Polygenic Effect on Tau Pathology Progression in Alzheimer's Disease.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
revised:
02
11
2022
received:
23
06
2022
accepted:
19
12
2022
medline:
29
3
2023
pubmed:
27
12
2022
entrez:
26
12
2022
Statut:
ppublish
Résumé
Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar-tau accumulation as a key driver of dementia symptoms is unclear. We combined the to-date largest number of genetic risk variants of AD (n = 85 lead single-nucleotide polymorphisms [SNPs]) from recent genome-wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau-positron emission tomography (PET), amyloid-PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid-PET, we predicted the rate of tau-PET increases in Braak-stage regions-of-interest and cognitive decline. We also assessed PGS-risk enrichment effects on the required sample size in clinical trials targeting tau pathology. We found that a higher PGS was associated with higher rates of tau-PET accumulation, in particular at elevated amyloid-PET levels. The tau-PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%. Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023;93:819-829.
Substances chimiques
tau Proteins
0
Biomarkers
0
Amyloid
0
Amyloid beta-Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
819-829Subventions
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Informations de copyright
© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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