Alzheimer's test could diagnose 'disease of exclusion' a lot earlier

Alzheimer’s disease is a “disease of exclusion”—that is, a condition that doctors settle on only when all others have been ruled out. But what if you could take a routine blood test at your annual physical that could show you’re on the way to developing it?

And then, if nefarious proteins in the blood are detected, what if you could be prescribed an inhalable drug that neutralizes them?

This is what Valerie Daggett, PhD, envisions for the future of treating Alzheimer’s disease. With her company AltPep, Daggett has developed an assay to detect disease-triggering proteins called toxic oligomers, precursors to the amyloid plaques characteristic of Alzheimer’s. 

Daggett is not alone in searching for new ways to diagnose Alzheimer’s. Major pharmaceutical companies like Roche and Eli Lilly have pointed to testing as critical to the future of treating the neurodegenerative disease.

In a paper published Dec. 5 in PNAS, Daggett’s team revealed a proof-of-concept preclinical study showing that the test was highly specific for the toxic oligomers in blood samples from humans with various stages of Alzheimer’s disease. Eventually, it could enable physicians to detect amyloid diseases decades before they form—and maybe even become the basis for a treatment someday.

“Imagine you’re screening the blood of the public—everybody 40 years of age and up, is what we’re aiming for—and when you detect those toxic oligomers you can get them treatment right away,” Daggett said.

The test, called the soluble oligomer binding assay, or SOBA, works by using a proprietary peptide developed by AltPep to scout out misfolded amyloid-beta proteins—the toxic oligomers—in patients’ blood. They accumulate and begin damaging the brain 10 to 20 years before symptoms start, ultimately leading to the cognitive deficits that characterize conditions like Alzheimer’s. If the oligomers are detected, a secondary test is run to determine whether their accumulation is due to Alzheimer’s, Parkinson’s, or another disease.

The researchers validated SOBA using 379 banked human plasma samples taken from controls and patients across the Alzheimer’s continuum, from individuals who hadn’t yet begun experiencing symptoms but would eventually go on to develop them to those in the late stages of the disease. They found that their assay was able to discriminate Alzheimer’s disease from other types of dementia, with a sensitivity and specificity rate of 99% compared to the neuropathological diagnosis based on autopsy and the clinical diagnosis that's made based on symptoms that can't be explained by any other illness. 

To understand how AltPep's technology differs from other diagnostics for amyloid diseases, it helps to know a little bit about how amyloid-beta plaques form. First, misfolded protein triplets called trimers come together to form the toxic oligomers, which then accumulate into long groups called protofibrils. Protofibrils organize into fibrils, and fibrils clump together to form plaques. 

In AltPep's tech, the capture agent is a peptide that binds to the alpha sheets of the toxic oligomers, before they become protofibrils and plaques. This is the first time researchers have developed an assay that is capable of detecting toxic oligomers. Another test under development by researchers from Sweden detects the protein tau, which doesn't show up until later in the disease course.

For comparison, an Alzheimer’s treatment developed by Roche’s Genentech unit called gantenerumab bound to the fibrils of the oligomers. Eisai and Biogen’s buzzy drug lecanemab, which recently reported positive results in late-stage clinical trials, binds to the protein during the later protofibril stage.

Fibrils and protofibrils are much more abundant in blood than oligomers, which Daggett describes as akin to finding “a needle in a haystack.”  

“You really have to have something that’s selective to be able to detect it well at these very low concentrations in blood,” Daggett said.

SOBA’s Alzheimer’s disease assay, SOBA AD, was designated a breakthrough device in March by the FDA for the detection of Alzheimer’s disease. The AltPep team is working on getting the same status for the assay for Parkinson’s and Lewy body disease, which will detect oligomers in plasma. Breakthrough status will help the tests get to the clinic more quickly.

AltPep already has some undisclosed partners who are interested in commercializing the technology, according to Daggett.

Until an effective treatment is approved,  AltPep’s tests may not be particularly helpful when it comes to changing clinical outcomes, but they could motivate patients to make lifestyle changes to potentially stave off symptoms.

That’s what Daggett hopes to tackle next. AltPep is working on a treatment in the form of a nasal inhaler that contains a therapeutic version of the company's peptides, which aim to bind to the toxic oligomers, neutralize them and stimulate brain cells called microglia to clear them.

Editor's Note: This article has been updated to correct that trimers, not dimers, are the precursors to toxic oligomers, and that Dr. Daggett is a PhD, not an MD. Additional information on AltPep's technology has been added as well.