The next big breakthroughs in Alzheimer’s science and treatment

Alzheimer's disease is one of humanity's most formidable foes. It affects 10 percent of people over age 65 and kills more people each year than breast cancer and prostate cancer combined. Its effects on patients' cognition and personalities are uniquely heartbreaking. And for decades, Alzheimer's remained hard to predict or diagnose, and impossible to treat.

But this stalemate may finally be coming to an end. Just two years ago, the FDA approved the first-ever drugs that actually forestall symptoms like memory loss. Now, discoveries in gene editing, brain imaging, blood testing and epidemiology are driving progress toward better and safer treatments, and even prevention.

"We've had thousands of failed clinical trials and made very little progress against this devastating disease for decades," says Martin Kampmann, professor of biochemistry and biophysics who studies the molecular aspects of dementia at UC San Francisco. "But just over the last five or so years, we've hit an inflection point. We're starting to get traction."

But what does all this mean for the millions of Americans who are living with Alzheimer's disease today, and countless more who worry about losing memories and lucidity as they age? We talked with five leading University of California researchers to find out how recent discoveries are quickly reshaping the outlook for America's cognitive health.

Better drugs are emerging to clear damaging protein deposits in the brain.

The two drugs approved by the FDA to treat the causes of Alzheimer's disease work by clearing out amyloid, a protein that forms damaging deposits in the brain.

The drugs delay cognitive impairment by up to seven months - valuable time saved for patients and their families. But the medicines don't cure or reverse the disease, and they come with some significant side effects.

"There is concern from some that these medicines are not as effective or as safe as desired for people with symptoms of Azheimer's," says UC San Francisco neurology professor Adam Boxer. "But this is just the first generation." He compares the state of Alzheimer's medication today to that of the earliest HIV drugs in the 1980s, which also came with lots of side effects and only modest benefits. But through years of research and trials, "now we have very effective treatments for HIV," Boxer says, and patients on medication can live long, healthy lives.

Boxer is leading a five-year clinical trial funded by the National Institutes of Health that will combine an anti-amyloid drug with experimental therapies that target tau, another protein that accumulates in the brains of Alzheimer's patients. "The thought is that a combination of an anti-amyloid and an anti-tau drug could have a much larger effect than either alone," Boxer says.

As drugs evolve to clear amyloid, tau, and eventually other dementia-associated proteins, Boxer says we could be well on our way to Alzheimer's going the way of HIV, from an inexorable menace to a treatable chronic disease.

Read more from UC San Francisco: UCSF-led trial will combine an anti-amyloid with tau therapies to arrest disease progression.

A new molecule shows promise for healing the brain.

A type of brain signal called a gamma oscillation helps with our short-term memory and other cognitive functions. In people with Alzheimer's disease, these signals don't fire as reliably. A molecule discovered at UCLA shows promise in ramping gamma oscillations back up, restoring cognitive function in mice. Credit: Getty Images / image_jungle

Despite the success of anti-amyloid drugs and progress towards medication to clear up tau, there are currently no treatments to help people recover from Alzheimer's disease or related dementias.

"The hope with the anti-amyloid drugs was that with the removal of the plaques, the disease would be cured," says Istvan Mody, professor of neurology and physiology at UCLA Health. "Unfortunately, that hasn't been the case. The removal of these toxic compounds still leaves an altered brain behind."

Mody's team may be close to solving this problem. They discovered a compound that increases gamma oscillations, a type of brain signal that orchestrates cognitive processes like working memory. The compound blocks the brain's natural process for moderating gamma oscillations, effectively releasing the brakes so neurons can spin out more gamma oscillations and ramp up cognition.

In a study published in 2024, Mody's team gave this molecule to mice with Alzheimer's disease. Before treatment, these mice couldn't remember the route out of a maze. After treatment, the Alzheimer's mice were almost as good at navigating the maze as mice without the disease.

"We've shown that this works in mice," Mody says. "If we can develop a therapy that's safe and effective for people, we may be able to restore cognitive function. That's the ultimate hope." If further testing shows the molecule is safe for people, a clinical trial to test its effectiveness could be on the horizon within five years.

Read more from UCLA Health: Molecule restores cognition, memory in Alzheimer's disease model mice

Blood tests are making diagnosis faster, easier and cheaper.

In May, the FDA approved the first-ever blood test for diagnosing Alzheimer's disease.

The test detects certain forms of tau and amyloid proteins circulating in the blood, which we now know correlate with the extent of these proteins' deposits in the brain.

This test is currently only approved for patients who show signs of dementia, at which point tau and amyloid may have already been accumulating for years, if not decades. Now, the search is on for other molecules in the blood that correlate with symptoms, or better yet, predict their eventual onset.

