<i><scp>ABCA</scp>7</i> and risk of dementia and vascular disease in the Danish population

Kjeldsen, Emilie Westerlin; Tybjærg‐Hansen, Anne; Nordestgaard, Børge G.; Frikke‐Schmidt, Ruth

doi:10.1002/acn3.506

Cited by 13 publications

(8 citation statements)

References 48 publications

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“…Stronger association with AMD was observed for another ABCA7 SNP (rs3752228), which was not in LD with any of the ABCA7 AD sentinel SNPs, hence suggesting a possible role of ABCA7 in AMD, but most likely through a different mechanism than AD [66]. Finally, a recent study examined the effect of ABCA7 sentinel SNP rs4147929 on vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, and lipid levels in 104,258 individuals from the Danish general population, but did not observe an association with these endophenotypes [67].…”

Section: Introductionmentioning

confidence: 99%

The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics

2019

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Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 ( ABCA7 ), as a novel risk gene of Alzheimer’s disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human-based studies has corroborated and extended this association, promoting ABCA7 as one of the most important risk genes of both early-onset and late-onset AD, harboring both common and rare risk variants with relatively large effect on AD risk. Within this review, we provide a comprehensive assessment of the literature on ABCA7 , with a focus on AD-related human -omics studies (e.g. genomics, transcriptomics, and methylomics). In European and African American populations, indirect ABCA7 GWAS associations are explained by expansion of an ABCA7 variable number tandem repeat (VNTR), and a common premature termination codon (PTC) variant, respectively. Rare ABCA7 PTC variants are strongly enriched in AD patients, and some of these have displayed inheritance patterns resembling autosomal dominant AD. In addition, rare missense variants are more frequent in AD patients than healthy controls, whereas a common ABCA7 missense variant may protect from disease. Methylation at several CpG sites in the ABCA7 locus is significantly associated with AD. Furthermore, ABCA7 contains many different isoforms and ABCA7 splicing has been shown to associate with AD. Besides associations with disease status, these genetic and epigenetic ABCA7 markers also showed significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human-based –omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism, and future studies should make clear if interventions on ABCA7 expression can serve as a valuable therapeutic target for AD.

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Section: Introductionmentioning

confidence: 99%

The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics

2019

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“…The above results indicate that SORL1 rs11218343 and ABCA7 rs4147929 are associated with AD in the Hong Kong Chinese population. To further characterize the risk effects of these two variants in AD, their association results from the other AD cohorts were retrieved and compared 2,38‐46 . Notably, the C allele of SORL1 rs11218343 exhibited a concordant AD protective effect in multiple ethnic groups including European‐descent cohorts, 38 Japanese and Korean cohorts, 39 and a mainland Chinese cohort 42 .…”

Section: Resultsmentioning

confidence: 99%

“…For SORL1 rs11218343 and ABCA7 rs4147929, AD association results (i.e., odds ratios and 95% confidence intervals) from previous studies on SORL1 2,38‐43 and ABCA7 2,41,44‐46 were converted to β ‐values with standard errors and submitted to METASOFT (v2.0.1) for meta‐analysis using Han and Eskin's random effects model (RE2) 47 . Heterogeneity was estimated by calculating Cochrane's Q and I 2 .…”

Section: Methodsmentioning

confidence: 99%

Genetic and polygenic risk score analysis for Alzheimer's disease in the Chinese population

Zhou

Chen

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

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Introduction Dozens of Alzheimer's disease (AD)‐associated loci have been identified in European‐descent populations, but their effects have not been thoroughly investigated in the Hong Kong Chinese population. Methods TaqMan array genotyping was performed for known AD‐associated variants in a Hong Kong Chinese cohort. Regression analysis was conducted to study the associations of variants with AD‐associated traits and biomarkers. Lasso regression was applied to establish a polygenic risk score (PRS) model for AD risk prediction. Results SORL1 is associated with AD in the Hong Kong Chinese population. Meta‐analysis corroborates the AD‐protective effect of the SORL1 rs11218343 C allele. The PRS is developed and associated with AD risk, cognitive status, and AD‐related endophenotypes. TREM2 H157Y might influence the amyloid beta 42/40 ratio and levels of immune‐associated proteins in plasma. Discussion SORL1 is associated with AD in the Hong Kong Chinese population. The PRS model can predict AD risk and cognitive status in this population.

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“…The present findings may emphasize the blood–brain barrier as a delicate border structure between brain and vasculature and supports the now widespread understanding of mixed pathology in most dementia cases. Thus, it is biologically meaningful that disruptions in this pathway affect both brain and vascular disease, in contrast to other dementia susceptibility genes, that exert their effects only in brain [ 65 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

Blood–brain barrier transcytosis genes, risk of dementia and stroke: a prospective cohort study of 74,754 individuals

et al. 2019

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To test whether genetic variants in PICALM , BIN1 , CD2AP , and RIN3 —suggested to be involved in blood–brain barrier amyloid-β transcytosis pathways—associate with Alzheimer’s disease, all dementia, suggested vascular dementia, and stroke, and whether such associations are independent of the strong ε4 APOE risk allele. In a prospective cohort study of 74,754 individuals from the general population we genotyped PICALM (rs10792832), BIN1 (rs6733839), CD2AP (rs10948363), and RIN3 (rs10498633), and generated a weighted and a simple allele score. Multifactorially adjusted hazard ratios for the fourth quartile versus the first quartile of the weighted allele score were 1.42 (95% confidence interval 1.22–1.64) for Alzheimer’s disease, and 1.33 (1.19–1.48) for all dementia. For suggested vascular dementia and stroke the corresponding estimates were 1.71 (1.18–2.49) and 1.12 (1.04–1.22), respectively. Hazard ratios were similar after APOE adjustment. Genetic variants in PICALM , BIN1 , CD2AP , and RIN3 are associated with increased risk of Alzheimer’s disease, all dementia, and suggested vascular dementia independent of the strong APOE ε4 allele. These findings may suggest that clathrin-mediated endocytosis in clearance of amyloid-β across the blood–brain barrier is important for the integrity of both brain tissue and cerebral vessels. Electronic supplementary material The online version of this article (10.1007/s10654-019-00498-2) contains supplementary material, which is available to authorized users.

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ABCA7 and risk of dementia and vascular disease in the Danish population

Cited by 13 publications

References 48 publications

The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics

The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics

Genetic and polygenic risk score analysis for Alzheimer's disease in the Chinese population

Blood–brain barrier transcytosis genes, risk of dementia and stroke: a prospective cohort study of 74,754 individuals

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