Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β.

Abstract

Importance\nApolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial.\n\n\nObjective\nTo determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age.\n\n\nDesign, Setting, and Participants\nThis is a study of 2 cross-sectional cohorts of volunteers who were cognitively normal, had mild cognitive impairment (MCI), or had Alzheimer disease dementia: the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2019) and the Alzheimer s Disease Neuroimaging Initiative (ADNI) (collected between November 2015 and June 2019). The first cohort (TRIAD) comprised cognitively normal elderly participants (n\u2009=\u2009124), participants with MCI (n\u2009=\u200950), and participants with Alzheimer disease (n\u2009=\u200950) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-β PET with [18F]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n\u2009=\u2009157), participants with MCI (n\u2009=\u200983), and participants with Alzheimer disease (n\u2009=\u200925) who underwent tau PET with [18F]flortaucipir and amyloid-β PET with [18F]florbetapir. Exclusion criteria were a history of other neurological disorders, stroke, or head trauma. There were 489 eligible participants, selected based on availability of amyloid-PET, tau-PET, magnetic resonance imaging, and genotyping for APOEε4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study.\n\n\nMain Outcomes and Measures\nA main association between APOEε4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio.\n\n\nResults\nThe mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOEε4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOEε4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-β, sex, age, and clinical status after multiple comparisons correction (TRIAD: β\u2009=\u20090.33; 95% CI, 0.19-0.49; ADNI: β\u2009=\u20090.13; 95% CI, 0.08-0.19; P\u2009<\u2009.001).\n\n\nConclusions and Relevance\nOur results indicate that the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results contribute to an evolving framework in which APOEε4 has deleterious consequences in Alzheimer disease beyond its link with amyloid-β and suggest APOEε4 as a potential target for future disease-modifying therapeutic trials targeting tau pathology.