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Brain Microbleeds May Cause Amyloid Plaques

Brain microbleeds are the result of small hemorrhages in the brain. In a laboratory model of AD, amyloid plaques developed near microbleeds, suggesting that the damage caused by microbleeds may seed amyloid plaques and lead to AD pathology.

Age, sex, and APOE4 status influenced the size and number of microbleeds. With increasing age, the number of microbleeds increased, but their size did not. Females fared worse than males, with more and larger microbleeds. The presence of the APOE4 gene increased the number of microbleeds further, with females once again affected to a greater extent. 

This study demonstrates that microbleeds, and therefore amyloid plaques, are exacerbated by the risk factors of age, sex, and APOE4 status.

Microbleeds can be visualized on an MRI and are evidence of a problem with the brain’s blood vessels. They become more common as we age and are associated with AD and cognitive decline. Microbleeds frequently occur at the same time as cerebral amyloid angiopathy (CAA)—a disorder where amyloid accumulates within blood vessels, making them fragile and prone to leaks. Because of this overlap in AD, it has been suggested that microbleeds are a result of blood vessels weakened by CAA. 

To determine if there is a relationship between microbleeds and CAA, researchers examined brain tissue from a laboratory mouse model of AD at three different ages to determine when microbleeds, amyloid deposits, and CAA occur.

Microbleeds were found at the earliest age examined and increased in number over time. Females eventually had almost twice the number of microbleeds as males. The APOE4 risk gene further increased the number of microbleeds, with female APOE4 carriers having the most damage. The amount of damage caused by the microbleed did not increase over time, suggesting that a single event caused it, and leakage from the nearby blood vessel did not continue.

While amyloid plaques were seen at the earliest age, they were far outnumbered by microbleeds. Over time, this proportion flipped, with the number of amyloid plaques exceeding the number of microbleeds. Sex and APOE4 status were once again factors. Females and APOE4 carriers had the greatest number of plaques, and those plaques were most likely to be associated with microbleeds. 

Most microbleeds occurred in the deepest layers of the brain, where smaller arteries are found. This is also where amyloid plaques initially formed. Conversely, CAA was restricted to the outer layers at the youngest ages. It took time before CAA appeared at the deeper levels. A separate study* conducted at Massachusetts General Hospital, and not associated with the Cure Alzheimer’s Fund, also noticed this separation between amyloid deposits and CAA in post-mortem human brain tissue.

Based on this evidence, the researchers concluded that microbleeds are not a result of damage caused by CAA to blood vessels. Instead, microbleeds might be responsible for seeding amyloid plaques. This hypothesis is supported by other work showing that when brain tissue is damaged in the lab, amyloid deposits form around the injury site.

Age, sex, and APOE4 status are substantial risk factors for AD. As shown in this study, they also influence the number of microbleeds that occur in the brain, which may ultimately trigger the formation of amyloid plaques and AD pathology. 

Published in Neurobiology of Aging.

Age, sex, and cerebral microbleeds in EFAD Alzheimer disease mice

Caleb Finch, Ph.D., University of Southern California

* van Veluw, S.J., Kuijf, H.J., Charidimou, A. et al. Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy. Acta Neuropathol 133, 409–415 (2017).