Cerebrovascular Pathology and Responsiveness to Treatment in Alzheimer's Disease: A Systematic Review

Responsiveness to treatment with cholinesterase inhibitors (ChEIs) is difficult to predict in Alzheimer's disease (AD). In the current review, vascular burden is considered as a potential moderator of treatment responsiveness. Cerebrovascular burden co-occurs in at least 30% of AD brains, although it is debated if vascular pathology plays a causal or synergistic role in AD pathogenesis. Vascular burden, therefore, could potentially limit response to treatment due to limited brain reserve or foster treatment efficacy as those with vascular pathology may represent a subgroup with comparable clinical expression but less progressed AD neurodegeneration.

A systematic search of Web of Science, Pubmed, Scopus and EthoS identified 32 papers which met the criteria for inclusion. Association of treatment response and vascular burden across five broad markers are discussed: cerebral hypoperfusion, intima-media thickness, white matter changes, cerebral microbleeds and co-existing diagnosis of cerebrovascular disease.

Analysis of frontal regional cerebral blood flow and intima-media thickness may have predictive ability to distinguish those with AD who may respond optimally to short-term treatment with ChEIs. The impact of white matter changes is less consistent; the majority of studies demonstrates no association with treatment response and those that do implicate changes in executive functioning. There is preliminary evidence that deep cerebral microbleeds limit treatment response in subcortical cognitive domains, but this finding requires replication. The use of diagnosis of co-occurring cerebrovascular disease yields no robust variability in response to ChEIs in AD.

There is limited evidence that markers of cerebral hypoperfusion, intima-media thickness and cerebral microbleeds moderate response to ChEIs. Findings for other markers of vascular burden are less consistent and do not support any moderating effect.