Cerebral small vessel disease is associated with amyloid-beta deposition in the brain, especially among APOE4 carriers.

Small vessel disease is a collection of conditions characterized by damage to arterioles and capillaries, resulting in reduced or interrupted blood flow to the affected organ. These conditions typically affect organs that receive substantial blood flow, such as the brain, kidney, and retina, and are principal drivers of chronic diseases such as strokes, renal failure, dementia, and blindness. Findings from a 2014 study suggest that people who have small vessel disease in the brain exhibit greater deposition of amyloid-beta plaques, especially if they are carriers of the APOE4 gene.

Amyloid-beta is a toxic 42-amino acid peptide that aggregates and forms plaques in the brain with age. Amyloid-beta deposition is associated with Alzheimer’s disease, a progressive neurodegenerative disease that can occur in middle or old age and is the most common cause of dementia.

APOE is a protein involved in lipid transport. A variant in the APOE gene, called apolipoprotein E4 (APOE4), is the major genetic risk factor for Alzheimer’s disease. Having one APOE4 allele increases a person’s Alzheimer’s disease risk as much as threefold; carrying two APOE4 alleles increases risk as much as 15-fold.

The cross-sectional study included more than 900 patients enrolled in the Amsterdam Dementia Cohort study who had been diagnosed as having Alzheimer’s disease, vascular dementia, or self-reported memory complaints. The investigators analyzed the patients' cerebrospinal fluid for the presence of amyloid-beta and other markers of Alzheimer’s disease and genotyped the patients to assess APOE status.

They also performed magnetic resonance imaging (MRI) of the patients' brains to identify the presence of white matter hyperintensities and microbleeds. White matter hyperintensities, areas in the brain that appear as intense white spots on MRIs, are often indicators of cerebral small vessel disease and are considered a risk factor for dementia. Microbleeds are small, chronic hemorrhages that are indicative of cerebral amyloid angiopathy, a condition in which amyloid-beta accumulates on the walls of brain arteries.

They found that patients with Alzheimer’s disease had lower levels of amyloid-beta in their cerebrospinal fluid, an effect that was more pronounced among APOE4 carriers. Patients with low amyloid-beta levels in their cerebrospinal fluid were more likely to have white matter hyperintensities and microbleeds, indicating a direct relationship between a pathological hallmark of Alzheimer’s disease and small vessel disease.

These findings suggest that Alzheimer’s disease and small vessel disease are intrinsically linked, especially among APOE4 carriers. [Learn more about small vessel disease in our overview article.](Coming soon)

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