Around 55 million people live with Alzheimer disease (AD) worldwide, according to estimates by the Alzheimer’s Association.

Alzheimer's and dementia. Alzheimer’s Association.

 

But encouraging results from a recent study indicate that two commonly prescribed psychiatric drugs may help slow the progress of this disease.

 

What to know about APOE4

Previous research efforts indicated that certain genes increase a person’s risk for AD; of these, a form of the apolipoprotein E gene known as APOE4 appears to be the strongest genetic risk factor.

Bryant E. Study reveals how APOE4 gene may increase risk for dementia. National Institutes of Health. March 16, 2021.

The exact reasons for this relationship are also unknown, but it may have something to do with the brain’s ability to process lipids. The APOE protein produced by the APOE gene helps cholesterol and other fats move throughout the bloodstream.

 

However, lipid imbalances in the brain may impact essential cellular processes, and the presence of APOE4 in a person’s genetic profile may result in the buildup of triglycerides and, as a result, unsaturated fatty acid chains. Lipid metabolism may also be affected.

Approximately 10–15% of the human population are carriers of APOE4, according to a 2022 study published in Alzheimer’s Research and Therapy (ART).

Johnson NR, Wang ACJ, Coughlan C, et al. Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition. Alzheimers Res Ther. 2022;14(1):88.

The risk of developing AD more than triples when one copy of APOE4 is present. When a person has two copies, the risk for AD jumps more than 12-fold.

 

Other research suggests APOE4 binds to amyloid-β (Aβ), acting as a catalyst for the development of Aβ oligomer and fibril formation. The gene appears to increase the stability of both structures while also encouraging their neurotoxicity.

The brains of those diagnosed with AD show that APOE is often co-deposited with amyloid plaques; this evidence points to APOE as a kind of “molecular chaperone” for Aβ aggregation in brain tissue.

 

Common psych drugs may improve cognition

Blocking the interactions of APOE4 and Aβ may be key to preventing, slowing, or stopping the progression of AD. In the 2022 ART study, researchers developed a series of high-throughput screening assays and identified eight separate compounds that helped prevent APOE4-Aβ interactions.

Further examination of these compounds showed that two of them—imipramine and olanzapine—acted as specific inhibitors of APOE4-Aβ interactions. These drugs are already commonly used in psychiatry as a tertiary amine tricyclic antidepressant and an atypical antipsychotic, respectively.

Fayez R, Gupta V. Imipramine. StatPearls Publishing. Updated July 16, 2022.

Thomas K, Saadabadi A. Olanzapine. StatPearls Publishing. Updated May 2, 2022.

 

This protein is also linked to neurodegeneration and cognitive decline. While neither imipramine and olanzapine were directly responsible for reversing the effects of pTau, they most likely reduced its pathology by interfering with the interaction between APOE4 and Aβ.

Many people living with AD already take antidepressants or antipsychotics to help manage their behavioral and psychological symptoms. Both demonstrate neuroprotective effects against factors such as Aβ accumulation, apoptosis, and Aβ-induced oxidative stress.

In the 2022 ART study, efficacy of these drugs was apparent at nanomolar concentrations.

Compared to previous research, patients enrolled in the ART study showed improved cognition and reduced level of diagnosis severity when taking imipramine or olanzapine. These compounds were shown to work more effectively in persons with the APOE4 gene.

When controlling for age and sex, those taking imipramine did not progress to a worse clinical diagnosis as often, while those taking olanzapine showed greater improvements in mini-mental state exam scores.

 

Further research needed

While the results of the 2022 ART study are certainly promising, the authors admitted that larger clinical trials involving more patients are necessary to validate its results.

Neither has shown particular efficacy for treating depression or psychosis in patients with AD.

However, the actions of these drugs as described in the study indicate that other prospective studies should take place, as long as the risk of adverse events is relatively low.