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Cited by 256Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Therriault, Joseph, Benedet, Andrea L., Pascoal, Tharick A., Mathotaarachchi, Sulantha, Chamoun, Mira, Savard, Melissa, Thomas, Emilie, Kang, Min Su +11 more·2020·JAMA Neurology
DOI 10.1001/jamaneurol.2019.4421PMC PMC6990684
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Abstract

Importance: Apolipoprotein 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. Objective: To determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, 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-β PET with [18F]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 [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. Main Outcomes and Measures: A 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. Results: The 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 = 0.33; 95% CI, 0.19-0.49; ADNI: β = 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 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.

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Cited by

Sorted by citations

Authors
Therriault, J., Benedet, A. L., Pascoal, T. A., Mathotaarachchi, S., Chamoun, M., Savard, M., Thomas, E., Kang, M. S., Lussier, F., Tissot, C., Parsons, M., Qureshi, M. N. I., Vitali, P., Massarweh, G., Soucy, J.-P., Rej, S., Saha-Chaudhuri, P., Gauthier, S., & Rosa-Neto, P.
Affiliations
  • Montreal Neurological Institute and Hospital (CA)
  • Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, Québec, Canada
  • Douglas Mental Health University Institute (CA)
  • McGill University (CA)
  • Department of Epidemiology and Biostatistics, McGill University, Montreal, Québec, Canada
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2020-04-01
Volume
77
Issue
4
Pages
470
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2019.4421
PMC
PMC6990684
OpenAlex
W2995524996
Cited by
256
References
11
Citations by year
2026: 44 · 2025: 33 · 2024: 24 · 2023: 51 · 2022: 35 · 2021: 42 · 2020: 27
FWCI
17.42
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • McGill University
  • National Institutes of Health (5u01ag024904-10)
  • Canadian Institutes of Health Research (#MOP-11-51-31)
  • National Institute on Aging (U01-AG-024904)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
APOE ε4, apolipoprotein E, Alzheimer's disease, tau PET, medial temporal lobe, amyloid-beta, genetic risk factors, mild cognitive impairment, neuroimaging biomarkers, flortaucipir, florbetapir, standardized uptake value ratio, sex differences, APOE ε4 carriers, APOE ε2
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Temporal Lobe, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Apolipoprotein E4, Neuroimaging, Cognitive Dysfunction

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