Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β.
Aged
Aged, 80 and over
Alzheimer Disease
/ diagnostic imaging
Amyloid beta-Peptides
/ metabolism
Apolipoprotein E4
/ genetics
Cognitive Dysfunction
/ diagnostic imaging
Female
Genotype
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Neuroimaging
Neuropsychological Tests
Positron-Emission Tomography
Temporal Lobe
/ diagnostic imaging
tau Proteins
/ metabolism
Journal
JAMA neurology
ISSN: 2168-6157
Titre abrégé: JAMA Neurol
Pays: United States
ID NLM: 101589536
Informations de publication
Date de publication:
01 04 2020
01 04 2020
Historique:
pubmed:
21
12
2019
medline:
7
7
2020
entrez:
21
12
2019
Statut:
ppublish
Résumé
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. To determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age. 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. 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. 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). 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.
Identifiants
pubmed: 31860000
pii: 2757605
doi: 10.1001/jamaneurol.2019.4421
pmc: PMC6990684
doi:
Substances chimiques
Amyloid beta-Peptides
0
Apolipoprotein E4
0
tau Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
470-479Subventions
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Organisme : CIHR
ID : MOP-11-51-31
Pays : Canada
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