Failure of Immunotherapy in Alzheimer’s Clinical Trials May Be Due to Presence of Another Form of Dementia

Immunotherapy for Alzheimer’s disease may not provide a clinical benefit in patients that also developed vascular cognitive impairment and dementia (VCID), another form of dementia, according to a new study.

The study, “Reduced Efficacy of Anti-Aβ Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity,” was published in the Journal of Neuroscience.

VCID is the second most common form of dementia behind Alzheimer’s disease, and it is estimated that 40 percent of Alzheimer’s patients also have some form of VCID. The main hallmark of Alzheimer’s disease is the accumulation of aggregates of the Aβ protein (Aβ plaques), whose presence disturbs neuronal function and brain activity.

For this reason, one promising technique for Alzheimer’s, called anti-Aβ immunotherapy, consists of the administration of proteins that react against these aggregates, clearing them from the brain.

“While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials,” the authors wrote. “We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the [Alzheimer’s] population.”

To test their hypothesis, researchers compared the effect of anti-Aβ immunotherapy in normal mice and mice with both Alzheimer’s and VCID. To do so, the scientists induced hyperhomocysteinemia (HHcy — a form of VCID) through diet in mice with Alzheimer’s disease. After three months on the diet, when cerebrovascular pathology was induced by HHcy, mice received injections of anti-Aβ immunotherapy for another three months.

Consistent with their hypothesis, researchers observed a decrease in the levels of the Aβ protein, but no cognitive benefit was induced by the anti-Aβ immunotherapy in mice. What’s more, this treatment induced an increase in microhemorrhages in mice carrying both diseases.

These results show that the treatment not only did not improve cognitive impairment, it also exacerbated adverse cerebrovascular events in mice carrying both diseases. The co-existence of VCID with Alzheimer’s disease may mute the response to anti-Aβ immunotherapy.

“These findings are important in that they provide a possible explanation for why clinical trials of anti-Aβ immunotherapy for Alzheimer’s disease have been historically unsuccessful,” one of the study’s authors, Donna Wilcock, PhD, said in a news release. “If up to 40 percent of people with Alzheimer’s also have VCID, treatment candidates that target only the [Alzheimer’s disease] physiology won’t be effective in those patients. It’s like treating only half the disease.”