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

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.”

3 comments

  1. DANTE MARCIANI says:

    For a therapy to be promising it should be focus on the right target, a condition that never has been fulfilled with Alzheimer’s immune therapy. Indeed, the induced immune response ignored the neurotoxic amyloid beta oligomers and worst, it released free cytotoxic oligomers that were immobilized as plaque. Indeed, recent reports have shown that those oligomers released by the wrong immune response cause or aggravate this disease. While quite possible that VCID is present in some cases with AD, it is very unlikely that the constant past failures of immune therapy are due to the presence of that disease. Indeed, if such was the case, the aducanumab studies should have also failed; yet, the clinical studies with such antibody, which recognizes the epitope present in oligomers, are promising. Hence, we should recognize that because the studies were done with the wrong vaccines or antibodies, with the exception of aducanumab, we cannot draw any conclusions from those past studies. Trying to do so, is creating more chaos in an already chaotic situation. Yet, in future studies extra efforts should be made to avoid patients having both diseases.

    • Robin Merrell says:

      As a lay person & caregiver, does this mean in your opinion prescribing Namenda would not be best on a person with VCID & Alz?

      • Dante Marciani says:

        My opinion was limited to immune therapy and I very much doubt that it can be extended to other types of treatments, like Namenda. The amyloid-beta aggregates have various mechanisms of toxicity that are still being elucidated, thus it will be premature to draw any conclusions at this time. Yet, when immune therapy is optimized and hopefully working, it will be interesting to see if it can show synergism with other drugs.

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