The aging brain

It is perhaps one of the greatest ironies of aging that once we reach the point in life when our memories tend to give us the most pleasure, our ability to preserve new ones can start to falter. All parts of our brains are subject to the ravages of time, but there are unique aspects of the regions responsible for memory and other higher-order cognitive functions that make them particularly vulnerable to aging.

Memory failures and difficulty with complicated brain processing tasks are common in older adults, even though many other brain functions typically remain intact well into our 80s and beyond. For example, we are more likely to forget where we put the car keys than to lose the ability to use our hands to pick up the keys.

The neurons and brain regions responsible for memory are typically the first to falter in people with Alzheimer’s disease, a progressive neurodegenerative disease that is the most common form of dementia and the fifth-leading cause of death among those 65 and older in the United States. Although Alzheimer’s disease is distinct from normal age-related memory loss, many of the same biological processes occur in both.

Researchers at Yale School of Medicine are deepening the understanding of the aging brain’s biology, making headway into new therapies for Alzheimer’s disease, and improving the efficacy of existing therapies. They’re also learning more about ways to protect the blood vessels that supply the brain with precious oxygen and nutrients—vessels whose age-related damage can lead to strokes, brain hemorrhage, or even dementia itself.

A year ago, lecanemab (Leqembi^®) became the first-ever disease-modifying treatment for Alzheimer’s disease to receive full approval by the Food and Drug Administration (FDA). Following on the heels of many failed Alzheimer’s drugs, the success of this monoclonal antibody may have been overlooked by many observers, but it represents a big step forward for the field and for patients, said Christopher van Dyck, MD, Elizabeth Mears and House Jameson Professor of Psychiatry and of Neurology and Neuroscience, and director of Yale’s Alzheimer’s Disease Research Unit and the Yale Alzheimer's Disease Research Center. “This comes on the end of decades of trying, so it is a huge moment in our field,” van Dyck said. “It is also the beginning of a new era. We’ll see still better drugs along the way.”

Van Dyck led the publication of a large clinical trial showing that lecanemab slows cognitive decline in patients with symptoms of early Alzheimer’s disease—the first such clinical success for any Alzheimer’s drug. Other drugs previously approved for Alzheimer’s can ameliorate cognitive symptoms to some extent but don’t touch the disease’s underlying neurodegenerative progression. The clinical trial of lecanemab ultimately led to the drug’s approval. Although lecanemab’s effect could be called modest—it slows cognitive decline by 27%—ongoing unpublished analyses of the original trial and its extension phase suggest that its effect is more pronounced for people with lower levels of brain pathology who take the drug at the earliest points in their disease. Researchers hope that addressing the disease as early as possible might slow its progression even more dramatically.

The hallmarks of Alzheimer’s disease are the accumulation of what are known as amyloid plaques—sticky clumps of a protein called amyloid beta that form between neurons in the brain—and phosphorylated tau, a modified version of the tau protein that piles up in misfolded tangles inside the neurons. Lecanemab is an antibody that targets specific forms of amyloid, reducing their levels in the brain. A number of previous experimental therapeutics also targeted amyloid but failed to alleviate patients’ symptoms or slow the progression of the disease. Lecanemab’s success appears to relate to the targeting of aggregated forms of amyloid. Many previous anti-amyloid therapies simply targeted monomers (single molecules) but not the more neurotoxic oligomers or “protofibrils.”

“It was simply wonderful,” van Dyck said when describing how it felt to see the approval of lecanemab after many decades working on Alzheimer’s drug development. “When you think about what preceded this, we had some really dark decades with no tangible new developments.” Further progress came on July 2, 2024, when the FDA also approved the amyloid-targeting drug donanemab (Kisunla^®) for early Alzheimer’s disease.

Van Dyck and his team are also engaged in another nationwide clinical trial, the AHEAD study, to test whether lecanemab may delay or prevent the onset of Alzheimer’s disease in people who have yet to show symptoms. Alzheimer’s is a disease of old age in part because it takes years, if not decades, for evidence of the accumulation of amyloid and other dysfunctional proteins in the brain to manifest outwardly. The AHEAD trial, which recently completed enrollment, uses blood tests and PET scans to look for the presence of amyloid in healthy older volunteers. Those who show elevated levels of amyloid are randomized to receive lecanemab or a placebo, and followed for four years to see whether their cognitive decline and amyloid accumulation in their brains are slowed.

