart diseases diagnosed at midlife did not increase the risk of later dementia and AD.

    CONCLUSION: Late-life heart diseases increase the subsequent risk of dementia and AD. Prevention and effective treatment of heart diseases may be important also from the perspective of brain health and cognitive functioning.

  • 39. Schöll, Michael
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Bogdanovic, Nenad
    Wall, Anders
    Långström, Bengt
    Viitanen, Matti
    Nordberg, Agneta
    Time Course of Glucose Metabolism in Relation to Cognitive Performance and Postmortem Neuropathology in Met146Val PSEN1 Mutation Carriers2011In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 24, no 3, p. 495-506Article in journal (Refereed)
    Abstract [en]

    Studies in carriers of mutations that cause early-onset familial Alzheimer's disease (eoFAD) are of significant interest. We showed previously that regional glucose hypometabolism could be detected many years before disease onset in presenilin 1 (PSEN1) mutation carriers. Here we studied four members of a family with a Met146Val PSEN1 mutation, two symptomatic carriers and two non-carriers, longitudinally with (18)F-FDG PET over a period of about two and four years, respectively. The two mutation carriers showed global cortical glucose hypometabolism over time with the most distinct decline occurring in the posterior cingulate, the parietal and parietotemporal cortex, which was also observed when compared with a group of 23 healthy controls and a group of 27 sporadic Alzheimer's disease (sAD) patients. This decline correlated with cognitive deterioration over time as measured by neuropsychological tests. Postmortem examination of brain tissue revealed substantially elevated levels of AD type neuropathology in terms of neuritic plaques and neurofibrillary tangles in the two mutation carriers compared with a reference group of 249 sAD patients. In the mutation carriers, the amount of neuritic plaques but not neurofibrillary tangles correlated hereby significantly with regional glucose metabolism as measured by (18)F-FDG on the last scanning occasions, which were performed four and approximately five years before death, respectively. We here show that FDG PET can depict in vivo the aggressive disease progression in eoFAD mutation carriers in relationship to neuropathology.

  • 40.
    Solomon, Alina
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Soininen, Hilkka
    Prevention of Alzheimer's Disease: Backward through the Lifespan2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 33, p. s465-S469Article, review/survey (Refereed)
    Abstract [en]

    This is a brief summary of experiences from Finland related to Alzheimer's disease (AD) prevention research. The first signals that AD may have vascular modifiable risk factors came from studies on cardiovascular conditions and diabetes. Cardiovascular prevention projects such as North Karelia Project and WHO-MONICA in the 1970-1980s were focused on younger populations, which led to the idea of looking for risk factors as far back as middle age. Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) is one of the few studies in the world focusing on late-life cognition with a large and representative population-based cohort, baseline examination at midlife, and follow-up time up to three decades. Since 1998, it has identified several modifiable risk factors for cognitive impairment/dementia, and produced the first risk score for estimating dementia risk based on midlife profiles. The CAIDE Dementia Risk Score has been used to select participants in the Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER). FINGER is an ongoing multicenter RCT involving 1,200 participants aged 60-77 years, and testing the effects of a two-year multi-domain intervention targeting several risk factors simultaneously. It started in September 2009 and will be completed at the end of 2013. The FINGER study is at the forefront of international collaborative efforts to solve the clinical and public health problems of early identification of individuals at increased risk of late-life cognitive impairment, and of developing intervention strategies to prevent or delay the onset of cognitive impairment and dementia.

  • 41. Subic, Ana
    et al.
    Cermakova, Pavla
    Religa, Dorota
    Han, Shuang
    von Euler, Mia
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Univ, Stockholm, Sweden.
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Bognandi, Liselia
    Winblad, Bengt
    Kramberger, Milica G.
    Eriksdotter, Maria
    Garcia-Ptacek, Sara
    Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 3, p. 1119-1128Article in journal (Refereed)
    Abstract [en]

    Background: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF).

    Objective: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF.

    Methods: Of 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death.

    Results: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment.

    Conclusions: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.

  • 42.
    Tan, Edwin C. K.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Monash University, Australia.
    Bell, J. Simon
    Lu, Christine Y.
    Toh, Sengwee
    National Trends in Outpatient Antihypertensive Prescribing in People with Dementia in the United States2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 54, no 4, p. 1425-1435Article in journal (Refereed)
    Abstract [en]

