Genome-wide association study identifies genetic risk factors for dementia

In groundbreaking research, scientists at the University of Texas Health Science Center at San Antonio (UT Health San Antonio) reported the largest ever genome-wide association study of all-cause dementia, revealing an overlap of genetic risks including neurodegeneration, vascular factors and cerebral small vessel disease.

Genome-wide association studies help scientists identify genes associated with a particular disease or trait by examining the entire set of DNA, or genome, of a large group of people – in this case a dataset of 800,597 individuals, with 46,902 and 8,702 cases of dementia from all causes and vascular dementia.

Dementia is a multifactorial disease with Alzheimer’s disease and vascular dementia pathologies being the major contributors – yet most genome-wide association studies focus exclusively on Alzheimer’s disease. We conducted such a study of all-cause dementia and found substantial genetic overlap with vascular dementia.”

Bernard Fongang, PhD, Assistant Professor of Bioinformatics, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio

Fongang, who is also affiliated with the departments of biochemistry and structural biology, and population health sciences, at the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio, is a corresponding contact for the study titled, “A Genome-Wide Association -meta-analysis of all-cause dementia and vascular dementia,” published July 24 by Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.

The study’s author is credited as the Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium, an international consortium of cohorts focused on the genetics of vascular cognitive impairment and dementia.

Two clinically different forms of dementia

According to the study, Alzheimer’s disease is traditionally considered the most common subtype of dementia, followed by vascular dementia. However, the two conditions are clinically different.

Vascular dementia is diagnosed based on the presence of stroke or extensive brain disease, with atherosclerosis and arteriolosclerosis considered to be the underlying pathologies. However, a wealth of evidence in recent years has highlighted the broad role of cerebral vascular damage as an important mechanism for cognitive impairment.

It is now increasingly recognized that a component of vascular pathology is prominent in all severe forms of dementia and acts synergistically with amyloid beta, tau and other neurodegenerative pathologies to influence dementia risk, the study notes.

Because most genome-wide association studies focused on Alzheimer’s disease, highlighting multiple genetic risk variants, Fongang’s team conducted such a study on all-cause dementia and examined the genetic overlap with vascular dementia.

The massive data set came from individuals comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the Alzheimer’s Disease Genetics Consortium (ADGC), the European Alzheimer Disease Biobank (EADB) and the UK Biobank (UKBB), which included four different reported ancestry: European (98.5%), African (1.0%), Asian (0.4%), and Hispanics/Latino (0.1%).

Known genetic variants associated with Alzheimer’s disease were replicated for all-cause dementia and vascular dementia. Functional analysis revealed the overlap of genetic risks of all-cause dementia with neurodegeneration, vascular risk factors such as hypertension and diabetes, and cerebral small vessel disease.

Essentially, known genetic variants for Alzheimer’s disease were identified as risk factors for all-cause dementia and vascular dementia.

“Our findings expand the current knowledge base of dementia genetics by focusing on both all-cause dementia and vascular dementia,” said Fongang. “We have identified several putative genetic variants and biological pathways associated with all-cause dementia and vascular dementia, and added additional support for the involvement of vascular mechanisms in the pathogenesis of dementia.”

The study concluded that the results need to be validated in additional data sets, including non-European individuals. UT Health San Antonio is the largest academic research institution in South Texas, with an annual research portfolio of $413 million.