Genetics of vascular dementia – review from the ICVD working group

Ikram, M. Arfan; Bersano, Anna; Manso-Calderón, Raquel; Jia, Jianping; Schmidt, Helena; Middleton, Lefkos T.; Nacmias, Benedetta; Siddiqi, Saima; Adams, Hieab H.H.

doi:10.1186/s12916-017-0813-9

Cited by 64 publications

(27 citation statements)

References 61 publications

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“…The main strength of the study is the proxy-phenotype approach, which resulted in over 42,000 proxy cases for the GWAS analysis. However, the question used to determine parental AD status may have resulted in some responders being unable to discriminate Alzheimer’s disease and dementia from other dementia sub-types, which have different presentations and genetic architectures 35 , 36 . This method of proxy-case ascertainment may have influenced the loci uncovered.…”

Section: Discussionmentioning

confidence: 99%

GWAS on family history of Alzheimer’s disease

et al. 2018

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Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P < 5 × 10−8) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.

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Section: Discussionmentioning

confidence: 99%

GWAS on family history of Alzheimer’s disease

et al. 2018

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“…6 However, the question used to determine parental AD status may have resulted in some responders being unable to discriminate Alzheimer’s disease and dementia from other dementia sub-types, which have different presentations and genetic architectures. 53,54 This method of proxy-case ascertainment may have influenced the loci uncovered. Parental dementia status is partly dependent on longevity, with age being the biggest risk factor for AD.…”

Section: Discussionmentioning

confidence: 99%

GWAS on family history of Alzheimer’s disease

Marioni

Harris

McRae

et al. 2018

Preprint

119

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Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. Using self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of over 300,000 participants from UK Biobank (32,222 maternal cases, 16,613 paternal cases) and meta-analysing with published consortium data (n=74,046 with 25,580 cases across the discovery and replication analyses), six new AD-associated loci (P<5x10−8) are identified. Three contain genes relevant for AD and neurodegeneration: ADAM10, ADAMTS4, and ACE. Suggestive loci include drug targets such as VKORC1 (warfarin dose) and BZRAP1 (benzodiazepine receptor). We report evidence that association of SNPs and AD at the PVR gene is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, given that many are existing drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.

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“…Cross-sectional studies were eligible if they assessed ePVS on MRI for patients with dementia and controls. Moreover, NOCTH 3 gene hereditary disorder, i.e., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which are likely to affect cognition due to vascular damage were also included [14]. Other conditions such as traumatic brain injury, sleep disturbance, or hydrocephalus which may affect the cerebral drainage system through non-vascular causes were excluded.…”

Section: Study Selectionmentioning

confidence: 99%

Enlarged Perivascular Spaces and Dementia: A Systematic Review

Smeijer

Ikram

Hilal

2019

JAD

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Perivascular compartments surrounding the penetrating arteries in the brain are part of a physiologic system, which facilitates fluids exchange and clearance of solutes from the brain. The perivascular compartments become visible on MRI when enlarged and are commonly referred to as perivascular spaces (ePVS). Previous studies on the association between ePVS and dementia have been inconsistent due to varying methods of measuring ePVS. As a frame of reference for future MRI studies on ePVS, we systematically review the literature on ePVS as a marker of vascular brain injury related to dementia from population-based as well as hospital-based settings. We identified three longitudinal and ten cross-sectional studies involving 7,581 persons. Potential outcomes were all-cause dementia, Alzheimer's disease, and vascular dementia. There was considerable heterogeneity in ePVS assessment: with studies using either visual inspection or segmentation, examining different brain locations and implementing different grading scales. Moreover, out of the total of 13 studies, all five studies on vascular dementia reported an association with presence of basal ganglia ePVS after adjustment for age, gender, and white matter hyperintensities. For seven studies on Alzheimer's disease and all-cause dementia, the results were ambiguous. This review did not identify an independent association of ePVS with prevalent or incident dementia. Harmonized methods for ePVS assessment, tested across different populations, may benefit future MRI studies on ePVS and dementia.

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Genetics of vascular dementia – review from the ICVD working group

Cited by 64 publications

References 61 publications

GWAS on family history of Alzheimer’s disease

GWAS on family history of Alzheimer’s disease

GWAS on family history of Alzheimer’s disease

Enlarged Perivascular Spaces and Dementia: A Systematic Review

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