    Objective: The objectives were to investigate national trends in outpatient antihypertensive prescribing in people with dementia in the United States between 2006 and 2012, and to investigate clinical and demographic factors associated with different antihypertensive prescribing patterns. Methods: This was an analysis of the National Ambulatory Medical Care Survey (NAMCS) and the outpatient department component of the National Hospital Ambulatory Medical Care Survey (NHAMCS). Outpatient visits by people aged >= 65 years with documented dementia were analyzed. Complex samples multivariate logistic regression was conducted to estimate temporal trends and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for factors associated with prescribing of antihypertensives, multiple antihypertensives and different antihypertensive classes. Results: There was a statistically significant increase in the proportion of physician visits by older people with dementia with a documented diagnosis of hypertension from 49.3% (95% CI: 41.3%-57.4%) in 2006 to 55.7% (95% CI: 50.2%-61.2%) in 2012. There were non-significant increases in overall antihypertensive use and the use of multiple antihypertensive classes. Male sex was associated with any antihypertensive use (AOR 1.37, 95% CI 1.02-1.84) and multiple antihypertensive class use (AOR 1.52, 95% CI 1.14-2.04). Black race (AOR 2.04, 95% CI 1.12-3.71) and Midwest residence (AOR 2.03, 95% CI 1.46-2.82) were associated with multiple antihypertensive use. Conclusion: There was an increase in documented hypertension in physician visits by older people with dementia from 2006 to 2012, but minimal increases in overall antihypertensive use. Various demographic and clinical factors were associated with the prescribing of antihypertensives in people with dementia.

  • 43.
    Tan, Edwin C. K.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Monash University, Australia.
    Eriksdotter, Maria
    Garcia-Ptacek, Sara
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Anticholinergic Burden and Risk of Stroke and Death in People with Different Types of Dementia2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 65, no 2, p. 589-596Article in journal (Refereed)
    Abstract [en]

    Background: Anticholinergic burden is associated with poorer cognitive and functional outcomes in people with dementia. However, the impact of anticholinergics on significant adverse outcomes such as stroke has not been studied previously.

    Objective: To investigate the association between total anticholinergic cognitive burden (ACB) and risk of stroke and death in people with different dementia subtypes.

    Methods: This was a cohort study of 39,107 people with dementia and no prior history of stroke registered in the Swedish Dementia Registry (SveDem) from 2008-2014. Data were extracted from the Swedish Prescribed Drug Register, the Swedish National Patient Register, and the Swedish Total Population Register. Competing risk regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-varying ACB score and risk of stroke and all-cause mortality.

    Results: During a mean follow-up period of 2.31 (standard deviation 1.66) years, 11,224 (28.7%) individuals had a stroke or died. Compared with non-users of anticholinergic medications, ACB score of 1 (HR 1.09, 95% CI 1.04-1.14) and ACB score of >= 2 (HR 1.20, 95% CI 1.14-1.26) increased the risk of developing the composite outcome of stroke and death. When stratifying by dementia disorder, the association remained significant in Alzheimer's disease, mixed dementia, and vascular dementia.

    Conclusions: The use of anticholinergic medicines may be associated with an increased risk of stroke and death in people with dementia. A dose-response relationship was observed. Careful consideration should be made when prescribing medications with anticholinergic properties to people with dementia.

  • 44.
    Tiiman, Ann
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Olsson, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindgren, Joel
    Jarvet, Jϋri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roose, Per
    Sholts, Sabrina B.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Museum of Natural History, USA.
    Rahimipour, Shai
    Abrahams, Jan Pieter
    Eriksson Karlström, Amelie
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 54, no 3, p. 971-982Article in journal (Refereed)
    Abstract [en]

    Aggregation of the amyloid-beta (A beta) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate A beta aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, A beta is found in various cellular locations including membranes. So far, Cu(II)/A beta interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with A beta bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the Z(A beta 3)(12-58) Y18L Affibody molecule). In all studied systems the A beta N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, A beta was found to bind Cu(II) and Zn(II) with the same ligands and the same K-D as in aqueous solution. ROS was generated in all Cu(II)/A beta complexes. These results indicate that binding of A beta to membranes, drugs, and other entities that do not interact with the A beta N-terminal part, appears not to compromise the N-terminal segment's ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.

  • 45. Tolppanen, Anna-Maija
    et al.
    Ngandu, Tiia
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Jönköping University, Sweden.
    Laatikainen, Tiina
    Rusanen, Minna
    Soininen, Hilkka
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska Institutet, Sweden; University of Eastern Finland, Finland.
    Midlife and Late-Life Body Mass Index and Late-Life Dementia: Results from a Prospective Population-Based Cohort2014In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 38, no 1, p. 201-209Article in journal (Refereed)
    Abstract [en]

