Study finds evidence of causal link between cerebral small vessel disease and Alzheimer's and dementia

Results from a large international study highlight the importance of a feature known as white matter hyperintensity (WMH) burden in dementia prevention strategies.

“Our findings provide converging evidence that WMHs are a key vascular factor associated with dementia risk,” said Muralidharan Sargurupremraj, PhD, assistant professor in the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases at UT Health San Antonio, “and support WMHs as a surrogate marker for clinical trials to prevent dementia by controlling vascular risk.”

Sargurpremraj is first author and co-corresponding author of the study, published May 22, titled “Genetic Complexity of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.” JAMA Network OpenA monthly open access medical journal published by the American Medical Association.

According to studies, with increasing life expectancy, the prevalence of dementia is expected to reach 75 million people worldwide by 2030, making devising strategies to prevent or delay its onset a major public health priority. It is widely recognized in the scientific community that most cases of dementia, including Alzheimer's disease, are associated with a combination of vascular and neurodegenerative pathologies.

Cerebral small vessel disease is also thought to be an underlying cause of cognitive decline and dementia, with studies pointing out that nearly half of dementia cases show neuropathological features of both Alzheimer's disease and cerebral small vessel disease.

Nevertheless, although observational studies have shown evidence of an association between white matter hyperintensity burden and increased risk of stroke and dementia, evidence of a causal relationship is limited.White matter hyperintensities are lesions in the brain that appear as areas of increased brightness on T2-weighted magnetic resonance images.

In the new study, the researchers were able to provide evidence of a causal relationship between vascular traits and Alzheimer's disease using a gene-counting variable analysis called Mendelian randomization, a method that takes advantage of the natural randomization of gene alleles to test how differences in gene effects in response to modifiable exposures affect disease risk.

Specifically, using the Alzheimer's Disease Genome-Wide Association Study of up to 75,000 European dementia cases in a two-year analysis up to 24 July 2022, and taking into account the pulse pressure effect, we found causal evidence showing an association between increasing WMH burden and increased disease risk.

The study also highlighted the importance of combining several complementary epidemiological approaches and data types, and of considering the caveats of instrumental variable analysis, when investigating the impact of vascular characteristics on late-onset diseases such as dementia.

“Because vascular disease is a treatable contributing factor to dementia risk, our findings have broad implications for prevention strategies for Alzheimer's disease and dementia overall,” Sargurpremraj concluded.

The researchers recommend future studies to examine whether their findings can be generalized to people of non-European descent.

Other institutions and organisations that took part in the study included University of Bordeaux (France), Washington University, University of Michigan, University of Tartu (Estonia), Erasmus MC University Medical Center (Rotterdam, Netherlands), Boston University and the National Heart, Lung and Blood Institute Framingham Heart Study, Icelandic Heart Association (Iceland), Washington University in St. Louis, University of Oxford (UK), Public Health Bordeaux (France), University of Pittsburgh, University of Lille (France), Radboud University Nijmegen (Netherlands), Santiago Adolfo Ibáñez University (Chile), University of Iceland (Iceland), Oslo University Hospital (Norway), Norwegian University of Science and Technology, Imperial College London (UK), National Institute on Aging, and University Hospital of Bordeaux (France).

UT Health San Antonio is a flagship of San Antonio's $44.1 billion healthcare and bioscience sector and the largest academic research institution in South Texas with an annual research portfolio of $413 million.