Olfaction and Plasma Biomarkers of Alzheimer Disease and Neurodegeneration in the Atherosclerosis Risk in Communities Study

Abstract

Background and objectives: Investigation of olfactory impairment, an early manifestation of Alzheimer disease (AD), in relation to plasma biomarkers of AD and neurodegeneration could provide insights into the disease's pathophysiology. Because few such studies based on large, diverse, community-based populations exist, we investigated associations of odor identification ability with plasma biomarkers of AD and other neurodegenerative pathologies in community-dwelling Black and White older adults.

Methods: This cross-sectional investigation included participants from the Atherosclerosis Risk in Communities study who attended visit 5 (2011-2013) and who completed olfactory testing and brain MRI examinations and had plasma biomarkers measured (namely, amyloid-beta [Aβ]₄₂/Aβ₄₀ ratio, phosphorylated-tau at threonine-181 [p-tau₁₈₁], p-tau₁₈₁/Aβ₄₂ ratio, glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]). Odor identification ability was measured by the 12-item Sniffin' Sticks test. Separate linear regression models were used to examine the association of continuous olfaction score and olfaction categories (anosmia: score 6; hyposmia: 7-8; moderate-normal: 9-10; good-normal: 11-12) with each biomarker (all were log-transformed), adjusting for sociodemographic and cardiovascular factors, head injury, APOE-ε4 status, and estimated glomerular filtration rate. We further examined whether any observed associations are explained by total and regional brain volumes.

Results: Among 1,545 participants (age: 76 ± 5 years, 60% women, 27% self-reported Black participants), the mean olfaction score was 9.2 ± 2.3; 14% had anosmia. Consistent with our hypotheses, poorer olfactory scores were associated with higher plasma p-tau₁₈₁ (β per 1-unit lower score: 0.026 [95% CI 0.012-0.040]), p-tau₁₈₁/Aβ₄₂ (β: 0.027 [95% CI 0.011- 0.044]), GFAP (β: 0.024 [95% CI 0.009-0.040]), and NfL (β: 0.034 [95% CI 0.019-0.050] and lower Aβ₄₂/Aβ₄₀ ratio (β: -0.007 [95% CI -0.015 to 0.000]). Likewise, compared with good-normal olfaction, anosmia showed associations with all biomarker levels indicative of greater neuropathology (e.g., β for plasma p-tau₁₈₁/Aβ₄₂: 0.235 [95% CI 0.113-0.358] and β for plasma NfL: 0.210 [95% CI 0.102-0.317]), although the association with Aβ₄₂/Aβ₄₀ ratio was not statistically significant (β: -0.054 [95% CI -0.108 to 0.001]). These biomarkers were not significantly associated with hyposmia or moderate-normal olfaction. Smaller medial-temporal lobe volumes partly explained olfaction's link with plasma p-tau₁₈₁, p-tau₁₈₁/Aβ₄₂, GFAP, and NfL.

Discussion: Our findings suggest that poor olfaction is associated with multiple AD-related and other neurodegenerative processes. Future studies should investigate how longitudinal changes in both olfaction and biomarkers relate to each other.