Editors' ChoiceDEMENTIA

AD and CAA: Independent risk factors for dementia

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Science Translational Medicine  16 Dec 2015:
Vol. 7, Issue 318, pp. 318ec214
DOI: 10.1126/scitranslmed.aad9005

Neuropathological studies have established that over 90% of Alzheimer's disease (AD) patients with confirmed plaques and tangles also have cerebral amyloid angiopathy (CAA), which involves infiltration of the brain's blood vessels with amyloid. The incidence of CAA in the nondemented elderly is also high, estimated at 20 to 40%. This overlap between classic AD and vascular brain pathology in dementia has been difficult to separate, given that both are associated with aging and the relative risk of dementia for those with CAA has been difficult to ascertain. In new work, Boyle et al. analyzed clinical and pathological outcomes in more than a thousand elderly subjects in community-based settings to test the hypothesis that independent of AD brain pathology, CAA also is associated with an increased risk of dementia.

The authors examined the relationship between CAA and AD using logistic regression, and the association of CAA with cognitive decline was then examined using linear mixed models that corrected for age, sex, education, and the presence of AD, stroke, and other underlying pathologies. Boyle et al. reported a decline in cognition across multiple domains as a function of the severity of CAA. Not only does this study confirm that CAA is strongly associated with AD, but it also shows that CAA is independently associated with dementia, after controlling for the severity of plaques and tangles and other prevalent brain pathology. This expands upon prior work by the same group showing that a majority of community-dwelling elderly persons have multiple types of incident brain pathology. Persons with AD pathology were previously shown to have a fourfold increased risk of dementia, whereas those with multiple underlying pathologies had a 10-fold increased risk. The new data demonstrate that the specific CAA contribution to dementia is significant. By examining both large and small blood vessels, the study also indicates that dementia is not simply related to microvascular disease, but rather the sum total of CAA burden. Other population-based studies and meta-analyses have examined the role of CAA in vascular dementia, but this study draws from an unbiased cohort of community-based elderly adults and rigorously adjusts for other prevalent conditions of aging.

There is still debate as to whether vascular dementia and AD are part of the same continuum of disease or represent distinct entities. To quote Nobel laureate Roald Hoffman, they are paradoxically "the same and not the same," which is manifest in the variety of amyloid precursor protein mutations that can cause either AD or CAA or both. Despite limitations in the amyloid cascade hypothesis, the fact remains that every hereditary form of AD is directly or indirectly involved with amyloid processing, and recent data suggest that the attributable risk of amyloid burden for dementia is over 50%. The translational significance of the Boyle et al. study is that AD and vascular dementia probably exist as a continuum of distinct but mechanistically related processes. As the classification of vascular and mixed dementia is further refined, it is clear that there is considerable pathological heterogeneity, and therapies aimed at CAA also may benefit AD.

P. A. Boyle et al., Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology 85, 1930–1936 (2015). [Abstract]

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