Background: The mechanisms underlying olfactory decline in aging need further investigation. Noticeably, the longitudinal relationship of biological markers with olfaction remains underexplored. We investigated whether baseline levels and progression of microvascular lesions and brain atrophy are associated with odor identification (OID) decline.

Methods: The association between structural MRI markers and OID decline was examined in participants from the SNAC-K MRI study who were free from dementia at baseline (n = 401, mean age = 70.2 years, 60% females). OID was repeatedly assessed over 15 years. Presence of lacunes, white matter hyperintensities (WMH), perivascular spaces (PVS), and lateral ventricular, hippocampal, amygdalar, and total gray matter (GM) volumes were assessed up to 6 years, concurrent with the first 6 years of olfactory assessments.

Results: Higher PVS count and lower hippocampal and GM volumes at baseline were associated with accelerated OID decline (p_FWE < 0.05). Longitudinally (n = 225), presence of lacunes at follow-up, faster WMH volume and PVS count increases, faster lateral ventricular enlargement, and faster hippocampal, amygdalar, and GM atrophy were associated with accelerated OID decline (p_FWE < 0.05).

Conclusion: Olfactory decline is related to both increased cerebrovascular burden and accelerated brain atrophy over time.

Odor recognition memory (ORM) combines olfaction and episodic memory, both linked to dementia and impaired in Parkinson’s Disease (PD). Measuring ORM may indicate early PD dementia and aid in selecting device-aided Parkinson therapy. This study investigates ORM capacity and hippocampal dynamic functional connectivity in PD. Thirty-one PD participants and 31 healthy controls (HC) underwent functional MRI during an ORM task. Co-activation pattern analysis identified active hippocampal networks. The PD group showed impaired ORM and a sequence of four activated hippocampal networks. The fourth network, involving the dorsal Attention Network (dAN), had fewer and shorter expressions during correct ORM responses in PD compared with HC. Hippocampal functional asymmetry was observed in HC but not in PD. These findings suggest that impaired ORM in PD is linked to reduced hippocampal functional asymmetry. Future research should explore differences in functional dynamics of odor memory-related brain regions in PD patients with and without cognitive decline.

Importance  Olfactory deficits are associated with higher mortality in older adults, but the mechanisms remain unclear. Further understanding this relationship could inform interventions to improve survival and quality of life for those with olfactory deficits.

Objective  To investigate the association of olfactory deficits with all-cause and cause-specific mortality and to explore potential mediating factors.

Design, Setting, and Participants  The Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), is an ongoing population-based, longitudinal cohort study with baseline between 2001 and 2004. Eligible participants were residents of Kungsholmen, Stockholm, Sweden, and aged between 60 and 99 years from March 21, 2001, to August 30, 2004. Twelve-year follow-up was completed in February 2013. Data analysis took place between February 2024 and July 2024.

Main Outcomes and Measures  Olfactory ability was tested with the 16-item Sniffin’ Sticks Odor Identification task. Mortality was determined through the Swedish National Cause of Death Register. Cox proportional hazards models examined the associations between olfaction and mortality over 6 years and 12 years. Competing hazard risks regression analyses assessed the olfactory-mortality association for specific death causes. Generalized structural equation models investigated mediators, including incident dementia, baseline chronic diseases, frailty, and malnutrition. The tested hypotheses were formulated after data collection.

Results  Among 2524 participants (baseline mean [SD] age, 71.9 [10.0] years; 1545 [61.2%] female), 445 (17.6%) had died at 6 and 969 (38.4%) at 12 years of follow-up. Each additional incorrect answer on the odor identification test was associated with a 6% increased all-cause mortality risk at 6 years (hazard ratio [HR], 1.06 [95% CI, 1.03-1.08]) and 5% increased risk at 12 years (HR, 1.05 [95% CI, 1.03-1.08]) in multiadjusted models. In cause-specific models, the olfaction-mortality association had the greatest risk in relation to neurodegenerative death causes. Meaningful mediators for death at 6 years included dementia (23% of total association), frailty (11% of total association), and malnutrition (5% of total association). At 12 years, frailty remained a mediator (9% of total association).

Conclusions and Relevance  The results of this cohort study underscore the importance of olfactory function as a mortality risk marker in older adults and highlight the evolving influence of neurodegeneration and frailty on this relationship. Further research is needed to assess the clinical utility of olfactory assessments in identifying individuals at risk of adverse health outcomes.

