Objective:

This study evaluates the relationship of hyposmia to entorhinal and hippocampal tau pathology in cognitively normal older adults.

Background:

Olfactory impairment is a known symptom of Alzheimer’s disease (AD). Its significance in preclinical AD remains unclear, especially in light of other early symptoms such as anxiety and subjective cognitive decline (SCD) that associate with AD biomarkers and progression.

Design/Methods:

Cognitively normal adults (N = 61; age: median 72 years, range 56-92 years; 72% female) evaluated at the NYU Alzheimer’s Disease Research Center underwent amyloid (18F-florbetaben) and tau (18F-MK6240) PET/MRI , and the University of Pennsylvania Smell Identification Test (UPSIT). Hyposmia was defined as UPSIT < 27. Anxiety was evaluated via the Neuropsychiatric Inventory Questionnaire. SCD was defined by Global Deterioration Scale stage 2. Amyloid burden was measured as the mean standardized uptake value ratio (SUVR) over a composite neocortical region against a whole cerebellum reference. Regional tau SUVR was measured against a cerebellar gray matter reference. Multiple variable linear regression was performed to determine correlation between regional tau burden and hyposmia, with age, amyloid SUVR, SCD status, and anxiety as covariates.

Results:

UPSIT scores ranged from 14-38 (median, 32; 16% hyposmic). Hippocampal (β = 0.16, SE: 0.08, p = 0.045) but not entorhinal (β = 0.13, SE: 0.12, p = 0.28) tau pathology was associated with hyposmia, independent of SCD, anxiety, or amyloid burden. Both hippocampal (β = 0.60, SE: 0.17, p = 0.0007) and entorhinal (β = 1.04, SE: 0.25, p = 0.0001) tau pathology showed associations with cerebral amyloid burden.

Conclusions:

Hyposmia is a predictor of hippocampal tau pathology independent of other preclinical AD symptoms such as anxiety and SCD, as well as amyloid burden. These findings demonstrate that in PET biomarker-enriched cohorts, hyposmia can help differentiate preclinical AD from normal aging.