A study published this year by UC San Diego neuroscientist Hector M. González and postdoctoral scholar Freddie Márquez points to three additional molecules that could detect Alzheimer's or related dementias through a blood test. In the Study of Latinos-Investigation of Neurocognitive Aging, which evaluated over 6,000 Latinos in the U.S., González's group found links between levels of these blood proteins and the extent of participants' self-reported cognitive decline. One of these proteins, a nerve cell injury marker known as NfL correlated with memory problems even in people who were otherwise still cognitively healthy - meaning NfL in the blood could be an early warning sign of cognitive problems to come.

By showing that patients' blood carries reliable information about their brain's condition and function, González says this study brings us closer to a future where people can discover their risk of dementia from a simple blood draw at their annual physical, well before they start showing symptoms.

Read more from UC San Diego: Blood test could streamline early Alzheimer's detection

New evidence points to a lifetime of ways to lower your dementia risk.

As testing improves, doctors may soon be able to pinpoint the cause of a patient's cognitive decline earlier or even predict its onset years in advance.

But that knowledge could cause more harm than good if a patient can't do much to change their fate, says Rachel Whitmer, who co-directs the NIH-funded UC Davis Alzheimer's Disease Research Center.

"The good news is, we now know that 45 percent of the overall population risk of dementia is accounted for by modifiable factors, like midlife hypertension, low social engagement, untreated hearing loss or hyperlipidemia, or exposure to air pollution" Whitmer says. "That means there are things you can do today that will lower your risk of dementia tomorrow."

Whitmer contributed some of the earliest science showing that people who develop cardiometabolic conditions like diabetes, hyperlipidemia, obesity, and high blood pressure in midlife were much likelier to develop dementia as they aged. Her latest research finds that improving cardiometabolic health, even as early as adolescence or young adulthood also yields benefits for brain health.

Whitmer is the lead UC Davis investigator for the Alzheimer's Association U.S. POINTER study. This two-year trial enrolled people at risk of dementia in an intensive program of physical and cognitive exercise, a healthy diet, and dozens of meetings with peers and clinicians. A second group followed a less intensive program. Both groups scored higher on tests of cognitive function at the end of the study, with bigger gains made by those who followed the more intensive program.

Previous studies have looked at the cognitive effects of changing diet, or exercise, or hypertension. "But what if it's not enough to target just one thing?" Whitmer says. "If we target a number of mechanisms simultaneously, I think we'll see a synergistic effect on brain health bigger than the sum of the parts."

Read more from UC Davis Health: U.S. POINTER Study shows lifestyle program improves cognition in older adults

CRISPR gene editing is identifying as-yet-unknown triggers of dementia.

UC San Francisco biochemist Martin Kampmann and Diane Nathaniel, staff research associate and lab manager. Kampmann's lab is editing the genes of cultivated brain tissue to study how different genetic states seem to hurt or help brain health. Credit: UC San Francisco

Decades of dogged focus on protein deposits yielded the first drugs that effectively treat Alzheimer's by clearing amyloid plaques from the brain. But these drugs don't postpone cognitive decline indefinitely - a fact that's spurring scientists to ask: Why not? And what might?

UC San Francisco biochemist Martin Kampmann is engineering new ways to answer those questions. His approach relies on CRISPR, the technology invented at UC Berkeley that allows scientists to edit specific lines of code in an organism's DNA. Kampmann's team uses CRISPR to efficiently make a whole bunch of edits to brain cells, generated from reprogrammed blood or skin cells donated by patients and cultured in a petri dish, causing those genes to produce different proteins. Then they analyze what Kampmann calls the "functional consequences" of these experimental gene edits. Some are bad, like neurons dying or toxic proteins building up, while others are good, like improved neuronal survival or function.

By studying which gene edits produced which outcomes, Kampmann's team is broadening our understanding of what's happening on a molecular level when a person experiences dementia. For instance, they've discovered the specific gene states that determine whether microglia, the brain's immune cells, cause damaging inflammation or kill too many neurons, instead of cleaning up toxic proteins, like microglia do in healthy brains. And they've determined the proteins that control those varying genetic states, so scientists can develop new drugs or repurpose existing ones to promote healthier states of microglia.

These new drugs will target parts of Alzheimer's biology that existing medications don't seem to fix, Kampmann says. "I think in the next five or 10 years we'll see that it's a combination of therapies, some that already exist and some that will be developed based on what we're learning in my lab and others, that can really be effective" to halt, reverse or even prevent the onset of dementia.

Read more from UC San Francisco: A CRISPR approach to neurodegenerative disease

UC leads the world in Alzheimer's research and care

Across UC's 10 campuses and six academic health centers, scientists and clinicians have contributed some of the most important discoveries and innovations to Alzheimer's science and care.

• UC is home to eight of 10 California Alzheimer's Disease Centers, a 40-year-old statewide network of dementia care and research hubs.

• Three UC campuses serve as National Institutes of Health-funded Alzheimer's Disease Research Centers.

But the momentum we've gathered against Alzheimer's disease is now at risk. Congress is considering deep cuts in the coming year to the federal science agencies that fund university research nationwide. Join the University of California in urging lawmakers to reinvest in American innovation: Speak up for science.