Immunotherapy for Alzheimer's Disease May Increase Risk of Brain Hemorrhages

Mouse models expressing a specific protein were the most likely to experience hemorrhages after immunotherapy.

Although using immunotherapy that reduces amyloid-beta proteins has shown benefits in mouse models, a recent study suggests that additional research is needed to understand the risks and benefits for this type of treatment.

Variants of apolipoprotein E (APOE) is a significant factor that can predict Alzheimer’s disease risk relating to amyloid beta plaques, according to a study presented at the Alzheimer’s Association International Conference.

Previous studies have shown that variant APOE ε4 increases the risk, and the variant APOE ε2 reduces the risk of developing Alzheimer’s disease. It is unknown what role APOE ε3 plays.

Immunotherapies that target amyloid beta plaque build-up have been seen to cause Amyloid Related Imaging Abnormalities (ARIA), including micro-hemorrhages in patients carrying the APOE ε4 variant, according to the study. The researchers examined how this immunotherapy effects Alzheimer’s transgenic mice with each variant of APOE.

Researchers discovered that mice expressing the APOE ε4 had the most beneficial effect from immunotherapy compared, with mice expressing other variants. When amyloid-beta deposits were cleared, microglia activation increased clearing amyloid-beta deposits even further, since microglia digest the proteins.

This effect was seen in increased levels among mice that expressed the APOE ε4 variant, compared with mice that expressed other variants. This could potentially cause harmful effects of stimulated microglia on the brain, the researchers wrote.

They also found that in the APOE variants had different effects on amyloid beta deposits on the walls of brain vessels. In mouse models with APOE ε4, amyloid beta was more likely to be deposited in large vessels, and mice with APOE ε2 had more deposits in micro-vessels.

They found that hemorrhaging was most common in mice expressing the APOE ε2 variant and mice expressing the APOE ε3 variant were least likely to experience this.

Researchers believe that findings from their study could potentially lead to new immunotherapy treatments for patients with Alzheimer’s disease.

“Our study identifies the previously underappreciated risk-promoting effect of APOE ε 2 and the protective effect of APOE ε 3 on the incidence of brain bleeding associated with amyloid-beta immunization,” lead researcher Martin Sadowski, MD, concluded. “This is an important observation in a mouse model that may influence how immunotherapy treatments, such as vaccines, for Alzheimer's are developed and one day tested in humans.”