Candidate gene analysis for Alzheimer's disease in adults with Down syndrome

Abstract

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer’s disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid β levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5–2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules.

Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s Disease

“…Both our human and mouse spatial datasets are the largest of our knowledge (n=119 total), altogether representing a rich data resource for the AD community. We identified regional differential gene expression changes shared between AD in the general population and DS, in line with previous accounts of shared genetic, clinical, and biomarker features 27,78,79 . Further, we generated the first snRNA-seq study of AD in DS and integrated previously published AD studies to identify cellular changes conserved between both populations.…”

Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s Disease

“…Both our human and mouse spatial datasets are the largest of our knowledge (n=119 total), altogether representing a rich data resource for the AD community. We identified regional differential gene expression changes shared between AD in the general population and DS, in line with previous accounts of shared genetic, clinical, and biomarker features 27,78,79 . Further, we generated the first snRNA-seq study of AD in DS and integrated previously published AD studies to identify cellular changes conserved between both populations.…”

Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome

“…A recent study in organoids generated from trisomy 21 iPSCs demonstrated that three copies of BACE2 protect against amyloid-β accumulation in that system [ 16 ]. These findings are consistent with gene-association studies implicating these genes in AD-risk in individuals who have DS [ 34 – 36 ].…”

Endosomal structure and APP biology are not altered in preclinical cellular models of Down syndrome

“…A recent study in organoids generated from trisomy 21 iPSCs demonstrated that three copies of BACE2 protect against amyloid-β accumulation in that system [17]. These findings are consistent with gene-association studies implicating these genes in AD-risk in individuals who have DS [34][35][36].…”

Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s Disease

“…Both our human and mouse spatial datasets are the largest of our knowledge (n=119 total), altogether representing a rich data resource for the AD community. We identified regional differential gene expression changes shared between AD in the general population and DS, in line with previous accounts of shared genetic, clinical, and biomarker features 27,78,79 . Further, we generated the first snRNA-seq study of AD in DS and integrated previously published AD studies to identify cellular changes conserved between both populations.…”

Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome

“…A recent study in organoids generated from trisomy 21 iPSCs demonstrated that three copies of BACE2 protect against amyloid-β accumulation in that system [ 16 ]. These findings are consistent with gene-association studies implicating these genes in AD-risk in individuals who have DS [ 34 – 36 ].…”

Endosomal structure and APP biology are not altered in preclinical cellular models of Down syndrome

“…A recent study in organoids generated from trisomy 21 iPSCs demonstrated that three copies of BACE2 protect against amyloid-β accumulation in that system [17]. These findings are consistent with gene-association studies implicating these genes in AD-risk in individuals who have DS [34][35][36].…”

Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s Disease

“…Both our human and mouse spatial datasets are the largest of our knowledge (n=119 total), altogether representing a rich data resource for the AD community. We identified regional differential gene expression changes shared between AD in the general population and DS, in line with previous accounts of shared genetic, clinical, and biomarker features 27,78,79 . Further, we generated the first snRNA-seq study of AD in DS and integrated previously published AD studies to identify cellular changes conserved between both populations.…”

Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome

“…A recent study in organoids generated from trisomy 21 iPSCs demonstrated that three copies of BACE2 protect against amyloid-β accumulation in that system [ 16 ]. These findings are consistent with gene-association studies implicating these genes in AD-risk in individuals who have DS [ 34 – 36 ].…”

Endosomal structure and APP biology are not altered in preclinical cellular models of Down syndrome

“…A recent study in organoids generated from trisomy 21 iPSCs demonstrated that three copies of BACE2 protect against amyloid-β accumulation in that system [17]. These findings are consistent with gene-association studies implicating these genes in AD-risk in individuals who have DS [34][35][36].…”