Olfactory deficits are hypothesized to precede cognitive decline and be independently associated with future dementia. Conversely, the concurrency of cognitive and olfactory impairments is expected to represent an advanced stage, associated with shorter time to diagnosis. Limited research has examined the association of isolated and concurrent cognitive and olfactory impairments with incident dementia. We aimed to estimate the 12-year dementia hazard for cognitive impairment no dementia (CIND), olfactory dysfunction (OD), and their combination in a population-based cohort of older adults. We classified 2406 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) based on baseline CIND and OD. Dementia hazard was estimated with Cox regressions for the whole period and two timeframes (baseline to 6-year follow-up and 6- to 12-year follow-up), and time until receiving a diagnosis via Laplace regressions. CIND+OD was associated with increased hazard ratio (HR) of dementia over 6 years (HR 11.38; 95% CI 6.70, 19.32; p < 0.001), higher for amnestic CIND+OD (HR 22.23; 95% CI 11.79, 41.90; p < 0.001). Isolated CIND was associated with dementia closest to baseline (HR 3.38; 95% CI 1.75, 6.49; p < 0.001), while isolated OD was associated with dementia closest (HR 2.56; 95% CI 1.48, 4.43; p < 0.001) and furthest (HR 2.12; 95% CI 1.41, 3.19; p < 0.001) to baseline. CIND+OD received their dementia diagnosis 3 years earlier. This study demonstrated that individuals with both cognitive and olfactory impairments have a higher short-term risk of progression to dementia and that OD may be a valuable early marker of dementia on its own.

Background: Impaired odor identification is a characteristic of sporadic Alzheimer’sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain. Objective: To investigate odor identification ability in mutation carriers (MC) and non-carriers (NC) of adAD in relation to years to estimated clinical onset clinical onset (YECO) of disease. Methods: Participants from six families with autosomal-dominant mutations (APP Swedish, APPArctic, and PSEN1 mutations) included 20 MC and 20 NC. The groups were comparable in age, gender, education, number of APOE ɛ4 alleles, and YECO, but differed in global cognition (Mini-Mental State Examination). The MC group included individuals in asymptomatic, symptomatic cognitively unimpaired, mild cognitive impairment, and dementia stages of disease, spanning approximately 40 years of the AD continuum. All NC were asymptomatic. Olfactory function was assessed by means of free and cued identification of common odors summarized as total identification. Results: MC performed poorer than NC in free and total identification. Four MC and none of the NC were anosmic. Olfactory functions in MC and NC were significantly and inversely related to time course (YECO) for both free and total identification. The decline in free identification began approximately 10 years prior to the estimated clinical onset of AD in MC. Odor identification proficiency was associated with episodic memory and executive function in MC and NC. Conclusions: Impaired odor identification is present well before the clinical diagnosis of AD in MC and is associated with disease progression. Odor identification ability may be a useful early biomarker for adAD.

INTRODUCTION: We evaluated short versions of a 16-item odor identification (OID) test, with regard to their ability to identify individuals at high dementia risk.

METHODS: Participants from the population-based SNAC-K study (n = 2418) were followed across 12 years. We formed 13 abbreviated clusters based on the identifiability and perceptual characteristics of the Sniffin’ Sticks Test (SST) items, and pre-existing test versions. Dementia hazard was estimated with Cox regressions.

RESULTS: Lower OID scores were associated with an increased dementia hazard across all odor clusters. Lower performance in the high identifiability cluster showed the strongest association with dementia (hazard ratio = 1.39, 95% confidence interval [1.28–1.51]). Moreover, the high-intensity odor cluster showed a stronger association with dementia than the low-intensity cluster (P = 0.02).

DISCUSSION: The findings suggest that the SST items differ with regard to their association with dementia and support using a reduced set size for clinical practice.

Introduction: We evaluated markers of olfactory dysfunction (OD) for estimating hazard of dementia in older adults.

Methods: Mild (hyposmia) and severe (anosmia) OD was classified in a population-based study of dementia-free persons (SNAC-K; n = 2473; mean age = 70 years) using the Sniffin sticks odor identification task. Combined variables were created for objective and subjective OD and for OD and APOE status. Hazard of dementia across 12 years was estimated with Cox regression.

