Title:Could Better Phenotyping Small Vessel Disease Provide New Insights into Alzheimer Disease and Improve Clinical Trial Outcomes?
Volume: 13
Issue: 7
Author(s): Michael Marnane and Ging-Yuek R. Hsiung
Affiliation:
Keywords:
Alzheimer disease, amyloid β, apolipoprotein E, cerebral amyloid angiopathy, small vessel disease, vascular risk
factors, white matter hyperintensities.
Abstract: Alzheimer Disease (AD) is the most common primary cause of dementia with a burgeoning epidemic as life
expectancy and general medical care improve worldwide. Recent data from pathologic studies has shown that the cooccurrence
of other neurodegenerative and vascular pathologies is in fact the rule rather than the exception. In late onset
AD, cerebral small vessel disease (SVD) is almost invariably co-existent to a greater or lesser extent and is known to
promote cognitive deterioration. Previous observational studies and clinical trials have largely sought to divide dementia
based on predominant neurodegenerative or vascular mechanisms. Given the high degree of overlap, findings from such
studies may be difficult to interpret and apply to population cohorts. Additionally opportunities may be lost for uncovering
novel interventions that target interactions between co-existent vascular and neurodegenerative pathologies. In the current
review, we consider potential pathophysiologic mechanisms through which SVD may be associated with and promote
AD pathology. In particular we explore shared environmental and genetic associations and how these may converge via
neuroinflammatory pathways potentially providing novel therapeutic targets. SVD has heterogenous manifestations on
cerebral imaging and at pathology. We discuss how studying SVD topography may enable us to better identify those at
risk for more rapid cognitive decline and improve future clinical trial design.