Scientists screened 595 FDA-approved drugs to see if they interfered with the activity of gene mutation ApoE4. Two of these — antidepressant imipramine and the antipsychotic olanzapine — appeared to improve cognition in people with Alzheimer’s.
Dozens of drugs designed to target and clear beta-amyloid plaques in the brain have failed to prevent or halt the progression of Alzheimer’s disease. Despite the shortcomings, several anti-amyloid drug candidates — gantenerumab, lecanemab, donanemab — are in the final stages of clinical trials. Meanwhile, Biogen and Eisai’s controversial anti-amyloid drug Aduhelm received approval from the Food and Drug Administration in 2021.
However, there is still a great deal of uncertainty about beta-amyloid’s role in Alzheimer’s disease. Is it a cause? Is it a byproduct? Is it a rampantly misunderstood noble brain health defender? While researchers stew over those questions, others are looking at other targets for treating Alzheimer’s disease, including a gene mutation called apolipoprotein E4 (ApoE4) — one of the disease’s most prominent genetic risk factors. What if there were already drugs on the market, designed to treat other conditions, that hold the power to treat Alzheimer’s by way of blocking the effects of ApoE4?
Repurposing existing drugs cuts the cost of developing a new drug and allows for treatments to reach patients faster — especially for disorders like Alzheimer’s disease, where every minute counts. Using this approach, a team of scientists at the University of Colorado’s Rocky Mountain Alzheimer’s Disease Center screened more than 595 FDA-approved drugs to see if any blocked the activity of ApoE4. They identified two drugs already on the market to treat psychiatric symptoms in Alzheimer’s — imipramine and olanzapine.
Looking at existing data in people with Alzheimer’s and mild cognitive impairment, researchers discovered that those taking these drugs showed improvements in cognition, suggesting a potential to treat symptoms and possibly disease modification. The research was published in Alzheimer’s Research & Therapy on June 29th, 2022.
“The people who received these drugs developed better cognition and actually improved in their clinical diagnosis,” said neurology professor Huntington Potter, the study’s senior author. “Compared to those who did not take these drugs, they reverted from Alzheimer’s disease to mild cognitive impairment or from mild cognitive impairment to normal.”
Uncovering the surprising effects of imipramine and olanzapine
Previous work suggested that ApoE4 sped up the formation of beta-amyloid plaques. Potter’s team developed a way to screen this interaction in cells to find existing compounds that blocked ApoE4, slowing beta-amyloid plaque formation. The antidepressant imipramine and the antipsychotic olanzapine emerged as top blockers of ApoE4 activity. Importantly, the authors point out, many people with Alzheimer’s already take these medications to treat psychiatric symptoms.
The researchers looked at existing data of people with mild cognitive impairment or Alzheimer’s disease that happened to take the most effective ApoE4 blockers identified in the drug screen.
“Our analyses show that, compared to the control populations, subjects taking imipramine or olanzapine had improved cognition and diagnoses, which are direct clinical measures of disease severity,” the researchers wrote in the study.
Their results showed that people with Alzheimer’s taking other antidepressants or antipsychotics did not show the same cognitive improvements, suggesting that the ApoE4-blocking ability of imipramine and olanzapine could be responsible for these effects. The study is limited because it looked at existing data, but the Potter’s team says it does make a compelling case for future clinical trials that test these drugs to treat Alzheimer’s.
Potter said that there are few effective treatments for the symptoms of Alzheimer’s disease and only one drug approved for disease modification.”So this is a very promising advance.”
Are these drugs safe for the treatment of Alzheimer’s symptoms today?
To be clear, these drugs are not approved specifically for the treatment of Alzheimer’s symptoms in people living with Alzheimer’s. The researchers note that more research is needed.
If a drug repurposing study’s findings prove out in future studies on efficacy, safety, proper dosage and other unknowns, the next step would be an FDA approval application process for a new, specific usage.
Further, it is important to note that all drugs come with potential risks or side effects. Antipsychotic drugs, in particular, are known for serious side effects for older adults.
For example, this drug class tends to make it more difficult to regulate body heat, increasing the risk of heat stroke in summer weather. Another recent study found that people with dementia who were using antipsychotic drugs were more likely to spend time in the hospital than those who weren’t on antipsychotics. Talk to your doctor about the benefits and risks of prescriptions.
A new potential treatment for people carrying the ApoE4 gene
This study only focused on identifying drugs that could counteract the effects of one genetic risk factor, ApoE4.
Recently, scientists also found that brexpiprazole — approved for treating schizophrenia and depression — reduced the symptom of agitation in people with Alzheimer’s. The drugmakers Lundbeck and Otsuka anticipate filing for FDA approval for Alzheimer’s by the end of 2022.