Two FDA-Approved Drugs Can Improve Cognition and Curb Alzheimer’s

The Psychiatric Medications Enhance Alzheimer’s Patient’s Cognition

According to a study by researchers at the University of Colorado Anschutz Medical Campus, two widely used psychiatric drugs show indications of treating Alzheimer’s disease symptoms, including enhancing cognition.

“The people who received these drugs developed better cognition and actually improved in their clinical diagnosis,” said the study’s senior author Huntington Potter, Ph.D., professor of neurology at the University of Colorado School of Medicine and director of the CU Alzheimer’s and Cognition Center. “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.”

The results were recently published in the journal Alzheimer’s Research & Therapy.

The Food and Drug Administration has previously given its approval to the antipsychotic olanzapine and antidepressant imipramine. Additionally, since depression and psychosis are prevalent in AD patients, many of them also take other medications to manage these problems, giving researchers a sizable control group on which to compare the effects.

Targeting APOE4 to Combat Alzheimer’s

The apolipoprotein E4 protein, also known as APOE4, is encoded by a gene variant that, when inherited, confers the highest risk for developing late-onset Alzheimer’s disease. The CU Anschutz research team, under the direction of Noah Johnson, Ph.D., had been searching for medications that block the effect of APOE4.

“We took a unique approach by targeting APOE4 because the usual drug targets, amyloid-beta and tau, have not produced a convincingly effective drug for people with AD despite decades of work,” said Johnson.

The researchers screened 595 compounds in a drug library from the National Institutes of Health and identified several compounds that specifically blocked the effect of APOE4 on Alzheimer’s amyloid formation.

“We then looked into the huge National Alzheimer’s Coordinating Center (NACC) database and asked what happened when someone was prescribed these drugs for normal indications but happened to be an Alzheimer’s patient,” Potter said.

Surprising Results from Retrospective Analysis

That’s when they found that psychiatric patients with AD using imipramine and olanzapine showed significant improvement in AD symptoms.

“The only things these drugs have in common is that they block the catalytic effect of APOE4 on the formation of amyloids in the brain,” Potter said, referring to the proteins that form clumps and disrupt cell function in AD.

The results were surprising.

“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 study said. “Notably, in our drug screen, we found that imipramine and olanzapine strongly inhibited the apoE4-catalyzed fibrillization of Aβ (amyloid beta), whereas none of the other antidepressants or antipsychotics whose use was reported in the NACC database had any such activity and none showed any benefit for AD patients.”

Potter cautioned that the study was retrospective, meaning they made the discovery while analyzing data collected for another purpose. The next step, he said, would be to test imipramine, which has fewer side effects than olanzapine, on a rodent model and if successful conduct a clinical trial.

“The number of human drugs that have shown any benefit to AD patients is maybe one or two or three,” Potter said. “So this is a very promising advance.”

Reference: “Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition” by Noah R. Johnson, Athena C.-J. Wang, Christina Coughlan, Stefan Sillau, Esteban Lucero, Lisa Viltz, Neil Markham, Cody Allen, A. Ranjitha Dhanasekaran, Heidi J. Chial and Huntington Potter, 29 June 2022, Alzheimer’s Research & Therapy.
DOI: 10.1186/s13195-022-01020-9

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