If the AHEAD trial is successful, it could herald a new paradigm in Alzheimer’s disease treatment, van Dyck said. Blood tests that indicate the presence of Alzheimer’s-associated proteins have improved dramatically in recent years. One could imagine a point in the not-too-distant future when these blood tests are part of a routine physical once people reach a certain age. Lecanemab or other potentially preventive treatments could then be prescribed if those blood tests or brain imaging reveals early preclinical signs of Alzheimer’s disease. The researchers hope that if the disease is caught early enough, anti-amyloid treatments or other therapies could slow decline to the point that patients could live most of their remaining years without experiencing debilitating cognitive symptoms.

Accumulating amyloid plaques and tau tangles are key characteristics of Alzheimer’s, but there are many other molecular and cellular changes that occur in the disease—some of which precede protein accumulation. Amy Arnsten, PhD, Albert E. Kent Professor of Neuroscience and professor of psychology, studies some of these changes to better understand why aging and Alzheimer’s affect memory more than other brain functions.

She’s found that many age-related changes that happen in memory neurons are due to the dysregulation of calcium in the brain—a dysfunction that is even worse in Alzheimer’s disease. Our neurons communicate by changing their internal calcium concentrations, but if these levels are out of balance, problems can arise. “You need high levels of calcium for memory, but if it’s not tightly regulated, levels can become too high and initiate toxic actions,” Arnsten said. “You can get abnormal mitochondria, which we need for energy. You lose connections between neurons, and you also see the beginnings of Alzheimer’s-like pathology.”

Although all neurons rely on calcium, an important dietary mineral, the neurons that represent our memories and perform higher cognitive functions are more vulnerable to calcium dysfunction. These neurons have an especially difficult task: they must keep firing even though they are not excited by stimulation from the outside world—meaning that they must maintain a higher level of activity than other kinds of neurons. All that activity requires a lot of calcium, but if the calcium is not tightly controlled, things can go wrong. Aging, stress, traumatic brain injury, and inflammation can all erode the mechanisms that keep calcium under control in a healthy young brain.

Arnsten and her team have found that in older rhesus monkeys who, like humans, naturally develop cognitive deficits with age, calcium dysfunction spurs the accumulation of phosphorylated tau, another hallmark of Alzheimer’s disease. The researchers showed that inhibiting inflammation with an experimental drug to restore calcium regulation improved the aged animals’ cognitive functioning and can reduce the levels of phosphorylated tau, suggesting a strategy for early protection of the aging human brain.

Despite lecanemab’s success, researchers like van Dyck and Arnsten are hoping for more dramatic results from drugs that target other disease-related proteins. Ongoing studies are testing antibodies against tau, and it’s possible that a combination therapy against both tau and amyloid could prove even more effective than targeting either alone, van Dyck said.

Stephen Strittmatter, MD, PhD, chair of neuroscience, Vincent Coates Professor of Neurology, professor of neuroscience, and a director of the Yale Alzheimer's Disease Research Center, is working on ways to directly protect neurons from Alzheimer’s damages.

When amyloid plaques form between neurons, they trigger a cascade that ultimately leads to Alzheimer’s broader effects. Immune reactions to the aberrant plaques prompt microglia, the brain’s immune cells, to rush to the affected neurons. Microglia then remove damaged synapses, the specialized connections between neurons. But in Alzheimer’s disease, their pruning is perhaps overzealous, leading to widespread synapse loss. In addition, amyloid plaques directly damage neurons, leading to even more lost synapses. It is the loss of these connections that manifests in Alzheimer’s early clinical stages before the disease progresses to cause neuronal death.

Strittmatter and his team have discovered in mouse studies that two neuronal proteins, known as the prion protein and the mGluR5 receptor, are responsible for the loss of synapses associated with Alzheimer’s disease. Blocking the activity of either of these proteins prevented Alzheimer’s-like symptoms in mice engineered to mimic the human disease. In collaboration with Strittmatter, Adam Mecca, MD, PhD, associate professor of psychiatry and associate director of the Alzheimer's Disease Research Unit, is now leading a clinical trial to test an experimental drug that blocks the mGluR5 receptor’s activity in healthy study volunteers and in those with Alzheimer’s disease.

