First come the misplaced keys. Then the unpaid bills, the conversations that dissolve mid-sentence, the names that refuse to surface. Families, with a mixture of dread and resignation, bring the question to the doctor: Could this be Alzheimer’s? 

By the time symptoms begin creating problems, the disease has been unfolding in the brain for years. Microscopic amyloid-beta plaques have accumulated between neurons, and later threads of neurofibrillary tau proteins have tangled themselves into tight knots inside brain cells. The two abnormalities — first described in 1906 by the German physician Alois Alzheimer — have become the twin hallmarks of the disease.

For decades, researchers have chased the question: If amyloid is a key component, could clearing it out stop or even reverse Alzheimer’s? The results are somewhat unclear. In trials, FDA-approved drugs that target amyloid plaques slow cognitive decline by about 30 percent but do not halt or reverse the disease. Many have the plaques but never display symptoms.

But new technologies — artificial intelligence that may be able to identify new genetic determinants of the disease, blood tests for proteins in the brain, and real-time brain monitoring that reveals how individual neurons die — are finding new ways to understand and possibly help treat Alzheimer’s.

In addition, new research at Harvard Medical School and elsewhere is taking a closer look at the possible role of lithium deficiency as a cause in the onset and progression of the disease.

It’s an urgent pursuit. As more Americans live longer, the number of people living with Alzheimer’s disease is expected to rise from about 7.2 million in 2025 to about 18.8 million in 2050.

Although numbers vary depending on methodologies, economic analyses have placed the total annual cost of care for patients with Alzheimer’s and other dementias at about $1.5 trillion in 2050, compared to about $226 billion in 2015. 

“We are in the midst of the silver tsunami,” said Steven Arnold, the principal investigator at the Alzheimer’s Clinical & Translational Research Unit at Massachusetts General Hospital. “If we are not able to change the course of the disease from a medical perspective, then our only real treatment is physical and palliative care of older adults.” 

Finding the tipping point

One of the confounding variables is that while amyloid plaques are the essential condition of Alzheimer’s disease, people can live with amyloid plaques for years, or even decades, without developing symptoms. Some never do.

Among people who meet the amyloid proteinopathy definition of Alzheimer’s, only 8 percent have full-fledged dementia, and only 17 percent have mild cognitive impairment, while 76 percent have no cognitive impairment at all. 

Reisa Sperling, director of the Mass General Brigham Center for Alzheimer’s Research and Treatment, is homing in on the tipping point when someone with unproblematic amyloid suddenly develops tau tangles, heralding cognitive decline. She calls it the “ca-tau-strophe.” 

“It’s kind of a weird pun, but we call it the cataustrophe because that is what’s really associated with this rapid spread of tau and imminent cognitive decline. We’ve really focused on: How do we predict who’s going to have this cataustrophe? Because that’s what we have to prevent.” 

Her first clinical trial, Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease, or the A4 Study, was designed to test that idea. She enrolled more than 1,100 people who had amyloid plaques but hadn’t yet developed clinical symptoms.

After 4.5 years, the anti-amyloid drug solanezumab failed to meaningfully clear plaque or slow progression of the disease. Although the trial still contributed important knowledge about what works and what doesn’t, it was yet another disappointment.

But science demands exhaustive inquiry. In an ongoing study called AHEAD 3-45, Sperling is testing a different antibody, lecanemab (the first FDA-approved anti-amyloid treatment) even earlier in the development of disease, in cognitively normal patients who have even less amyloid accumulation. The question is: Can treating amyloid earlier prevent the cataustrophe?

To determine if drugs like the ones Sperling is testing are working, researchers need better ways to track the disease. That’s where Ted Zwang’s work comes in. In a lab just around the block from Sperling’s, Zwang is using flexible brain electronics in mouse models to get a better look at the molecular basis of disease over time. 

“We can see both neurons and tau tangles and see what changes from one week to the next, and we can identify neurons that are dying.” 

If Zwang’s work translates from mice to humans, it could allow the monitoring of whether the anti-amyloid drugs Sperling is studying are working in real time.

“Instead of having amyloid PET or tau PET, what if we have a marker for the neurons that are in the process of dying?” Zwang said. “That would be a much more direct way of trying to assess if a treatment is helping.” 

The shift to a more precise, data-driven approach is also the focus for MGH data scientist Sudeshna Das. She is using artificial intelligence to sift through massive datasets for new insights.

Her group’s multiscale graph neural network (GNN) model, which they called ALZ-PINNACLE, captures nearly 15,000 proteins and more than 200,000 interactions across seven cell types, painting a more layered picture of the disease. 

Through her big-data lens, Alzheimer’s looks less like a uniform illness and more like a collection of overlapping subtypes.

“Although it’s defined by amyloid and tau, there are so many other genes and pathways: Genetics, metabolism, vascular health, inflammation, and even psychosocial factors like depression and isolation, all play a role. We call it a biopsychosocial disease,” she said.

