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Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?

OBJECTIVE: Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (Aβ) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for...

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Autores principales: McMillan, Corey T., Lee, Edward B., Jefferson‐George, Kyra, Naj, Adam, Van Deerlin, Vivianna M., Trojanowski, John Q., Wolk, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093846/
https://www.ncbi.nlm.nih.gov/pubmed/30128317
http://dx.doi.org/10.1002/acn3.581
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author McMillan, Corey T.
Lee, Edward B.
Jefferson‐George, Kyra
Naj, Adam
Van Deerlin, Vivianna M.
Trojanowski, John Q.
Wolk, David A.
author_facet McMillan, Corey T.
Lee, Edward B.
Jefferson‐George, Kyra
Naj, Adam
Van Deerlin, Vivianna M.
Trojanowski, John Q.
Wolk, David A.
author_sort McMillan, Corey T.
collection PubMed
description OBJECTIVE: Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (Aβ) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and Aβ, we investigated genotypic frequencies of AD susceptibility loci between autopsy‐confirmed AD and primary age‐related tauopathy (PART), a neuropathological condition defined by characteristic neurofibrillary tau tangles (NFTs) with minimal or absent Aβ. METHODS: General linear models assessed the odds of AD (N = 1190) relative to PART (N = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank (PENN; AD N = 312; PART N = 65) and National Alzheimer's Coordinating Center (NACC; AD N = 878; PART N = 311). We also evaluated the odds of Braak stage NFT burden. RESULTS: Three genotypes significantly associated with reduced AD risk relative to PART in the PENN (N = 377) and NACC (N = 1189) cohorts including APOE ε4, APOE ε2, and rs6656401 in the CR1 gene. The genotypes rs6733839 in the BIN1 gene and rs28834970 in the PTK2B gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis (N = 1566), APOE ε4 dosage was highly associated with higher Braak stage of NFT burden in Probable PART and AD, but not Definite PART. INTERPRETATION: The presence of genotypic differences between PART and AD suggest that PART can provide a genetic model of NFT risk and potential Aβ resistance to inform disease‐modifying therapies.
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spelling pubmed-60938462018-08-20 Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance? McMillan, Corey T. Lee, Edward B. Jefferson‐George, Kyra Naj, Adam Van Deerlin, Vivianna M. Trojanowski, John Q. Wolk, David A. Ann Clin Transl Neurol Research Articles OBJECTIVE: Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (Aβ) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and Aβ, we investigated genotypic frequencies of AD susceptibility loci between autopsy‐confirmed AD and primary age‐related tauopathy (PART), a neuropathological condition defined by characteristic neurofibrillary tau tangles (NFTs) with minimal or absent Aβ. METHODS: General linear models assessed the odds of AD (N = 1190) relative to PART (N = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank (PENN; AD N = 312; PART N = 65) and National Alzheimer's Coordinating Center (NACC; AD N = 878; PART N = 311). We also evaluated the odds of Braak stage NFT burden. RESULTS: Three genotypes significantly associated with reduced AD risk relative to PART in the PENN (N = 377) and NACC (N = 1189) cohorts including APOE ε4, APOE ε2, and rs6656401 in the CR1 gene. The genotypes rs6733839 in the BIN1 gene and rs28834970 in the PTK2B gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis (N = 1566), APOE ε4 dosage was highly associated with higher Braak stage of NFT burden in Probable PART and AD, but not Definite PART. INTERPRETATION: The presence of genotypic differences between PART and AD suggest that PART can provide a genetic model of NFT risk and potential Aβ resistance to inform disease‐modifying therapies. John Wiley and Sons Inc. 2018-06-19 /pmc/articles/PMC6093846/ /pubmed/30128317 http://dx.doi.org/10.1002/acn3.581 Text en © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
McMillan, Corey T.
Lee, Edward B.
Jefferson‐George, Kyra
Naj, Adam
Van Deerlin, Vivianna M.
Trojanowski, John Q.
Wolk, David A.
Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?
title Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?
title_full Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?
title_fullStr Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?
title_full_unstemmed Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?
title_short Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?
title_sort alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093846/
https://www.ncbi.nlm.nih.gov/pubmed/30128317
http://dx.doi.org/10.1002/acn3.581
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