The Next Frontier in Alzheimer’s Research

Ophthalmologists are used to looking into the eyes of patients to see if they have signs of hypertension, diabetic retinopathy and a host of other conditions. Fekrat is evaluating retinal imaging for the diagnosis of Alzheimer's disease in a large-scale clinical trial.

"We're imaging as many people as we can enroll in the trial and hope to calculate a person's risk of Alzheimer's disease by looking at their retina and optic nerve. It is the ultimate ideal. It's plausible, and I think we are on the cusp of something potentially very promising,” she says.

In other eye-related research, investigators at the University of California, San Diego, School of Medicine are studying pupil response during cognitive tests as an early measure of presymptomatic, or very early-stage, Alzheimer's.

Evaluating “synaptic” health

Researchers have long thought that high levels of amyloid and tau tangles play a role in the development of Alzheimer's, but they have only recently begun looking at synapses, or junctions between nerve cells where messages pass through, as another major piece of the puzzle.

Christopher van Dyck, director of the Alzheimer's disease research unit at Yale University School of Medicine, in New Haven, Connecticut, and his team have begun using positron-emission tomography (PET) imaging to measure what he calls “synaptic health.” This is done by scanning for a protein called synaptic vesicle glycoprotein 2A (SV2A), which changes as synapses degenerate. This, he explains, “lets us measure the loss of brain cells across synapses.”

Expanding PET imaging beyond amyloid and tau tangles to include a look at brain structure and function across synapses could provide a much more complete picture of how Alzheimer's affects the brain or how it spreads.

Discovering new genes

You may have heard of the APOE gene, which made big news with the finding that it makes the protein APOE4, linked to late-onset Alzheimer's and the development of amyloid deposits in the brain of those with the disease. Now, researchers have found more genes, MS4A and TREM2, that have been implicated in potentially causing or protecting against the disease.

Carlos Cruchaga of Washington University School of Medicine in St. Louis, Missouri, says that just a few years ago, researchers didn't understand the biology of these genes. Today, they have found that a variant of MS4A regulates TREM2 levels, which are what protect against the disease. “If we can regulate TREM2 levels, we can also modify the risk of getting Alzheimer's disease,” he says.

"I think this opens up a whole new approach,” Cruchaga adds. “We need combination therapies similar to what is being used in HIV treatment. We are still very far away, but we need to try new approaches."

Exploring links to glucose and insulin

Suzanne Craft at Wake Forest Baptist Medical Center, in Winston-Salem, North Carolina, is studying whether intranasal insulin can be used to treat Alzheimer's, because many patients with the disease have insulin resistance. “We've seen a two-year delay in symptoms with use of the drug and our delivery device,” says Craft, who is moving to a phase 3 trial of the device next fall.

Craft is also studying whether people at risk for Alzheimer's would benefit from following a ketogenic diet, because it reduces blood glucose and body weight as well as increases blood ketone levels, which play a role in glucose metabolism.

Timing the test

As researchers such as Douglas Scharre, professor of clinical neurology and psychology at the Ohio State University, tell it, finding a biomarker — some measurable flag in the body — that would signal problems with cognition early on is one of the “holy grails” of Alzheimer's research.

Scharre's hypothesis is that such early detection could also happen through a novel way of measuring cognitive skills: specifically, the time it takes to respond to a question on a memory skills test or to perform a standard task such as drawing a clockface. Scharre and his team are digitizing cognitive screening tools, like the SAGE test (self-administered gerocognitive exam) for mild cognitive impairment (MCI), and then studying the timing of the responses. “Time mode is going to make Alzheimer's disease testing more accurate and predictable than what it is now,” he says.

Editing genes

Many of the drugs that target amyloid in patients with Alzheimer's failed because they were given too late, says Randall Bateman, a neurologist at the Washington University School of Medicine.

"You need to treat plaques when they're growing and starting,” he says.

Bateman and his colleagues are preparing to launch three trials of an entirely new class of drugs that will target tau proteins, which aggregate and grow when dementia first becomes symptomatic.

These new drugs are designed with CRISPR technology — a genetic editing tool. They will try to silence the growth of tau genes by changing the DNA and RNA of an affected persons’ cells.

"I think in general, you need to throw a lot of drugs at this disease. You just don't want to be too myopic,” he says. “This is a very powerful approach that is very different.”

Cheryl Platzman Weinstock is an award–winning journalist who reports about health and science research and its impact on society for national media outlets including National Public Radio and The New York Times.