Association of Apolipoprotein E epsilon 4 With Medial Temporal Tau Independent of Amyloid-beta

This study investigates whether apolipoprotein E epsilon 4 is associated with medial temporal tau pathology independently of amyloid-beta, sex, clinical status, and age. Importance Apolipoprotein E epsilon 4 (APOE epsilon 4) is the single most important genetic risk factor for Alzheimer disease. While APOE epsilon 4 is associated with increased amyloid-beta burden, its association with cerebral tau pathology has been controversial. Objective To determine whether APOE epsilon 4 is associated with medial temporal tau pathology independently of amyloid-beta, sex, clinical status, and age. Design, Setting, and Participants This 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 = 124), participants with MCI (n = 50), and participants with Alzheimer disease (n = 50) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-beta PET with [F-18]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n = 157), participants with MCI (n = 83), and participants with Alzheimer disease (n = 25) who underwent tau PET with [F-18]flortaucipir and amyloid-beta PET with [F-18]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 APOE epsilon 4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study. Main Outcomes and Measures A main association between APOE epsilon 4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio. Results The mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOE epsilon 4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOE epsilon 4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-beta, sex, age, and clinical status after multiple comparisons correction (TRIAD: beta = 0.33; 95% CI, 0.19-0.49; ADNI: beta = 0.13; 95% CI, 0.08-0.19; P < .001). Conclusions and Relevance Our results indicate that the elevated risk of developing dementia conferred by APOE epsilon 4 genotype involves mechanisms associated with both amyloid-beta and tau aggregation. These results contribute to an evolving framework in which APOE epsilon 4 has deleterious consequences in Alzheimer disease beyond its link with amyloid-beta and suggest APOE epsilon 4 as a potential target for future disease-modifying therapeutic trials targeting tau pathology. Question Is the apolipoprotein E epsilon 4 (APOE epsilon 4) genotype associated with tau pathology independently of amyloid-beta? Findings In this study of 2 cross-sectional cohorts (total n = 489), individuals who were APOE epsilon 4 carriers had significantly higher entorhinal and hippocampal tau positron emission tomography signal than APOE epsilon 4 noncarriers, controlling for cortical amyloid-beta burden, age, sex, and clinical status. Meaning Carriership of APOE epsilon 4 is associated with tau pathology in medial temporal structures independently of amyloid-beta, extending previous reports of greater medial temporal neurodegeneration and memory impairment in APOE epsilon 4 carriers.