The Puzzle of Alzheimer’s Disease

In the 120 years since Alzheimer’s disease was first identified, scientists have worked to unravel the biological details of how it develops and progresses, with the goal of finding ways to prevent it or slow its effects.

Since the 1980s, much of that research has centered on two proteins implicated in the pathology of the disease — amyloid beta protein, which forms plaques between brain cells, and tau protein, which forms twisted fibers called neurofibrillary tangles inside neurons. Scientific interest in Alzheimer’s has been bolstered by the disease’s enormous impact on the aging population: It is currently estimated to affect more than 55 million people worldwide, and that number is expected to rise to more than 150 million by 2050.

“Alzheimer’s disease has proven to be a difficult clinical and scientific problem that until recently has resisted effective therapeutic intervention,” says Bruce Yankner, a professor of genetics in the Blavatnik Institute at Harvard Medical School who studies the molecular genetics of aging and neurodegenerative disorders. “For many years, the focus was on the constituent proteins of the pathology, but there was limited understanding of the disease in its entirety.”

Currently, there is no cure for Alzheimer’s, but the FDA recently approved two new drugs that partially remove amyloid plaques. The therapies, lecanemab and donanemab, mark an important advance in Alzheimer’s treatment “because they address causal factors in the disease rather than just the symptoms,” Yankner says. He notes, however, that while the drugs reduce the rate of cognitive decline in people with early Alzheimer’s, they do not prevent the disease from progressing or restore lost cognitive function. “It is a good first step, but we have some distance to go in treating this disease,” he says.

Yankner, who is also a co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard, leads one of an interconnected network of Alzheimer’s labs at HMS and its affiliated hospitals studying everything from the most basic biology of the disease to the most promising new avenues for treatment. His recent research focuses on gene regulation and the role of lithium — recently found to be a physiological element — in cognitive function, aging, and the onset of Alzheimer’s disease. Sandeep Robert Datta and Chenghua Gu, both professors of neurobiology at HMS, have pivoted more recently to Alzheimer’s research. Datta is focusing on how the immune system may interact with proteins in the brain to cause the disease, and Gu’s newly launched project is investigating how vascular changes in the brain may contribute.

Together, Yankner, Datta, and Gu are tackling the basic biology of Alzheimer’s from three different angles — a strategy that they feel is essential in a field where progress toward effective treatments has been slow. “I think it’s very important to have a broad research approach, because it’s impossible to predict what is going to bear the most fruit — and sometimes major advances come from unrelated areas of research,” Yankner says.

“I think we should be pluralistic and not partisan,” Datta adds. “There are many, many potential drug targets, any of which could be the key.”

Moreover, Gu notes, casting a wide net protects against devoting too much time and energy to a single research topic in what has proven to be a highly complex and multifaceted disease. “If you bark up the wrong tree, the whole field can be delayed for a long time,” she cautions.

Wide-ranging research

The Yankner Lab initially described how genes are regulated during the aging of the brain and what drives the transition from normal aging to Alzheimer’s disease at a molecular level. Researchers in the lab recently discovered that lithium is found naturally in the brain and other tissues and may play a key role in the disease. An important observation was that lithium is significantly depleted in the brains of older adults with early memory loss, and this change becomes more pronounced with progression to Alzheimer’s disease. “Lithium deficiency appears to occur at two levels: an early reduction in the brain related to reduced uptake, and a later sequestration of brain lithium by amyloid plaques that renders it inaccessible to brain cells,” Yankner says.

When the lab replicated this loss of lithium in mice, the animals developed the cardinal pathological features and cognitive symptoms that define Alzheimer’s disease. The researchers built on these findings to discover a new class of lithium compounds that resist inactivation by amyloid and are highly effective at reducing the pathology of the disease and restoring memory in mouse models. Together, the results provide a new conceptual paradigm for how Alzheimer’s disease may begin.

Yankner says that lithium may help explain a long-standing conundrum in the field: why in some people there is little correlation between dementia and the amount of plaques and tangles in the brain. “People who are able to maintain higher lithium levels may be resistant to the pathology,” he says. “We have data suggesting a correlation between brain lithium and cognitive function in the normal aging population. This is consistent with our experiments in mice in which lithium deprivation during aging results in memory loss even in the absence of Alzheimer-type pathology.” His lab plans to test the hypothesis in larger, long-term studies of the aging human population.

