Research team finds genetic risk-factor overlap between Alzheimer’s disease, and all-cause and vascular dementias

In landmark research, scientists at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) have reported the largest-ever genome-wide association study of dementia from all causes, 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 exploring 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 all-cause dementia and vascular dementia, respectively.

“Dementia is a multifactorial disease with Alzheimer’s disease and vascular dementia pathologies making the largest contributions—and yet, most genome-wide association studies focus just on Alzheimer’s disease,” said Bernard Fongang, Ph.D., with the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio. “We conducted such a study of all-cause dementia and discovered a substantial genetic overlap with vascular dementia.”

Fongang, who also is 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 corresponding contact for the study titled “A genome-wide association meta-analysis of all-cause and vascular dementia,” published July 24 in Alzheimer’s & Dementia.

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

Two clinically distinct dementias

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

Vascular dementia is diagnosed based on the presence of stroke or extensive cerebral vascular disease, with atherosclerosis and arteriolosclerosis considered the underlying pathologies. But a wealth of evidence from recent years has emphasized a broad role for brain vascular damage as a major mechanism for cognitive impairment.

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

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

Its vast dataset drew 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), encompassing four different reported ancestries: 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,” Fongang said. “We 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 dementia pathogenesis.”

The study concluded that the results should be validated in additional datasets including non-European individuals.