Odor identification as a biomarker of preclinical AD in older adults at risk

Abstract

Objective: To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease (AD) pathogenesis in cognitively normal aging individuals at increased risk of AD dementia.

Methods: In 274 members of the PREVENT-AD cohort of healthy aging persons with a parental or multiple-sibling history of AD dementia, we assessed the cross-sectional association of OI with potential indicators of presymptomatic AD. Some 101 participants donated CSF, thus enabling assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P₁₈₁-tau), and their ratios with β-amyloid (Aβ_1-42). Adjusted analyses considered age, cognition, APOE ε4 status, education, and sex as covariates. We measured OI using the University of Pennsylvania Smell Identification Test and cognitive performance using the Repeatable Battery for Assessment of Neuropsychological Status. Standard kits provided assays of the AD biomarkers. Analyses used robust-fit linear regression models.

Results: Reduced OI was associated with lower cognitive score and older age, as well as increased ratios of CSF t-tau and P₁₈₁-tau to Aβ_1-42 (all p < 0.02). However, the observed associations of OI with age and cognition were unapparent in adjusted models that restricted observations to CSF donors and included AD biomarkers. OI showed little association with CSF Aβ_1-42 alone except in APOE ε4 carriers having lowest-quartile Aβ_1-42 levels.

Conclusions: These findings from healthy high-risk older individuals suggest that OI reflects degree of preclinical AD pathology, while its relationships with age and cognition result from the association of these latter variables with such pathology. Diminished OI may be a practical and affordable biomarker of AD pathology.

Figure 1. Robust-fit linear regression models of UPSIT error score vs CSF biomarkers of AD

(A) CSF t-tau/Aβ_1-42 (β = 0.287, p = 0.00494, n = 100). (B) CSF P₁₈₁-tau/Aβ_1-42 (β = 1.77, p = 0.0165, n = 100). (C) CSF t-tau (β = 3.61 ×10⁻⁴, p = 0.0257, n = 100). (D) CSF P₁₈₁-tau (β = 2.10 ×10⁻³, p = 0.0724, n = 100). (E) CSF Aβ_1-42 (β = −7.01 ×10⁻⁵, p = 0.359, n = 100) and in individuals with CSF Aβ_1-42 levels below the 25th percentile (β = −0.000827, p = 0.0135, n = 25). (F) CSF t-tau/Aβ_1-42 in individuals with CSF Aβ_1-42 levels below the 25th percentile (β = 0.399, p = 0.00260, n = 25). In panel (E), blue circles represent the top 3 quartiles for Aβ concentrations, while red circles in panels (E) and (F) are data from the lowest quartile of Aβ concentrations (suggesting that they have more advanced preclinical AD). Aβ = β-amyloid; AD = Alzheimer disease; P₁₈₁-tau = phospho-tau; t-tau = total tau; UPSIT = University of Pennsylvania Smell Identification Test.

Figure 2. Robust-fit linear regression models of UPSIT error score vs CSF biomarkers, stratified by APOE ε4 status

Red circles represent APOE ε4 carriers. Blue circles represent APOE ε4 noncarriers. (A) CSF t-tau/Aβ_1-42 in carriers (β = 0.352, p = 0.0158, n = 33) and in noncarriers (β = 0.252, p = 0.131, n = 67). (B) CSF P₁₈₁-tau/Aβ_1-42 in carriers (β = 2.416, p = 0.0270, n = 33) and in noncarriers (β = 0.980, p = 0.408, n = 67). (C) CSF t-tau in carriers (β = 4.68 ×10⁻⁴, p = 0.0914, n = 33) and in noncarriers (β = 0.000312, p = 0.144, n = 67). (D) CSF P₁₈₁-tau in carriers (β = 2.76 ×10⁻³, p = 0.204, n = 33) and in noncarriers (β = 0.00178, p = 0.218, n = 67). (E) CSF Aβ_1-42 in carriers (β = −3.76 ×10⁻⁴, p = 0.00841, n = 33) and in noncarriers (β = 4.890e−05, p = 0.598, n = 67). Aβ = β-amyloid; AD = Alzheimer disease; P₁₈₁-tau = phospho-tau; t-tau = total tau; UPSIT = University of Pennsylvania Smell Identification Test.