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Alzheimer’s Biomarkers 101: What Does Beta-Amyloid Do In the Brain?

By Amanda Loudin | October 24th, 2022

One of Alzheimer’s disease’s key players, beta-amyloid presents a complex picture.

If you or a loved one is going through the diagnostic process for Alzheimer’s, one of the terms you’re likely to hear quite a bit is beta-amyloid. Because this protein is found aggregating in clumps in the brains of people with Alzheimer’s, it is considered one of the disease’s key biomarkers.

By identifying it in a patient’s brain, physicians have one piece of the overall picture. Here’s what you need to know about what beta-amyloid is, its role in neurodegeneration, how it’s detected, and how it can be treated. 

What is beta-amyloid protein, and what does beta-amyloid do in the brain?

When diagnosing Alzheimer’s disease, researchers have looked at the brain for two anomalies: One is neurofibrillary tangles of built-up tau protein. In a healthy brain, tau proteins bind to brain cells to help transport necessary nutrients and other molecules. But in brains with Alzheimer’s, tau starts sticking to itself, clumping up into long threads that tangle up in knots and weigh neurons down.

The other anomaly is plaque deposits of peptides classified as beta-amyloid. (A peptide is a collection of the amino acid molecules that make up a protein.) Beta-amyloid peptides also may be found all stuck together in brains with Alzheimer’s, forming beta-amyloid plaques that clog up the works. This is linked to neurodegenerative changes that many scientists believe are the early phases of Alzheimer’s.

While researchers have yet to completely understand the exact way that beta-amyloid operates, there are theories that early on, smaller clumps of beta-amyloid oligomers — or proteins — lead to cognitive impairment and, down the road, Alzheimer’s

That puts beta-amyloid front and center in the “amyloid hypothesis,” a working theory that beta-amyloid gums up the works, disrupting the brain’s connectivity, leading to cell death in certain key regions of the brain, and causing Alzheimer’s dementia.

Studies have not succeeded in determining the exact role beta-amyloid plays in the disease, but one line of thinking is that early on, beta-amyloid sets off a domino effect. Once started, the brain’s degeneration is progressive, attacking region by region. 

What causes beta-amyloid build-up in the brain?

Scientists aren’t sure exactly why beta-amyloid and tau clump together in some brains and not others, and why some people with these clumps and tangles develop Alzheimer’s, while others don’t. Aging brains are more likely to have these anomalies. But beta-amyloid clumps can appear in very young brains, too.

Identifying beta-amyloid and diagnosing Alzheimer’s

At this point, diagnoses for Alzheimer’s are still limited and, with that, often inaccurate.

The most definitive tests include searching for amyloid plaques post-mortem, in the brains of suspected Alzheimer’s patients. But there are a few other tools available in a clinical setting: For starters, diagnostic methods include MRI imaging of the brain, which helps to rule out other conditions, and can help point to brain changes that provide clues about Alzheimer’s, like revealing areas of brain atrophy, which is associated with plaque presence. This is particularly useful when scanning particular regions of the brain that are most often impacted by Alzheimer’s, such as the medial lobe. 

For more definitive results, currently a patient needs to get an amyloid PET scan (which stands for positron emission tomography) to reveal a helpful picture of amyloid plaques in the brain, or a lumbar puncture (also known as a spinal tap) to help clinicians look for biomarkers in cerebrospinal fluid, like amyloid and tau protein. These tests are generally standard for people who are, for example, participating in clinical trials for Alzheimer’s treatments.  

However, only a small percentage of people ultimately have access to PET scans: They may be hard to come by, especially away from major cities and big hospitals, and on top of that, they are expensive and not typically covered by insurance. To solve for this inaccessibility, diagnostic companies are racing to find alternative solutions, like using just a quick blood draw to reveal more concrete evidence.

New diagnostic technologies that look for Alzheimer’s biomarkers like beta-amyloid are in development, including retinal scans and blood tests, and AI-powered diagnostic tools, including a virtual microscope. In December of 2020, the very first blood test for Alzheimer’s became commercially available, for around $1,250. However, it has yet to secure FDA approval.

Going after beta-amyloid to stop Alzheimer’s?

Guided by the amyloid hypothesis, many of the drug treatment efforts have targeted beta-amyloid plaques. The recent FDA approval of Aduhelm, in fact, is the result of this research. It is not without controversy, however. 

While no one questions the fact that the drug can successfully remove these amyloid deposits, critics argue the effectiveness of that approach. While some people who took part in the Aduhelm (generic name aducanumab) clinical trials have said they suspected that the drug helped them feel clearer-headed or kept their Alzheimer’s symptoms at bay, efficacy data from the trial was, by many accounts, unconvincing

This is a double-edged sword,” Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at USC told Being Patient, ”By approving the medication on the basis of a change in the biomarker, the FDA has essentially elevated that biomarker — the amyloid in general — to a premier place, to a major place.”  

Indeed, anti-amyloid drugs like Aduhelm have a long history of failed trials. As such, researchers are looking at other avenues for drug development too, such as treatments that target tau proteins and inflammation. But drug developers aren’t ready to give up on it yet. And their determination may prove to be a good thing. A new experimental anti-amyloid, lecanemab, recently revealed encouraging early trial results — including more cognitive benefits and fewer side effects than its predecessor Aduhelm.

Could beta-amyloid actually be a good thing?

One camp of scientists is positing a theory for why the beta-amyloid hypothesis has not been proven. What if clearing beta-amyloid doesn’t halt disease progression? What if, instead, it protects the brain?

This idea builds on a growing body of research: Some scientists are taking it one step farther, looking into whether increasing the levels of this protein could treat Alzheimer’s. Bruno Imbimbo, a researcher and Alzheimer’s drug developer at the pharmaceutical company Chiesi Farmaceutici, recently wrote a provocative editorial in the journal Pharmacological Research, discussing this possibility.

Considering a long list of failed Alzheimer’s drugs, Imbimbo points to a class of drugs called secretase inhibitors, which prevent beta-amyloid from being produced in the first place. He points out that, when tested against Alzheimer’s, these drugs actually appeared to worsen cognitive performance.

“Both g-secretase and b-secretase inhibitors, which strongly inhibit amyloid-beta production, worsen cognitive and clinical performance in early and late stages of Alzheimer’s disease,” he told Being Patient. “B-secretase inhibitors have been shown to worsen cognitive performance even in unimpaired participants at risk of developing Alzheimer’s disease.”

Instead of clearing beta-amyloid, he said, treatments for Alzheimer’s disease may need to increase the amount of this “good” beta-amyloid in the brain.

Treating Alzheimer’s by targeting beta-amyloid

So far, there is no “magic bullet” for treating Alzheimer’s, and that may well be the case in the future, too. Instead, some experts say the disease, which affects different people in different ways, will require a multi-pronged drug approach. 

No matter what, beta-amyloid will continue to play a key role in how doctors identify and potentially treat Alzheimer’s patients. Understanding its place in the complex Alzheimer’s picture will continue as an area of focus for a long time to come.

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