The Early Alzheimer’s Signals We’ve Been Missing (Until Now)

By the time Alzheimer’s disease is officially diagnosed in a doctor’s office, precious cells and brain function have already been lost. For Mark Ebbert, PhD, Alzheimer’s Disease Research grant recipient and associate professor at the University of Kentucky, this timing represents both medicine’s greatest challenge and its most important opportunity.

“We can’t heal from neurodegeneration, and even if we could, we likely couldn’t recover lost memories,” he said. “We must be able to detect disease before symptoms onset.”

This pursuit led Dr. Ebbert into uncharted waters, looking at results that, in theory, shouldn’t have existed. His examination of Alzheimer’s brain samples had revealed molecular differences that previous technology had completely missed.

In a proof-of-principle study, nearly 100 distinct genetic signals were different between Alzheimer’s and non-impaired brains that were overlooked using standard approaches. The findings of this study were published in Nature Biotechnology. Preliminary results from a much larger study will be presented publicly later in 2025 and are showing even stronger signals, according to Dr. Ebbert.

What Scientists Have Been Missing

Dr. Ebbert has seen the toll that Alzheimer’s disease takes on families and aims to work toward a more hopeful future. While he’s drawn to what he calls one of the most complex and challenging puzzles in medicine, his research focus remains clear: “It only matters if we can meaningfully improve the lives of patients and their loved ones.”

His breakthrough began with recognizing that researchers have been studying Alzheimer’s genes like looking at a family photo and seeing only one person. Scientists have long known that certain genes are involved in the disease, but they’ve been treating each gene as if it produces just one protein.

The reality is far more complex. Most genes actually produce multiple different proteins, called isoforms, that can behave completely differently from one another. “The top Alzheimer’s disease genes code for approximately 12 different proteins on average,” Dr. Ebbert explained. Yet, most research has been forced to lump them all together because of the technical limitations of older technology.

“When you collapse all isoforms of a gene into a single signal, you’re throwing out critical information,” he said. “We believe that some of the key signals have been buried in this oversimplification.”

The Technology That Sees More

The solution came through long-read sequencing technology. Think of traditional genetic sequencing like trying to understand a book by reading random sentences scattered throughout the pages, then attempting to piece together the story. Long-read sequencing can read entire chapters at once.

“Traditional methods use short-read sequencing, which can only sequence tiny pieces of DNA or RNA. We then have to try to stitch them back together,” Dr. Ebbert explained. “That’s useful for a lot of things, but it can miss the bigger picture—especially when it comes to the full structure of RNA molecules.”

Long-read sequencing provides unprecedented resolution. “We now know that many genes produce multiple distinct versions that can behave very differently,” he said. “Long-read technology gives us the resolution to see these differences more clearly, which opens new doors for understanding the disease at a much finer level.”

A Stunning Discovery for Alzheimer’s

Dr. Ebbert’s team, led by PhD candidate Bernardo Aguzzoli-Heberle and Dr. Ja Brandon, put their approach to the test with brain tissue from 12 deceased organ donors—six with Alzheimer’s disease and six without cognitive impairment—and they uncovered something remarkable.

First, they discovered 700 RNA isoforms that had never been described before. Entirely new molecular players in the brain that science had yet to uncover.

But the real breakthrough came next. Using long-read sequencing, they identified nearly 100 isoforms that showed significant differences between Alzheimer’s and healthy brains. These differences were completely invisible using standard methods.

“We observed changes in Alzheimer’s disease brains for these nearly 100 isoforms when their respective genes as a whole did not show any statistical difference,” Dr. Ebbert explains. “The differences would have been washed out using standard approaches.”

This discovery suggests that researchers may have been missing crucial disease mechanisms all along. The tools simply weren’t sensitive enough to see what was really happening.

Building the Foundation for Early Detection

For families affected by Alzheimer’s disease, Dr. Ebbert’s work could offer something that has been elusive for decades: a reliable way to catch the disease years before it steals what matters most and when treatments are most effective.

“We must be able to detect disease before symptoms onset.”

Dr. Ebbert’s team is now scaling up dramatically. They are conducting a validation study with more than 300 brain samples—25 times larger than their initial work. If the patterns hold, they’ll have robust evidence that these molecular changes are reliable markers of disease.

If these molecular signatures can be detected in blood or cerebrospinal fluid, tissues that doctors can actually access from living patients, they could form the basis of an early diagnostic test.

“Diseases always leave evidence of their destruction. We just have to find it and measure it,” Dr. Ebbert explained. “But that requires a lot of resources and a lot of work.”

He credits BrightFocus Foundation’s Alzheimer’s Disease Research program with providing essential support when his laboratory needed it most.

“It gave us the flexibility to optimize our long-read protocol and generate foundational data that we’re now using to build out much larger studies,” he said. “I think this kind of support is helping shift the field toward more innovative approaches to Alzheimer’s, and we need as much support as possible.”

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