TY - JOUR
T1 - The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity
AU - Tesi, Niccolò
AU - Hulsman, Marc
AU - van der Lee, Sven J.
AU - Jansen, Iris E.
AU - Stringa, Najada
AU - van Schoor, Natasja M.
AU - Scheltens, Philip
AU - van der Flier, Wiesje M.
AU - Huisman, Martijn
AU - Reinders, Marcel J. T.
AU - Holstege, Henne
N1 - Funding Information:
The Alzheimer center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. The SCIENCe project is supported by a research grant from Gieskes-Strijbis fonds and stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank), funded by the JPco-fuND FP-829–029 (ZonMW projectnumber 733051061).
Funding Information:
The Alzheimer center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. The SCIENCe project is supported by a research grant from Gieskes-Strijbis fonds and stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank), funded by the JPco-fuND FP-829?029 (ZonMW projectnumber 733051061). The 100-plus Study was supported by Stichting Alzheimer Nederland (WE09.2014?03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814), and Stichting VUmc fonds. Genotyping of the 100-plus study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829?029 (ZonMW projectnumber 733051061). Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care.
Publisher Copyright:
Copyright © 2021 Tesi, Hulsman, van der Lee, Jansen, Stringa, van Schoor, Scheltens, van der Flier, Huisman, Reinders and Holstege.
PY - 2021/12/21
Y1 - 2021/12/21
N2 - Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.
AB - Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.
KW - aging
KW - alzheimer’s disease
KW - centenarians
KW - cognitively healthy
KW - effect on aging
KW - protective variants
UR - http://www.scopus.com/inward/record.url?scp=85122212387&partnerID=8YFLogxK
U2 - 10.3389/fgene.2021.748781
DO - 10.3389/fgene.2021.748781
M3 - Article
C2 - 34992629
SN - 1664-8021
VL - 12
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 748781
ER -