Cerebral Small Vessel Disease as a Contribution to Alzheimer's Disease
For all that a great deal of evidence points to cardiovascular disease as a contributing factor in the development of forms of dementia, there remains debate over the degree to which this is the case, and which aspects of cardiovascular disease are more or less important. Here, researchers on cerebral small vessel disease, a catch-all bucket for all dysfunctions affecting the microvasculature of the brain as a result of the accumulated molecular damage of aging, either directly or indirectly. The visible signs seen in imaging are tiny volumes of damaged tissue where vessels have ruptured. The brain doesn't recover this lost tissue, and over time this is though to have a growing effect on cognitive function. Separately, leakage of the blood-brain barrier likely sets up a disrupted, inflamed metabolism in the brain, the foundation for neurodegenerative conditions such as Alzheimer's disease.
The scientific community widely recognizes that most dementia cases, including Alzheimer's disease, are related to a combination of vascular and neurodegenerative lesions. And cerebral small-vessel disease is thought to be the main underlying contribution to cognitive decline and dementia, with nearly half of dementia cases showing both Alzheimer's and cerebral small-vessel disease neuropathologic characteristics. Still, while observational studies had shown evidence of an association between white matter hyperintensity burden and increased risk of stroke and dementia, causal evidence had been limited. White matter hyperintensities (WMHs) are lesions in the brain that show up as areas of increased brightness in magnetic resonance imaging.
In the new study, researchers were able to provide evidence of a causal link between vascular traits and Alzheimer's disease, using genetic instrument variable analyses known as Mendelian randomization - a method that leverages the natural randomization of genetic alleles to test how differences in the genetic effect on modifiable exposure influence disease risk. Specifically, in a two-year analysis ending in 2022, and using Alzheimer's disease genome-wide association studies of up to 75,000 European dementia cases, they found causal evidence of an association of larger WMH burden with increased risk of the disease, accounting for pulse-pressure effects. "As vascular disease is a treatable contributor to dementia risk, our findings have broad significance for prevention strategies of Alzheimer's and dementia as a whole."