    Background: Obesity has been consistently associated with dementia. The role of certain risk factors of dementia may change during life, and the importance of having a life-course perspective has been acknowledged. Objective: The aim of this study was to investigate the association of midlife and late-life body mass index (BMI) with late-life dementia/ Alzheimer's disease (AD) and whether the association was independent of other obesity-related co-morbidities. Methods: The association between midlife BMI (mean age 50.2, SD 6.0) and late-life BMI (mean age 71.2, SD 4.0) and incident dementia later in life (mean age 75.7, SD 5.0) were investigated among 1,304 participants of the longitudinal population-based Cardiovascular risk factors, Aging and Dementia (CAIDE) study, conducted in Eastern Finland. The duration of follow-up was 26 years. The diagnosis of dementia was based on DSM-IV criteria and the probable and possible AD on the NINCDS-ADRDA criteria. Results: Higher midlife BMI was associated with higher risk of incident dementia (adjusted HR, 95% CI 1.07, 1.00-1.14). However, decrease in BMI from midlife to late-life was associated with higher risk of dementia (1.14, 1.03-1.25 for one-unit decrease) andAD(1.20, 1.09-1.33). High late-lifeBMIwas associated with lower risk ofAD(0.89, 0.81-0.98) but the association with dementia was less evident (0.94, 0.86-1.03). Conclusion: Higher midlife BMI is related to higher risk of dementia and AD, independently of obesity-related risk factors and co-morbidities. Steeper decrease of BMI and low late-life BMI are associated with higher risk of dementia and AD. These findings highlight the importance of life-course perspective when assessing the association between BMI and cognition.

  • 46. Tolppanen, Anna-Maija
    et al.
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). 1Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland.
    Soininen, Hilkka
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Midlife Vascular Risk Factors and Alzheimer's Disease: Evidence from Epidemiological Studies2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 32, no 3, p. 531-540Article in journal (Refereed)
    Abstract [en]

    The shared risk factor profile between cardiovascular diseases and Alzheimer's disease (AD), observations on vascular pathology in AD, and altered cerebral blood flow in AD brains have led to the suggestion that AD might be a vascular disorder with neurodegenerative consequences. Targeting vascular and metabolic risk factors could be an effective way to prevent AD. Higher body mass index, elevated blood pressure, serum cholesterol concentrations, and impaired glucose regulation have been associated with increased risk of AD. Interestingly, the associations between these factors measured at mid-life are stronger, or even opposite, than with the risk factors measured at late-life. This may reflect true differences in the association (i.e., mid-life risk factors being a better measure of vascular load during adulthood), reverse causality, or bias. The vascular risk factors can directly increase the susceptibility to AD, or the effect can be mediated via cardio- and cerebrovascular diseases.

  • 47.
    Wallin, Karin
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Tuomilehto, Jaakko
    Soininen, Hilkka
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: a population based study2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 3, p. 669-676Article in journal (Refereed)
    Abstract [en]

    Inflammation has been associated with Alzheimer's disease (AD) and dementia. The association between rheumatoid arthritis (RA) or arthritis and dementia/AD has been investigated in several case-control or hospital- and register-based studies with mixed results. This long-term population-based study investigates the association between presence of joint disorders (RA and other joint disorders) in midlife and cognitive status later in life. 1,449 participants were first evaluated in 1972, 1977, 1982, and 1987 and follow-up was performed after 21 years. A self-administered questionnaire including questions on joint disorders was used at both evaluations. Cognitive status (control, mild cognitive impairment, dementia/AD) was assessed at follow-up. The presence of any joint disorder in midlife was significantly associated with a worse cognitive status later in life: OR (95% CI) in an ordinal logistic regression analysis adjusted for age, gender, follow-up time, education, APOE epsilon 4, body mass index, smoking, drug treatment, and diabetes was 1.96 (1.17-3.28). For RA only, OR (95% CI) was 2.77 (1.26-6.10). The correlation remained significant for RA when AD was considered instead of dementia OR (95% CI) 2.49 (1.09-5.67). The presence of joint disorders, especially RA, at midlife seems to be associated with a worse cognitive status later in life. Given the chronic inflammatory component of RA, this study suggests that inflammatory mechanisms may have an important role in increasing the risk of cognitive impairment and dementia/AD.

  • 48.
    Wimo, Anders
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska Institutet, Sweden; Uppsala University/County Council of Gävleborg, Sweden.
    Sjölund, Britt-Marie
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Gävle, Sweden.
    Sköldunger, Anders
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Qiu, Chengxuan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Klarin, Inga
    Nordberg, Gunilla
    von Strauss, Eva
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). The Swedish Red Cross University College, Sweden.
    Cohort Effects in the Prevalence and Survival of People with Dementia in a Rural Area in Northern Sweden2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 50, no 2, p. 387-396Article in journal (Refereed)
    Abstract [en]

    Background: Recent studies suggest that trends in cardiovascular risk may result in a decrease in age-specific prevalence of dementia. Studies in rural areas are rare.

