Cerebral vascular damage from small-vessel disease appears to aggravate the deposition of amyloid, particularly in patients carrying the apolipoprotein E e4 genotype, according to a report 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 (AD) or vascular dementia support "the hypothesis that the pathways of small-vessel disease and AD pathology are interconnected." In addition, the ApoE e4 genotype seems to upregulate this association, said Dr. Maartje I. Kester of the Alzheimer center, department of neurology, Vrije University Medical Center, Amsterdam, and her associates.
"Small-vessel disease could provoke amyloid pathology, while AD-associated cerebral amyloid pathology may lead to auxiliary vascular damage," they noted.
Dr. Kester and her colleagues explored the relationship between small-vessel disease pathology and AD pathology by assessing MRI images of microbleeds, white-matter hyperintensities, and lacunes and correlating these with CSF (cerebrospinal fluid) levels of beta-amyloid 42, total tau, and p-tau. They performed these analyses in 914 patients participating in the Amsterdam Dementia Cohort who had all undergone brain MRI and CSF assessments as part of that study.
For their study, Dr. Kester and her associates included 547 patients diagnosed as having AD, 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 both microbleeds and white-matter intensities were associated with lower CSF levels of beta-amyloid 42, "indicating a direct relationship between [small-vessel disease] and AD pathology." The effects on CSF beta-amyloid 42 levels were largest in patients who carried the ApoE e4 genotype, suggesting "an inducing role" of this genotype "in the relation between AD and vascular pathology," the investigators said.
"It is conceivable that [cerebral amyloid angiopathy], which is commonly seen in patients with AD 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 (JAMA Neurol. 2014 May 12 [doi:10.1001/jamaneurol.2014.754]).
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. Lacunes and AD pathology seem to lead independently to cognitive decline, while a combination of enough additive damage leads to clinical (vascular) dementia," they added.
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 her associates wrote.
This study was supported in part by Alzheimer Nederland and Stichting Dioraphte. Dr. Kester reported no financial conflicts of interest; her associates reported ties to numerous industry sources.