Abstract
While amyloidosis is an early event in the Alzheimer disease (AD) biomarker cascade, a complex interplay among the apolipoprotein E (APOE) ɛ4 allele, educational levels, and sex may be associated with an individual's resilience to dementia. To assess whether APOE ɛ4, educational levels, and sex are associated with regional tau deposition and tau-mediated metabolic dysfunction in older adults. 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. 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. Using linear regression, APOE ɛ4 status and years of education were the primary exposure variables, with sex additionally investigated through interaction models. The sample included 325 individuals (173 [53%] male; mean [SD] age, 76.1 [7.2] years; 291 [90%] cognitively unimpaired). Although APOE ɛ4 was nominally associated with higher tau deposition (β = 0.05 [95% CI, 0.02-0.09]; P = .001; Cohen d = 0.40) and lower FDG to tau ratio (β = -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 ɛ4 and global amyloid burden on tau (β = 0.25; SE = 0.06; P < .001) and between sex and tau burden on FDG metabolism (β = 0.10; SE = 0.05; P = .049). These results suggest that (1) tau deposition is most significantly associated with amyloidosis; (2) in the presence of abundant amyloidosis, APOE ɛ4 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.
Highlights
The precise mechanistic interactions between the defining proteinopathies of Alzheimer disease (AD), amyloid and tau, are still elusive
apolipoprotein E (APOE) ε4 was nominally associated with higher tau deposition (β = 0.05 [95% CI, 0.02-0.09]; P = .001; Cohen d = 0.40) and lower FDG to tau ratio (β = −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
Significant interactions were identified between APOE ε4 and global amyloid burden on tau (β = 0.25; SE = 0.06; P < .001) and between sex and tau burden on FDG metabolism (β = 0.10; SE = 0.05; P = .049)
Summary
The precise mechanistic interactions between the defining proteinopathies of Alzheimer disease (AD), amyloid and tau, are still elusive. APOE ε4 has been associated with increased amyloid burden and decreased fluorodeoxyglucose (FDG) metabolism assessed via positron emission tomography (PET).[5,6,7,8,9,10] the association of APOE ε4 with tau is less clear. An amyloid-independent effect of APOE on tau has been suggested by studies in cultured neurons and animal models,[11,12,13] but whether this hypothesis holds in vivo in humans is less clear
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