Results: OD was associated with increased hazard of dementia (2.01; 95% confidence interval [CI] 1.60-2.52), with the strongest association for anosmia (2.92; 95% CI 2.14-3.98). Results remained consistent after adjusting for potential confounders and across age and sex subgroups. APOE ε4 carriers with anosmia had the highest hazard of dementia (ε4: 6.95; 95% CI 4.16-11.62; ε4/ε4: 19.84; 95% CI 6.17-63.78).

Discussion: OD is associated with increased risk of dementia, especially severe impairment in combination with genetic risk of Alzheimer's disease.

Little is known about the neural basis of lower- and higher-order olfactory functions such as odor memory, compared with other sensory systems. The aim of this study was to explore neural networks and correlates associated with 3 functions: passive smelling (PS), odor encoding (OE), and in particular odor recognition memory (ORM). Twenty-six healthy participants were examined using functional magnetic resonance imaging conducted across 3 sessions, one for each function. Independent component analysis revealed a difference between sessions where a distinct ORM component incorporating hippocampus and posterior cingulate showed delayed triggering dissociated from odor stimulation and recognition. By contrasting Hit for ORM (target odors correctly recognized as old) and a combination of PS and detected odors from OE, we found significantly lower activations in amygdala, piriform cortex, insula, thalamus, and the inferior parietal lobule. Region of interest analysis including anterior insula, posterior cingulate gyrus, dentate gyrus, left middle frontal gyrus, amygdala, and piriform cortex demonstrated that Hit were associated with lower activations compared with other memory responses. In summary, our findings suggest that successful recognition of familiar odors (odor familiarity) is associated with neural suppression in the abovementioned regions of interest. Additionally, network including the hippocampus and posterior cingulate is engaged in a postrecognition process. This process may be related to incidental encoding of less familiar and more novel odors (odor novelty) and should be subject for future research.

Human olfaction can be extraordinarily sensitive, and its most common assessment method is odor identification (OID), where everyday odors are matched to word labels in a multiple-choice format. However, many older persons are unable to identify familiar odors, a deficit that is associated with the risk of future dementia and mortality. The underlying processes subserving OID in older adults are poorly understood. Here, we analyzed error patterns in OID to test whether errors could be explained by perceptual and/or semantic similarities among the response alternatives. We investigated the OID response patterns in a large, population-based sample of older adults in Sweden (n = 2479; age 60–100 years). Olfaction was assessed by a ‘Sniffin ́ TOM OID test with 16 odors; each trial involved matching a target odor to a correct label among three distractors. We analyzed the pattern of misidentifications, and the results showed that some distractors were more frequently selected than others, suggesting cognitive or perceptual factors may be present. Relatedly, we conducted a large online survey of older adults (n = 959, age 60–90 years) who were asked to imagine and rate the perceptual similarity of the target odors and the three corresponding distractors (e.g. “How similar are these smells: apple and mint?”). We then used data from the Swedish web corpus and the Word2Vec neural network algorithm to quantify the semantic association strength between the labels of each target odor and its three distractors. These data sources were used to predict odor identification errors. We found that the error patterns were partly explained by both the semantic similarity between target-distractor pairs, and the imagined perceptual similarity of the target-distractor pair. Both factors had, however, a diminished prediction in older ages, as responses became gradually less systematic. In sum, our results suggest that OID tests not only reflect olfactory perception, but also likely involve the mental processing of odor-semantic associations. This may be the reason why these tests are useful in predicting dementia onset. Our insights into olfactory-language interactions could be harnessed to develop new olfactory tests that are tailored for specific clinical purposes.

Background: Olfactory impairment has been associated with both cognitive impairment and dementia and Alzheimer’s disease (AD). This study aimed to investigate the association between olfactory dysfunction (OD) and change trajectories in different cognitive domains in aging. Method: Participants (n = 2473, mean age = 72 years, 61% female) from the population-based Swedish National study on Aging and Care-Kungsholmen (SNAC-K) were repeatedly assessed with tasks measuring episodic memory, semantic memory, verbal fluency, and perceptual speed across 12 years. OD was measured at baseline and participants were categorized as normosmic, hyposmic, or anosmic based on the Sniffin’ Sticks odor identification task. Linear mixed-effects models were used to assess the associations between baseline OD and rates of cognitive decline. Result: OD was related to poorer baseline performance and faster rates of decline during follow-up in all examined domains, as well as in global cognition. Associations were generally more pronounced for anosmia compared to hyposmia. Conclusion: Olfactory impairment is associated with accelerated decline in aging across a wide range of cognitive domains.