The interaction between the brain and the vascular system could hold the key to lowering disease risk.
According to the Alzheimer Society of Canada, one in four Canadians over the age of 85 is living with dementia, with Alzheimer’s disease (AD) accounting for more than 60% of those cases.
While Alzheimer’s is commonly associated with the buildup of abnormal proteins in the brain, forming plaques and tangles, a new study from researchers at the University of Calgary suggests that the brain’s blood vessels may also play a critical role in the disease.
The research highlights the importance of a protein called CD2AP, which may offer new insight into how Alzheimer’s develops. This finding could significantly shift current understanding and approaches to treatment, says Dr. Minh Dang Nguyen, PhD, the study’s lead investigator and a professor in the Department of Clinical Neurosciences at the Cumming School of Medicine, as well as a member of the Hotchkiss Brain Institute.
Nguyen compares the brain’s vascular system to a tree. The complex branches—arteries, capillaries, and veins—are critical to delivering nutrients throughout the brain. The cerebrovascular system in AD patients, he says, doesn’t deliver those nutrients properly.
AD may be more related to diseases of the vascular system, such as arteriosclerosis or diabetes, than anticipated, he says.
The Role of CD2AP in Brain Health
Nguyen says the discovery, published in the journal Neuron, reveals important factors to consider about how the brain interacts with the vascular system and, particularly, the cells that form the brain blood vessels, called brain endothelial cells.
Importantly, the researchers discovered that the levels of CD2AP are reduced in the brain blood vessels of patients who died with AD.
“The lower the levels, the worse was their memory function prior to death,” says Nguyen. “This correlation is particularly striking in males.”
Sex-Based Differences and CD2AP
The researchers dived deeper and applied what they observed in human samples to studies using mice that have altered levels of CD2AP.
“We saw a lot of differences in how the vasculature was functioning related to CD2AP levels with consequences on memory function,” says Dr. Milène Vandal, PhD, first author on the study.
In fact, says Vandal, CD2AP may be protective for females, adding to the sex-dependent result. More research into new approaches based on sex may be needed.
“If you’re trying to improve the vascular system of a person to reduce their risk of AD, you might want to have different strategies for men and women, because their vascular system is just not reacting the same way,” she says.
While this discovery could lead to future treatments that target CD2AP—at least in half the population—Vandal says the timeline for most new drugs is very long.
Instead, the researchers say there are easier ways to reduce the risk of AD and all other vascular diseases.
“I think the immediate strategy is, really, take care of yourself and your lifestyle—anything that affects the vascular system,” says Nguyen. “A good diet, exercise, less stress, and better sleep—interventions that work for both sexes.”
Reference: “Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction” by Milène Vandal, Adam Institoris, Louise Reveret, Ben Korin, Colin Gunn, Sotaro Hirai, Yulan Jiang, Sukyoung Lee, Jiyeon Lee, Philippe Bourassa, Ramesh C. Mishra, Govind Peringod, Faye Arellano, Camille Belzil, Cyntia Tremblay, Mada Hashem, Kelsea Gorzo, Esteban Elias, Jinjing Yao, Bill Meilandt, Oded Foreman, Meron Roose-Girma, Steven Shin, Daniel Muruve, Wilten Nicola, Jakob Körbelin, Jeff F. Dunn, Wayne Chen, Sang-Ki Park, Andrew P. Braun, David A. Bennett, Grant R.J. Gordon, Frédéric Calon, Andrey S. Shaw and Minh Dang Nguyen, 31 January 2025, Neuron.
DOI: 10.1016/j.neuron.2025.01.006
The study was funded by the Canadian Institutes of Health Research and the Krembil Foundation.
