Association of Apolipoprotein E ɛ4, Educational Level, and Sex With Tau Deposition and Tau-Mediated Metabolic Dysfunction in Older Adults | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network
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    Original Investigation
    October 23, 2019

    Association of Apolipoprotein E ɛ4, Educational Level, and Sex With Tau Deposition and Tau-Mediated Metabolic Dysfunction in Older Adults

    Author Affiliations
    • 1Department of Neurology, Mayo Clinic–Rochester, Rochester, Minnesota
    • 2Department of Health Sciences Research, Mayo Clinic–Rochester, Rochester, Minnesota
    • 3Department of Radiology, Mayo Clinic–Rochester, Rochester, Minnesota
    JAMA Netw Open. 2019;2(10):e1913909. doi:10.1001/jamanetworkopen.2019.13909
    Key Points español 中文 (chinese)

    Question  Are the apolipoprotein E ɛ4 allele, educational levels, and sex associated with tau deposition and tau-mediated metabolic dysfunction in older adults?

    Findings  In a population-based cohort study, regional tau deposition was most significantly associated with global amyloid burden without any main associations of apolipoprotein E ɛ4, education, or sex. Via interaction models, women displayed a higher degree of tau-mediated metabolic dysfunction in the entorhinal cortex compared with men.

    Meaning  These findings suggest that in older adults, tau deposition is most significantly associated with amyloidosis, but other factors, including sex, may be associated with differential resilience to tau pathology.


    Importance  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.

    Objective  To assess whether APOE ɛ4, 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 ɛ4 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 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).

    Conclusions and Relevance  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.