scholarly journals The effect of Alzheimer’s disease-associated genetic variants on longevity

2021 ◽  
Author(s):  
Niccolò Tesi ◽  
Marc Hulsman ◽  
Sven J. van der Lee ◽  
Iris E. Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Longevity ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Immune Signaling ◽  
Age Related ◽  
Increased Risk ◽  
Parental Longevity ◽  
Effect Size Distribution

AbstractThe genetics underlying human longevity is influenced by the genetic risk to develop -or escape- age-related diseases. As Alzheimer’s disease (AD) represents one of the most common conditions at old age, an interplay between genetic factors for AD and longevity is expected.We explored this interplay by studying the prevalence of 38 AD-associated single-nucleotide-polymorphisms (SNPs) identified in AD-GWAS, in self-reported cognitively healthy centenarians, and we replicated findings in the largest GWAS on parental-longevity.We found that 28/38 SNPs identified to associate with increased AD-risk also associated with decreased odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. When grouping the SNPs based on these distributions, we found three groups: 17 variants increased AD-risk more than they decreased the risk of longevity (AD-group): these variants were functionally enriched for β-amyloid metabolism and immune signaling, and they were enriched in microglia. 11 variants reported a larger effect on longevity as compared to their AD-effect (Longevity-group): these variants were enriched for endocytosis/immune signaling, and at the cell-type level were enriched in microglia and endothelial cells. Next to AD, these variants were previously associated with other aging-related diseases, including cardiovascular and autoimmune diseases, and cancer. Unexpectedly, 10 variants associated with an increased risk of both AD and longevity (Unexpected-group). The effect of the SNPs in AD- and Longevity-groups replicated in the largest GWAS on parental-longevity, while the effects on longevity of the SNPs in the Unexpected-group could not be replicated, suggesting that these effects may not be robust across different studies.Our study shows that some AD-associated variants negatively affect longevity primarily by their increased risk of AD, while other variants negatively affect longevity through an increased risk of multiple age-related diseases, including AD.

scholarly journals The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

2021 ◽  
Vol 12 ◽  
Author(s):  
Niccolò Tesi ◽  
Marc Hulsman ◽  
Sven J. van der Lee ◽  
Iris E. Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Longevity ◽  
Longevity Risk ◽  
Nucleotide Polymorphisms ◽  
Immune Signaling ◽  
Factors Affecting ◽  
Age Related ◽  
Increased Risk ◽  
Parental Longevity

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.

Gene polymorphisms associated with an increased risk of exudative age-related macular degeneration in a Spanish population

2021 ◽  
pp. 112067212110026
Author(s):  
Pablo Gili ◽  
Leyre Lloreda Martín ◽  
José-Carlos Martín-Rodrigo ◽  
Naon Kim-Yeon ◽  
Laura Modamio-Gardeta ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Gene Polymorphisms ◽  
Age Related Macular Degeneration ◽  
Spanish Population ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Exudative Amd ◽  
Age Related ◽  
Increased Risk

Purpose: To identify the association between single-nucleotide polymorphisms (SNPs) in CFH, ARMS2, HTRA1, CFB, C2, and C3 genes and exudative age-related macular degeneration (AMD) in a Spanish population. Methods: In 187 exudative AMD patients and 196 healthy controls (61% women, mean age 75 years), 12 SNPs as risk factors for AMD in CFH (rs1410996, rs1061170, r380390), ARMS2 (rs10490924, rs10490923), HTRA1 (rs11200638), CFB (rs641153), C2 (rs547154, rs9332739), and C3 (rs147859257, rs2230199, rs1047286) genes were analyzed. Results: The G allele was the most frequent in CFH gene (rs1410996) with a 7-fold increased risk of AMD (OR 7.69, 95% CI 3.17–18.69), whereas carriers of C allele in CFH (rs1061170) showed a 3-fold increased risk for AMD (OR 3.22, 95% CI 1.93–5.40). In CFH (rs380390), the presence of G allele increased the risk for AMD by 2-fold (OR 2.52, 95% CI 1.47–4.30). In ARMS2 (rs10490924), the T-allele was associated with an almost 5-fold increased risk (OR 5.49, 95% CI 3.23–9.31). The A allele in HTRA1 (rs11200638) was more prevalent in AMD versus controls (OR 6.44, 95% CI 3.62–11.47). In C2 gene (rs9332739) the presence of C increased risk for AMD by 3-fold (OR 3.10, 95% CI 1.06–9.06). Conclusion: SNPs in CFH, ARMS2, HTRA1, and C2 genes were associated in our study with an increased risk for exudative AMD in Spanish patients.

scholarly journals Polymorphisms inHSD17B1: Early Onset and Increased Risk of Alzheimer’s Disease in Women with Down Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Joseph H. Lee ◽  
Susan Gurney ◽  
Deborah Pang ◽  
Alexis Temkin ◽  
Naeun Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Age At Onset ◽  
Nucleotide Polymorphisms ◽  
Risk Alleles ◽  
Increased Risk ◽  
Estrogen Activity ◽  
Intron 4

Background/Aims. Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). In women with Down syndrome, we examined the relation of polymorphisms in hydroxysteroid-17beta-dehydrogenase (HSD17B1) to age at onset and risk of AD.HSD17B1encodes the enzyme 17β-hydroxysteroid dehydrogenase (HSD1), which catalyzes the conversion of estrone to estradiol.Methods. Two hundred and thirty-eight women with DS, nondemented at baseline, 31–78 years of age, were followed at 14–18-month intervals for 4.5 years. Women were genotyped for 5 haplotype-tagging single-nucleotide polymorphisms (SNPs) in theHSD17B1gene region, and their association with incident AD was examined.Results. Age at onset was earlier, and risk of AD was elevated from two- to threefold among women homozygous for the minor allele at 3 SNPs in intron 4 (rs676387), exon 6 (rs605059), and exon 4 inCOASY(rs598126). Carriers of the haplotype TCC, based on the risk alleles for these three SNPs, had an almost twofold increased risk of developing AD (hazard ratio = 1.8, 95% CI, 1.1–3.1).Conclusion. These findings support experimental and clinical studies of the neuroprotective role of estrogen.

IL-1β, IL-6, IL-10, and TNFα Single Nucleotide Polymorphisms in Human Influence the Susceptibility to Alzheimer’s Disease Pathology

2020 ◽  
Vol 75 (3) ◽  
pp. 1029-1047 ◽  
Author(s):  
Mirjana Babić Leko ◽  
Matea Nikolac Perković ◽  
Nataša Klepac ◽  
Dubravka Švob Štrac ◽  
Fran Borovečki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Human Influence ◽  
Single Nucleotide

scholarly journals Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms

2020 ◽  
Vol 73 (1) ◽  
pp. 135-145
Author(s):  
Mirjana Babić Leko ◽  
Matea Nikolac Perković ◽  
Nataša Klepac ◽  
Dubravka Švob Štrac ◽  
Fran Borovečki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Disease Biomarkers

scholarly journals Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

2019 ◽  
Vol 9 (10) ◽  
pp. 262 ◽  
Author(s):  
Hayden
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Late Onset ◽  
Neurovascular Unit ◽  
Age Related ◽  
Increased Risk

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease–dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments and metabolic factors, which increase the cellular vulnerability to develop an increased risk of age-related LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. Aging (chronic age-related diseases); ii. metabolic (hyperglycemia advanced glycation end products and its receptor (AGE/RAGE) interactions and hyperinsulinemia-insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen–nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis—vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

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