Das believes effective treatment depends on distinguishing subtypes of Alzheimer’s. With AI, she believes those subtypes could be identified within the next few years. The approach would move the field toward truly personalized medicine. 

Exploring paths toward resilience

As some researchers look for treatments for Alzheimer’s, others focus on resilience — the collection of behaviors and traits that seem to protect against developing Alzheimer’s.

Research suggests that people who inherit an uncommon form of the Apolipoprotein E gene, called ApoE2, are resistant to Alzheimer’s disease. By contrast, another form of the gene, ApoE4, increases risk as much as 10-fold.

Bradley Hyman, John B. Penney Jr. Professor of Neurology at HMS, recently showed that a mouse model with the ApoeE4 predisposition could be treated successfully, reversing much of the damage, by introducing ApoE2 using gene therapy approaches.

“Those approaches are already in clinical practice for other diseases, but we are not yet able to take ApoE2 into patients,” said Hyman, who also directs the Alzheimer’s disease research unit at the MassGeneral Institute for Neurodegenerative Diseases (MIND). “Yet it is an exciting approach, and we continue to work on how to add a factor that nature tells us is protective in rare individuals back to everyone.”

Years ago, a chance encounter sent Steven Arnold down a path toward a completely different approach to resilience: immunotherapy. He ran into a colleague, MGH endocrinologist Denise Faustman, who had been looking into a century-old tuberculosis vaccine for Type 1 diabetes treatment.

“She said, ‘You should look at that in the brain,’” Arnold remembered.

Emerging evidence suggested that people who had received the Bacillus Calmette-Guérin (BCG) vaccine, which also can be used to treat bladder cancer, had lower all-cause mortality. 

“It just seemed to fine-tune the immune system to help protect against a wide variety of things — not just infections, but auto-immune conditions, multiple sclerosis,” he said. “And then some epidemiological data started coming out that people who received BCG had a lower rate of developing Alzheimer’s or Parkinson’s disease.” 

His team had become interested in a specific kind of over-inflammation they were seeing in Alzheimer’s patients. As he explained, immune cells in the brain play a critical dual role: They clean up damaged tissue, but they also fine-tune healthy brain connections.

“You don’t want [the immune system] underactive. You don’t want it overactive,” he said. “You want it rightly active.” 

In 2023, Arnold and colleagues, including Das, found that BCG immunotherapy for bladder cancer was associated with a 20 percent lower risk of subsequent Alzheimer’s disease and related dementia, with the protective association greater in those aged 70 or older.

While previous research had linked the BCG vaccine to a lower risk of dementia, the studies were limited by size, study design, or analytical methods. 

It’s a promising start, but it’s just a start.

Arnold is looking at other factors that can help prevent the disease: lifestyle choices. 

“We recognize that a lot of the same kinds of cardiovascular and metabolic risk factors for heart attack and stroke — high blood pressure, high cholesterol, diabetes, obesity — are drivers that can affect both the likelihood someone may develop Alzheimer’s, and also the manifestations of the disease,” he said. 

In a 2024 study, Arnold collaborated in a study that found that over a 20-week period, intensive diet and lifestyle changes could improve biomarkers of amyloid in the brains of patients with early dementia due to Alzheimer’s disease, and could even improve cognitive function.

The findings back up The Lancet’s 14 key modifiable lifestyle factors that contribute to Alzheimer’s, including limited education, hearing loss, high LDL cholesterol, social isolation, depression, traumatic brain injury, and physical inactivity. Individually only minor contributors, taken together, these factors could collectively prevent or delay up to 45 percent of Alzheimer’s cases if eliminated, according to a 2024 Lancet report.

Seeking novel approaches

Emerging research at Harvard, much of it competitively funded by the National Institutes of Health, continues to offer new pathways and new treatment possibilities.

A 2023 paper by an international team led by Harvard Medical School investigators at MGH and Massachusetts Eye and Ear identified a new genetic variant that protects against Alzheimer’s.

Bruce Yankner, professor of genetics and neurology in the Blavatnik Institute at HMS, in August this year offered a new theory of lithium deficiency as an underlying cause of the disease. The results, which were a decade in the making, show that lithium, which is used to treat mood disorders, occurs naturally in the brain and shields it from neurodegeneration.

Researchers found that as amyloid-beta begins to form in the early stages of the disease it binds to lithium, reducing its ability to function. Treating mice with lithium orotate, which doesn’t bind to amyloid-beta, reversed the disease and its symptoms.

Each new insight requires years of continued investigation — and funding — before medications can be approved for the public. 

Researchers like Zwang remain cautiously optimistic. “We’re at a very transformational period in the understanding of Alzheimer’s disease, thanks to a lot of the new ways of observing what’s happening in living people,” he said. “Things are progressing so rapidly, just with these treatments being tested, these models being made, that I wouldn’t be surprised if we have some really good treatment in the next few years.”