Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β
Authors: Joseph Therriault, Andrea L. Benedet, Tharick A. Pascoal, Sulantha Mathotaarachchi, Mira Chamoun, Melissa Savard, Emilie Thomas, Min Su Kang, Firoza Lussier, Cecile Tissot, Marlee Parsons, Muhammad Naveed Iqbal Qureshi, Paolo Vitali, Gassan Massarweh, Jean-Paul Soucy, Soham Rej, Paramita Saha-Chaudhuri, Serge Gauthier, Pedro Rosa-Neto
Journal: JAMA Neurology (2019)

<h3>Importance</h3> Apolipoprotein E ε4 (<i>APOEε4</i>) is the single most important genetic risk factor for Alzheimer disease. While<i>APOEε4</i>is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial. <h3>Objective</h3> To determine whether<i>APOEε4</i>is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age. <h3>Design, Setting, and Participants</h3> 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-β PET with [<sup>18</sup>F]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 [<sup>18</sup>F]flortaucipir and amyloid-β PET with [<sup>18</sup>F]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<i>APOEε4</i>. Forty-five young adults (&lt;30 years) from the TRIAD cohort were not selected for this study. <h3>Main Outcomes and Measures</h3> A main association between<i>APOEε4</i>and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio. <h3>Results</h3> The mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were<i>APOEε4</i>carriers (34.9%), and 230 of 489 were men. In both cohorts,<i>APOEε4</i>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 = 0.33; 95% CI, 0.19-0.49; ADNI: β = 0.13; 95% CI, 0.08-0.19;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Our results indicate that the elevated risk of developing dementia conferred by<i>APOEε4</i>genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results contribute to an evolving framework in which<i>APOEε4</i>has deleterious consequences in Alzheimer disease beyond its link with amyloid-β and suggest<i>APOEε4</i>as a potential target for future disease-modifying therapeutic trials targeting tau pathology.