    Objectives: To study cohort effects in dementia prevalence and survival of people with dementia in a Swedish rural area.

    Methods: Participants were from the 1995-1998 Nordanstig Project (NP) (n = 303) and the 2001-2003 Swedish National study on Aging and Care in Nordanstig (SNAC-N) (n = 384). Overall 6-year dementia prevalence and mortality in NP and SNAC-N were compared for people 78 years and older. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for dementia occurrence using the NP study population as the reference group. Cox regression models were used to analyze time to death.

    Results: The crude prevalence of dementia was 21.8% in NP and 17.4% in SNAC-N. When the NP cohort was used as the reference group, the age- and gender-adjusted OR of dementia was 0.71 (95% CI 0.48-1.04) in SNAC-N; the OR was 0.47 (0.24-0.90) for men and 0.88 (0.54-1.44) for women. In the extended model, the OR of dementia was significantly lower in SNAC-N than in the NP cohort as a whole (0.63; 0.39-0.99) and in men (0.34; 0.15-0.79), but not in women (0.81; 0.46-1.44). The Cox regression models indicated that the hazard ratio of dying was lower in the SNAC-N than NP population.

    Conclusions: Trends toward a lower prevalence of dementia in high-income countries seem to be evident in this Swedish rural area, at least in men.

  • 49.
    Xu, Wei-Li
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Caracciolo, Barbara
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Santoni, Giola
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Accelerated Progression from Mild Cognitive Impairment to Dementia Among APOE epsilon 4 epsilon 4 Carriers2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 33, no 2, p. 507-515Article in journal (Refereed)
    Abstract [en]

    The impact of APOE ε4 on mild cognitive impairment (MCI) and its progression to dementia remain controversial. We aimed to examine the association of APOE ε4 with MCI, and to verify the hypothesis that ε4 accelerates progression from MCI to dementia. In the Kungsholmen project, 756 cognitively healthy participants and 212 people with MCI aged ≥75 years were identified at baseline. Amnestic MCI (aMCI) and other cognitive impairment no dementia (oCIND) as two subtypes of MCI were assessed based on standard definitions. The two cohorts were followed for 9 years to detect incident cases of MCI and dementia following international criteria. APOE genotypes were assessed at baseline. Data were analyzed using Cox models. During the follow-up, in the cognitively healthy cohort, 165 people developed MCI (40 aMCI and 125 oCIND) and 176 developed dementia; in the MCI cohort, 118 persons progressed to dementia. Compared with APOE ε3ε3, the hazard ratios (HRs) (95% CIs) of ε2ε4/ε3ε4 were 2.24 (1.10-4.57) for aMCI and 1.78 (1.15-2.75) for oCIND, while the ε4ε4 was related to dementia with a HR of 4.35 (1.97-9.63) in the cognitively healthy cohort. In the MCI cohort, the ε4ε4 genotype led to a multi-adjusted HR of 2.89 (1.12-7.48) for dementia and accelerated the progression to dementia by 3.36 years. The APOE ε4 heterozygotes are associated with an increased risk of aMCI and oCIND. The ε4 homozygote substantially accelerates progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI.

  • 50. Zhang, Yanlei
    et al.
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland.
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland.
    Wimo, Anders
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska Institutet.
    Cost-effectiveness of a health intervention program with risk reductions for getting demented: results of a Markov model in a Swedish/Finnish setting2011In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 26, no 4, p. 735-744Article in journal (Refereed)
    Abstract [en]

    Risk scores based on modifiable factors have recently been developed for dementia. This study aims to estimate the cost-effectiveness of a potential preventive intervention program meant to lower the score related to increased dementia risk. Analyses were based on a Markov model adapted to Swedish circumstances. Risk score categories and risk probabilities were derived from the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) study in Finland. Figures of costs, utilities, and mortality were obtained from literature or databases. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to investigate the robustness of the model and to identify which model inputs had most impact on the results. In the base case, the usual care had a cost of 621,000 SEK and utilities of 11.8438 quality-adjusted life year (QALYs). The intervention had a cost of 599, 026 SEK and utilities of 11.8950 QALYs. The cost was 21,974 SEK lower in the intervention with 0.0511 QALYs gained over a 20 years horizon, indicating absolute dominance. The support for cost-effectiveness was insensitive to changes in the value of QALY for demented, mortality, and risk of dementia. If the intervention program was assumed to run every year, the incremental cost-effectiveness ratio did not show absolute dominance but was still under the willingness-to-pay level. The probabilistic sensitivity analysis indicated cost effectiveness in 67% of the samplings given a willingness-to-pay level of 600,000 SEK/year. This is a promising outlook for future research on preventive interventions in dementia, emphasizing the need of conducting multi-domain randomized trials.

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