Another Alzheimer’s treatment takes a different route than the rest

About Liz Seegert and Tara Haelle

Liz Seegert (@lseegert) is AHCJ’s topic leader on aging. Her work has appeared in NextAvenue.com, Journal of Active Aging, Cancer Today and other outlets. Tara Haelle (@TaraHaelle) is medical studies core topic leader, helping journalists translate evidence into accurate information.

Photo: Isaac Mao via Flickr

Photo: Isaac Mao via Flickr

Editor’s Note: This is part 2 of a two-part package on the pipeline for Alzheimer’s disease drugs. Check out part 1.

While the controversy surrounding the FDA’s approval of Biogen’s adumanucab for Alzheimer’s disease continues, several other drug companies are developing their own therapies to prevent or slow the progression of the disease.

One of those new drugs, ALZ-801, began National Institute of Aging-funded Phase 3 trials on June 4. Unlike aducanumab or other drug candidates from Eisai, Eli Lilly and Roche, which attack amyloid plaque after it forms in the brain, biotech startup Alzheon, Inc. aims to help people with AD who have two copies of the ε4 allele of the apolipoprotein E gene (APOE4/4), a known risk factor for Alzheimer’s disease. The goal is to prevent plaque from forming in the first place or prevent additional plaque from forming in those who already show clinical symptoms of Alzheimer’s. ALZ-801 is also the only drug currently under investigation administered orally and which uses precision medicine strategy (factoring in individual genetics and lifestyle), according to the company.

Most people carry the APOE 3 gene, which neither increases nor decreases the risk of AD, but one form of this gene can affect AD risk.

Someone with one copy of APOE4 — a variation of the APOE 3 gene — has three times the risk of Alzheimer’s, compared to those without it. Two copies of the gene can increase AD risk tenfold. The National Institutes of Health estimates 25% of the world’s population carries one copy of APOE4, and 2%–3% carry two copies. While not everyone who has this variant will develop AD, the gene is present in more than half of Alzheimer’s patients, according to Michael Greicius, M.D., MPH, an associate professor of neurology and neurological sciences and director of the Stanford Center for Memory Disorders.

Since ALZ-801 singles out a specific genetic marker, it can be used as a targeted subclinical treatment long before clear clinical symptoms appear. The new study, for example, is testing the drug in people diagnosed with mild cognitive impairment or mild dementia that resembles early AD, based on NIA criteria.

“So far, our approach has shown better efficacy (vs. aducanumab) with none of the side effects of removing toxins,” Martin Tolar, M.D., Ph.D., Alzheon’s founder and CEO, said in a phone interview. The company is reporting a “favorable safety profile” and has not yet reported what side effects, if any, participants may have experienced.

ALZ-801 has only been tested in people with two sets of APOE4, but potentially it could be effective in other populations as well, according to Tolar.

Tolar made a case for targeting the APOE 4/4 gene in a 2020 article in the journal Alzheimer’s Research & Therapy, comparing the mechanisms of action of various amyloid-targeting drugs currently under clinical investigation. The company expects to have the first data read-outs of its Phase 2 biomarker trial of ALZ-801 later this year.

Another pathway to Alzheimer’s?

Most research into Alzheimer’s treatments has focused on the buildup of amyloid plaque, but new research suggests another target is worth pursuing, which may or may not be related to how plaque is able to build up in the brain. Usually, it’s very difficult for pathogens to enter the brain or even for disease processes to begin in the brain because of the blood-brain barrier. This barrier can be compared to a border of bouncers that keeps out most of the molecules that generally can freely enter other parts of the body. It’s made up of blood vessel cells and neurons that control what ions, molecules and cells are allowed to cross into the brain, thereby protecting the body’s control center and most important organ.

Without the blood-brain barrier, the brain is vulnerable to all kinds of assaults — and that’s what appears to make APOE4 such a threat. An April 2020 study in the journal Nature suggests how APOE4 increases the likelihood of developing Alzheimer’s by causing an inflammatory response in blood vessels, leading to a breakdown in parts of the blood-brain barrier.

Scientists already had learned that people with early signs of cognitive decline have more “leakage” in their blood vessels, whether they have any plaque in their brains or not. Cells called pericytes line the blood vessels of the brain and are the key “bouncers” of that barrier. It turns out that APOE4 causes these pericytes to degrade in the hippocampus and medial temporal lobe, thereby compromising the integrity of the blood-brain barrier in those parts of the brain. (The hippocampus plays a key role in learning and memory. The medial temporal lobe, which includes the hippocampus and amygdala, is important for short-term and spatial memory.)

The laboratory of the Nature article’s senior author, Berislav Zlokovic, has developed a biomarker test that can detect damaged pericytes in cerebrospinal fluid, which may help in identifying potentially appropriate patients for receiving any drug that could prevent the breakdown of these cells.

But scientists still have other questions to investigate. The breakdown in pericytes wasn’t related to measured amounts of amyloid protein in the Nature study, even though high levels of damaged pericytes did predict later cognitive impairment in those with APOE4. This means APOE4’s role in the development of Alzheimer’s might be independent of plaque buildup.

It’s also quite possible that ALZ-801 could be used in combination with aducanumab or any of the antibodies that clear toxic amyloid from the brain.

“This may especially work well with donanemab, which is administered for six to nine months until all plaque is cleared from the brain,” Tolar said in an email. “An oral tablet ALZ-801 will be suitable for the long-term maintenance without concerns for safety events such as vasogenic edema and microhemorrhage.”

One interesting story angle revolves around genetic testing. This blog post on the website Being Patient points out some key issues that arise when people find out they carry the APOE 4 biomarker. What are experts advising, considering there is no approved drug at this point to prevent Alzheimer’s disease?

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