Cerebral vascular damage from small-vessel disease appears to aggravate the deposition of amyloid, particularly in patients who have the APOE ε4 genotype, according to a study published online May 12 in JAMA Neurology.
This and other findings from a cross-sectional cohort study involving 914 Dutch patients with Alzheimer’s disease or vascular dementia support “the hypothesis that the pathways of small-vessel disease and Alzheimer’s disease pathology are interconnected,” reported Maartje I. Kester, MD, of the Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, and colleagues. In addition, the APOE ε4 genotype seems to upregulate this association, according to the researchers.
“Small-vessel disease could provoke amyloid pathology, while Alzheimer’s disease–associated cerebral amyloid pathology may lead to auxiliary vascular damage,” the researchers noted.
Dr. Kester and her colleagues explored the relationship between small-vessel disease pathology and Alzheimer’s disease pathology by assessing MRI images of microbleeds, white-matter hyperintensities, and lacunes and correlating these with CSF levels of beta-amyloid 42, total tau, and p-tau. The investigators performed these analyses in 914 patients participating in the Amsterdam Dementia Cohort who had all undergone brain MRI and CSF assessments.
Dr. Kester and her associates included 547 patients diagnosed as having Alzheimer’s disease, 30 patients diagnosed as having vascular dementia, and 337 patients with subjective memory complaints but no dementia, who served as control subjects.
The researchers found that microbleeds and white matter intensities were associated with lower CSF levels of beta-amyloid 42, “indicating a direct relationship between [small-vessel disease] and Alzheimer’s disease pathology.” The effects on CSF beta-amyloid 42 levels were largest in patients who carried the APOE ε4 genotype, suggesting “an inducing role” of this genotype “in the relation between Alzheimer’s disease and vascular pathology,” the investigators reported.
“It is conceivable that [cerebral amyloid angiopathy], which is commonly seen in patients with Alzheimer’s disease and is associated with parenchymal amyloid, may lead to ischemic vascular events in the brain like [white matter hyperintensities], microinfarcts, and [microbleeds]. Conversely, ischemic changes could accelerate the rate of amyloid deposition, and vessel wall stiffness may impair perivascular drainage of cerebral amyloid, both leading to more deposition,” Dr. Kester and her associates wrote.
Lacunes appeared to represent a different type of pathology. “We found a positive association between [beta-amyloid 42] and lacunes in patients with [vascular dementia], indicating that lacunes are associated with lower amounts of amyloid in the brain,” the researchers stated. “Lacunes and Alzheimer’s disease pathology seem to lead independently to cognitive decline, while a combination of enough additive damage leads to clinical (vascular) dementia.”
One limitation of the study is that the number of patients with vascular dementia was fairly small. “However, pure [vascular dementia] is a rare disorder and large data sets are difficult to attain,” Dr. Kester and colleagues wrote.
—Mary Ann Moon