Alzheimer’s disease and cerebrovascular biomarkers in relation to odor identification in a naturalistic clinical cohort

Abstract Introduction Olfactory deficits, especially in odor identification (OID), have been linked to Alzheimer’s disease (AD), likely due to regional proteinopathy and atrophy in the olfactory brain circuit. Their cognitive and biological correlates across the clinical spectrum, particularly in individuals with no evident cognitive impairment, have been underexplored. This examination is relevant because many individuals of this group will not progress to dementia, and olfactory deficits may reflect ongoing pathological processes and could enrich risk stratification. Methods We analyzed data from a cohort of 233 subjective cognitive impairment (SCI, n =152), mild cognitive impairment (MCI, n =50), and AD dementia ( n =31) individuals from the Karolinska University Hospital Memory Clinic (Solna, Sweden). We examined the association of performance on the 16-item Sniffin’ Sticks OID test (free and total free or cued identification scores) with a range of markers: cognitive performance, cerebrospinal fluid biomarkers, AD- and olfactory-related brain volumes, and white matter hyperintensities volume. We performed correlation analyses, generalized additive models, and threshold regressions, adjusted for sociodemographic factors and APOE status. Results OID performance was better in SCI compared to MCI and AD. Aβ42/40 ratio was positively associated with OID in SCI and AD, with APOE ε4 carriers driving this association in SCI. Hippocampal volume was positively associated with OID in AD. Higher volume of white matter hyperintensities was negatively associated with OID in MCI. The relationships of OID with Aβ42/40 and hippocampal volume were linear in the whole cohort. Worse verbal episodic memory performance was associated with lower OID scores only in the AD group. Free OID showed a broader and stronger pattern of associations with episodic memory and biomarkers compared with total OID. Threshold regression between free OID and Aβ42/40 identified a subthreshold value (<0.94) above the clinical cutoff (<0.86), capturing nine non-demented individuals within the gray zone between these cutoffs. Conclusions Our findings support an association between amyloid levels and olfactory performance in the AD spectrum, underscoring the potential of smell tests as cost-effective tools in multimodal stratification frameworks. In dementia stages, medial temporal atrophy accompanied by memory impairment may be the main correlate of olfactory deficits.