Progranulin mutations in clinical and neuropathological Alzheimer’s disease
Fecha
2022-12-10Autor
Vardarajan, Badri N.
Reyes-Dumeyer, Dolly
L. Piriz1, Angel
Lantigua, Rafael A.
Medrano, Martin
Rivera, Diones
Jiménez-Velázquez, Ivonne Z.
Martin, Eden
Pericak-Vance, Margaret A.
Bush, William
Farrer, Lindsay
Haines, Jonathan L.
Wang, Li-San
Yee Leung, Yuk
Schellenberg, Gerard
Kukull, Walter
De Jager, Philip
Bennett, David A.
Schneider, Julie A.
Alzheimer’s Disease Sequencing Project
Mayeux, Richard
Metadatos
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Progranulin (GRN) mutations occur in frontotemporal lobar degeneration
(FTLD) and in Alzheimer’s disease (AD), often with TDP-43 pathology.
We determined the frequency of rs5848 and rare, pathogenic GRN mutations
in two autopsy and one family cohort.We compared Braak stage, β-amyloid load,
hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers
and non-carriers. Pathogenic GRN mutations were more frequent in all cohorts compared to the
Genome Aggregation Database (gnomAD), but there was no evidence for association
with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density
adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher
frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare,
pathogenic GRN variants were observed in the family cohort.
Discussion: GRN mutations in clinical and neuropathological AD increase the burden
of tau-related brain pathology but show no specific association with β-amyloid load
or AD.
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