Though it is difficult, to the point of impracticality, to remove all the amyloid from the brain, said Strittmatter, “what really matters is protecting neurons from the amyloid plaques. If we can block these receptors at the synapse … you can have a brain with a lot of amyloid in it, but it doesn’t have the synaptic derangements—and therefore symptoms are relieved, at least in animal models.”

Strittmatter also co-leads the newly established Carol and Gene Ludwig Program for the Study of Neuroimmune Interactions in Dementia. Recognizing the importance of the immune system in healthy brain function and disease, this program focuses on bridging a gap between neuroscience and immunology research. The program’s goal is to better understand how brain cells and immune cells interact, and how those interactions go awry in Alzheimer’s disease and other forms of dementia. Ultimately, researchers hope to identify new drug targets by studying these interactions.

But it’s not just brain cells that influence brain aging and disease. Our circulatory system also plays a vital role in keeping our brains healthy as we age. In fact, similar forms of the protein that triggers Alzheimer’s disease—amyloid beta—can also build up inside blood vessels that supply the brain in older adults. Known as cerebral amyloid angiopathy, this phenomenon often accompanies Alzheimer’s and leads to vessel damage that can, in turn, cause strokes or brain hemorrhage. Lifestyle and other risk factors, including smoking, high blood pressure, poor sleep or diet, and high cholesterol, can further contribute to blood vessel disease over time.

“Stroke is one consequence of having poor cerebrovascular health,” said Kevin Sheth, MD, professor of neurology and neurosurgery, and a director of the Yale Center for Brain & Mind Health. “But when the vascular system goes awry, there are many other brain aging consequences.” Those other consequences include such chronic disorders as cognitive decline, dementia, and depression. The good news is that, if caught early, vascular dysfunction can often be corrected with lifestyle modifications or medication.

Sheth led the development and deployment of a portable MRI machine that could be used to find signs of poor cerebrovascular health in hospital patients or even in individuals in community clinics before it has dire effects. The imaging method looks for reduced brain volume and a phenomenon known as white matter hyperintensities—brain matter lesions that often don’t cause symptoms but signal a higher risk of Alzheimer’s disease and stroke. Sheth and his colleagues found that in people with high blood pressure, more than 50% have white matter hyperintensities. Treating the underlying hypertension could go a long way toward improving brain health in this population, Sheth said.

The Yale scientists are hoping to use that technology in a not-yet-started trial to test lecanemab in patients with early stages of Alzheimer’s who are also at high risk of vascular complications—a population that was excluded from the drug’s initial trial. These patients can be difficult to treat, especially because one of the potential side effects of lecanemab is brain swelling and hemorrhage. But the researchers hope that the drug’s benefits may outweigh the risk even in this more vulnerable group.

Sheth is also co-leading another trial of people with atrial fibrillation who’ve had a previous brain hemorrhage. Both of these conditions are more common in older adults, and atrial fibrillation is a risk factor for future strokes. Standard treatment for people with atrial fibrillation is to start an anticoagulant medication to prevent stroke, but it’s not known whether these medications are safe for those with a history of hemorrhage. Through the ASPIRE trial, Yale researchers are asking whether the anticoagulant apixaban (Eliquis^®) can prevent stroke in this population compared to daily low doses of aspirin.

There are many other aspects of human lives that inform brain health in older age. Complicating matters, there have been few studies of how neurodiversity and psychiatric disorders affect age-related brain diseases. It is known that Down syndrome increases the risk of Alzheimer’s disease, and that early-onset dementia is more common among adults with autism, but it’s not clear what underlies these differences or how aging intersects with other forms of neurodiversity.

Insults to our brain and body during all stages of life can affect brain aging. Traumatic brain injuries, type 2 diabetes, chronic stress, and depression are all linked to Alzheimer’s and other forms of dementia. Like Alzheimer’s, depression and chronic stress cause loss of connections between neurons, said Christopher Pittenger, MD, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry and a director of the Center for Brain & Mind Health. Antidepressants and exercise have been shown to enhance those connections—potentially explaining why exercise offers such potent protection against Alzheimer’s disease.

Understanding how our entire lives impact the way we age is both daunting and empowering, Pittenger said. “The impact of the world around us on our bodies and our brains isn’t something that starts at age 65,” he said. “Cognitive decline may happen at the end of life, but it’s the tail end of lifelong processes. That’s depressing because we all want to preserve the fantasy of immortality for as long as we can. But it’s encouraging because it means we can intervene in ways that can have profound benefits decades down the line.”