Imaging Vascular Disease and Amyloid in the Aging Brain: Implications for Treatment

Abstract

Vascular risk factors (e.g. hypertension, dyslipidemia and diabetes) are well known risk factors for Alzheimer' disease. These vascular risk factors lead to vascular brain injuries, which also increase the likelihood of dementia. The advent of amyloid PET imaging has helped establish that vascular risk factors also lead to Alzheimer's disease via pathways that are independent from vascular brain injuries, at least, when vascular brain injuries are measured as white matter lesions and infarcts. While vascular brain injuries (white matter lesions and infarcts) do not seem to influence amyloid pathology, some evidence from amyloid imaging suggests that increased vascular risk is related to increased amyloid burden. Furthermore, while vascular brain injuries and amyloid have an additive and independent impact on brain integrity, vascular risk factors might potentiate the impact of amyloid on cortical thickness on brain regions vulnerable to Alzheimer's disease. New research should further explore and confirm, or refute, possible interactions between amyloid and vascular risk factors on brain integrity and cognition. Neuroimaging tools used to assess vascular brain integrity should also be expanded. Measuring cortical blood flow or damage to the capillary system might, for instance, give insight about how vascular risk factors can be associated to amyloid burden and impact. These findings also stress the need for monitoring vascular risk factors in midlife as a strategy for Alzheimer's disease prevention.

Keywords: Alzheimer’ disease; amyloid; treatment; vascular brain injuries; vascular risk factors.

Fig. 1. Independent Alzheimer and vascular pathways: an autopsy based model

Autopsy studies suggest that Alzheimer and vascular pathologies increase the risk of AD via independent and additive pathways. Because both pathologies frequently co-occur and because vascular risk factors such as hypertension and diabetes are well known risk factors for AD, mixed dementia is often considered the most frequent type of dementia. VBI : vascular brain injuries Aβ: amyloid-beta

Fig. 2. Alzheimer and vascular independent and shared pathways : an in-vivo based model

Proposed conception of the relationship between AD and vascular factors. While Aβ burden and vascular brain injuries (VBI, white matter lesions and infarcts) still have distinct pathways, vascular risk factors are associated with both Aβ burden and VBI. Vascular risk factors are also associated with brain integrity via a pathway that is independent from Aβ and VBI. Accordingly, vascular risk factors should be a particular target for prevention. Aβ: amyloid-beta BBB: blood brain carrier CBF: cerebral blood flow

Fig 3. Impact of Aβ, VBI and vascular risk factors on cortical thickness in older adults with a spectrum of vascular diseases

Statistical cortical maps showing the association among Aβ, VBI (white matter hyperintensity), vascular risk (FCRP score) and cortical thickness in a sample of 66 older (64 for VBI) adults enriched for vascular diseases. Results suggest that increased vascular risk, increased Aβ burden and increased VBI are associated with thinner cortex. Statistical surface maps were created using a vertex-wise statistical thresholds of p < 0.05. The analyses are corrected for age, cognitive status, and multiple comparisons. This figure is based on a previously publication