Association of Apolipoprotein E ε4, Educational Level, and Sex With Tau Deposition and Tau-Mediated Metabolic Dysfunction in Older Adults

IMPORTANCE While amyloidosis is an early event in the Alzheimer disease (AD) biomarker cascade, a complex interplay among the apolipoprotein E (APOE) epsilon 4 allele, educational levels, and sexmay be associated with an individual's resilience to dementia. OBJECTIVE To assess whether APOE epsilon 4, educational levels, and sex are associated with regional tau deposition and tau-mediated metabolic dysfunction in older adults. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of individuals aged 65 years and older enrolled between January 1, 2004, and May 1, 2018, in the Mayo Clinic Study of Aging, a prospective longitudinal study of cognitive aging in Olmsted County, Minnesota. MAIN OUTCOMES AND MEASURES The primary outcomes were cross-sectional tau burden and the fluorodeoxyglucose (FDG) to tau ratio (as a measure of tau-mediated metabolic dysfunction) assessed by positron emission tomography for 43 atlas-defined regions, with specific focus on the entorhinal, inferior temporal, and posterior cingulate cortices. EXPOSURES Using linear regression, APOE epsilon 4 status and years of education were the primary exposure variables, with sex additionally investigated through interaction models. RESULTS The sample included 325 individuals (173 [53%] male; mean [SD] age, 76.1 [7.2] years; 291 [90%] cognitively unimpaired). Although APOE epsilon 4 was nominally associated with higher tau deposition (beta = 0.05 [95% CI, 0.02-0.09]; P =.001; Cohen d = 0.40) and lower FDG to tau ratio (beta = -0.05 [95% CI, -0.08 to -0.01]; P =.008; Cohen d = 0.33) in the entorhinal cortex, these associations were completely attenuated after controlling for global amyloid burden. Education was not associated with regional tau burden or FDG to tau ratio. In the 3 regions of interest, global amyloid burden accounted for the largest proportion of variance in tau deposition among the candidate variables assessed. In the entorhinal cortex, significant interactions were identified between APOE epsilon 4 and global amyloid burden on tau (beta = 0.25; SE = 0.06; P <.001) and between sex and tau burden on FDG metabolism (beta = 0.10; SE = 0.05; P =.049). CONCLUSIONS AND RELEVANCE These results suggest that (1) tau deposition is most significantly associated with amyloidosis; (2) in the presence of abundant amyloidosis, APOE epsilon 4 may be associated with accelerated entorhinal cortex tau deposition; and (3) women may have lower resilience to tau, manifested by a higher degree of metabolic dysfunction in the entorhinal cortex in response to tau pathology.