Yankner is also collaborating with physicians at Massachusetts General Hospital and Brigham and Women’s Hospital on a clinical trial that will test whether one of the newly discovered lithium compounds, lithium orotate, is safe and effective in aging individuals with early memory loss and Alzheimer’s. “The results in mouse models are encouraging, but we won’t know about the potential of lithium orotate as a treatment for Alzheimer’s disease until we test it in a randomized clinical trial,” he says.

Datta followed his work on the basic biology of smell into Alzheimer’s research: Over a decade ago, his team discovered a new family of odor receptors that express a gene also implicated as an Alzheimer’s risk factor.

Datta and his team are investigating how this gene might promote Alzheimer’s. They observed that inactivating the gene in mice reduced some Alzheimer’s symptoms. Then, they figured out that the gene enables communication between two types of immune cells: microglia inside the brain and T cells outside the brain. In mice with Alzheimer’s, tau activated microglia, which recruited T cells into the brain and worked with them to cause damage via inflammation. When the gene was inactivated in microglia or T cells, the immune cells stopped interacting.

“This single Alzheimer’s risk gene appears to be acting on two different cell types to facilitate communication between immune systems in the brain and blood, and that interaction seems to be critical for generating Alzheimer’s disease,” Datta says. He adds that the results may also help explain why “just having your brain filled with amyloid or tau isn’t enough to develop Alzheimer’s.”

Datta’s research is ongoing, but he is hopeful that it may offer a new treatment strategy that centers on targeting immune cells — particularly T cells, which are accessible in the blood. “It’s now obvious that your whole immune system changes as a consequence of Alzheimer’s, and that has a lot of practical implications,” he says.

Gu’s entry into Alzheimer’s research is even more recent than Datta’s. Her lab studies two key parts of the brain’s vascular system: the blood-brain barrier, a tightly woven layer of cells that controls access to the brain, and neurovascular coupling, the brain’s mechanism for increasing blood flow to active areas on demand.

Gu’s previous work explored how cells in and around the blood-brain barrier regulate its permeability. Her research on neurovascular coupling revealed how cells lining blood vessels in the brain communicate where blood is needed.

As Gu delved deeper into these systems, she learned that both are known to break down in the early stages of Alzheimer’s. The blood-brain barrier becomes leaky, allowing substances that may damage neurons to enter the brain, while neurovascular coupling becomes impaired, so the brain can no longer efficiently and selectively direct blood.

Gu’s new project is exploring what she calls a “chicken-or-egg” question: whether changes to blood vessels and blood flow in the brain result from or cause Alzheimer’s. Her lab is developing mouse models to probe the genes and pathways that may drive these changes. Since they occur long before amyloid or tau build up, she thinks studying them is essential for understanding the earliest stages of disease.

“I think there’s been a gradual realization in the field that these vascular changes may be an important contributor to Alzheimer’s,” she says.

A focus on the basics

The researchers agree that progress on Alzheimer’s treatments has been hindered by a lack of basic biological understanding, and that scientists need to interrogate every facet of the disease’s fundamental biology, from proteins and genes to immune components and vascular changes.

“I think pretending that we can cure a disease we don’t fully understand is not really a thing — we can’t just try a bunch of stuff and hope something works,” Datta says. “We need a rational approach, and that is going to take time and understanding of biology.”

Datta adds that because Alzheimer’s involves multiple, interacting systems in the body, understanding it will require an integrative view of its biology. “There is definitely a greater appreciation that as this disease progresses, it moves through phases in which the key players are evolving,” he says. “We need to study all of the players to understand the steps that take you from healthy to sick.”

Or, as Gu puts it, “It’s like we are all working on different corners of a puzzle, and at some point, the full picture will emerge.”

Yet even while focusing on the basic biology, the researchers keep the ultimate goal top of mind: to translate findings from the lab to the clinic. “You always ask yourself, when is the best time to develop a therapy?” Gu says. “If you know very little, the biology won’t be correct and the therapy won’t work — but you also don’t need to wait until everything is known.”

Datta is especially encouraged by the fact that current Alzheimer’s medications do seem to help some patients in certain situations. “That’s a crucial proof of concept that this is an intervenable disease, which has basically changed the conversation,” he says. “It’s clear that you can build a drug that works in humans and changes lives.”

The researchers remain optimistic that as a more complete picture of the biology of Alzheimer’s emerges, so too will new and more effective treatments and interventions. “I think we’re now poised to have a substantial impact on the disease. This is the time to push the boundaries of research on Alzheimer’s in many directions,” Yankner says.

Catherine Caruso is a senior science writer in the HMS Office of Communications and External Relations.