medRxiv · Jun 3, 2026

APOE and amyloid-tau pathology in cognitively unimpaired older adults

By Morillo CA, Zheng L, Ghanbarian E et al.

INTRODUCTION: 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 harmonized multi-cohort ADSP-PHC data from 4,380 CU participants across 4 cohorts with APOE genotype, amyloid PET, and cognitive data from four domains of memory, language, executive, and visuospatial function, including a subset of 758 with tau PET imaging. RESULTS: APOE ε4 showed a strong dose-dependent association with amyloid burden and amyloid positivity, with the highest levels observed among ε4 homozygotes. Associations between APOE and global tau burden 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 burden was associated with lower memory and language performance. CONCLUSIONS: In CU older adults, APOE ε4 was most strongly associated with amyloid burden, with more modest associations observed for medial temporal tau burden.

doi.org/10.64898/2026.06.02.26354753 Open access PubMed 42282183 Mechanisms