APOE and amyloid‐tau pathology in cognitively unimpaired older adults

Abstract INTRODUCTION Apolipoprotein E (APOE) genotype shows well‐established dose‐dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized.

Methods

We performed a cross‐sectional analysis of CU participants from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4), Alzheimer's Disease Neuroimaging Initiative (ADNI), Wisconsin Registry for Alzheimer's Prevention (WRAP), and National Alzheimer's Coordinating Center (NACC) within the harmonized multi‐cohort Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP‐PHC) data. A total of 4380 CU participants were included with APOE genotype, amyloid PET, and cognitive data (memory, language, executive, and visuospatial function), including a subset of 758 with tau PET imaging.

Results

Compared with ε33, ε24 (β = 18.340), ε34 (β = 23.850), and ε44 (β = 44.820) showed higher amyloid burden (all p < .001). Similarly, ε24 (OR = 4.180), ε34 (OR = 4.540), and ε44 (OR = 14.150) had higher odds of amyloid positivity (all p < .001). After adjustment for amyloid burden, ε4 carriers had higher tau burden in the entorhinal cortex (β = 0.026; false discovery rate [FDR] ‐adjusted p = 0.041) and amygdala (β = 0.040; FDR‐adjusted p = 0.003). Higher tau burden was associated with lower memory (β = −0.439; FDR‐adjusted p = 0.012) and language performance (β = −0.610; FDR‐adjusted p = 0.020).

Discussion

APOE ε4 showed a strong dose‐dependent association with amyloid, with the highest levels observed among ε4 homozygotes. Associations between APOE and global tau were more modest and appeared to be driven mainly by ε4 homozygotes, while regional analyses showed localized APOE ε4‐related associations in medial temporal regions. Independently, higher tau was associated with lower memory and language performance.