CAA is vascular disease of the brain in which beta-amyloid is deposited in the walls of small arteries and capillaries. The amyloid replaces smooth muscle cells, causing vessel wall thickening and stiffness. This can result in leaks and reduced blood flow in these small blood vessels. Tiny hemorrhages and small strokes are seen surrounding the affected blood vessels. In the elderly, CAA is a major cause of serious bleeding in the various lobes of the brain. Genetically, it can occur sporadically or in families. There is often but not always an overlap with Alzheimer’s disease.

However, there is a darker side to anti-amyloid monoclonal antibodies including lecanemab. ARIA, an acronym for amyloid-related imaging abnormalities, have occurred in all trials of anti-amyloid MABs. They occur in two forms, swelling (edema) of the brain (ARIA-E) and microhemorrhages (ARIA-H). Most of the time they are harmless and without symptoms, and they usually resolve within a month or two after stopping the drug. Rarely, they can be severe. As described in a case study, I was one of the subjects in the aducanumab trial who had severe ARIA of both types, swelling and bleeding. I required ICU care for two days, but I eventually fully recovered over the next few months. So far, three research subjects have died during the lecanemab clinical trial.

In January 2023, researchers from Eisai and its partner Biogen published positive results in a phase 3 trial of the anti-amyloid monoclonal antibody, lecanemab. All research subjects had either mild cognitive impairment or early dementia due to Alzheimer’s disease. The primary endpoint was the Clinical Dementia Rating – Sum of Boxes (CDR-SB). This is a numeric scale used to quantify the severity of symptoms of dementia. It is based on interviews of people living with dementia and their caregivers by qualified professionals who assess cognitive and functional performance in six areas: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The total score of the six areas is the score of the CDR-SB. After 18 months, those receiving lecanemab had 27% less decline of the CDR-SB compared to those receiving a placebo. This was highly significant statistically (p = 0.00005). Brain swelling (ARIA-E) occurred in 12.3% of subjects, about one third the occurrence rate seen in the aducanumab phase 3 trials. However, participants with two copies of the APOE-4 allele were approximately six times more likely to experience symptomatic ARIA with brain swelling and more than three times more likely to experience ARIA with brain bleeding than APOE-4 noncarriers.