Underdiagnosis of Key Alzheimer’s Sign Raises Concerns Amid Expected Surge in Cases

Jean and Mike Bland have been married for 41 years. They found each other after difficult first marriages and immediately fell in love. But a few years ago, Mike began to notice changes in Jean’s behavior: She was getting confused while driving in her familiar hometown of Oceanside, California.

He initially dismissed her confusion as a normal part of aging — after all, they were both in their late 70s at this point. But there were other worrisome changes in Jean’s behavior. A former nurse, Jean was in the habit of showing up at doctors’ appointments with a carefully compiled list of questions. But now she no longer did this. The doctors suggested testing her cognition and found that Jean had mild cognitive impairment (MCI), a condition that may be an early sign of Alzheimer’s disease.

The diagnosis “scared me to death,” Jean says. “I really didn’t know how to handle it at first. So, I had to think about it, read about it and then eventually admit that something was wrong.” She is now taking one of the new drugs that can slow cognitive decline. But because it’s only effective when taken early, it’s fortunate that she was diagnosed when she was.

At USC Dornsife, researchers are studying dementia and Alzheimer’s not only to understand how to prevent them but to discover treatments. The urgency of their mission is underscored by the daunting statistics: 47.5 million people worldwide are living with dementia, with 7.7 million new cases emerging annually. Without groundbreaking medical advances to halt cognitive decline, the number of people living with Alzheimer’s is expected to triple by 2050.

Because people commonly chalk up mental changes to normal aging, the diagnosis of MCI — which can be an early sign of Alzheimer’s — is often missed. A recent study by Soeren Mattke, director of the Brain Health Observatory at USC Dornsife’s Center for Economic and Social Research, found that MCI is alarmingly underdiagnosed: Among Americans 65 and older, 7.4 million are unknowingly living with the condition. Even more startling, half of these individuals are silently battling Alzheimer’s disease.

Mattke and his colleagues analyzed data from 40 million Medicare beneficiaries and compared the proportion diagnosed as having MCI with the expected rate for this age group. They found that fewer than 8% of expected cases were actually diagnosed. A second study looked at more than 200,000 individual primary care clinicians and found that 99% of them underdiagnosed MCI.

Symptoms of MCI are mostly forgetfulness and struggles with tasks, such as balancing a checkbook or following a recipe, that require executive functioning. Underdiagnosis is commonly associated with patients not wanting to discuss their challenges with their doctor and short clinical visits with no discussion of brain health.

The study is a wake-up call to identify MCI early, says Mattke, professor (research) of economics.

“Once you’ve lost brain cells, they are irreversibly lost,” he says. “And this is why we need to find these cases very, very early on in this MCI phase so that we have the potential to treat it.”

Understanding dementia’s causes — and seeking a cure
Researchers at USC Dornsife are also using synthetic biology to better understand the changes in brain structure that signal the onset of Alzheimer’s.

Thanks to a joint gift of $50 million from the Epstein Family Foundation to USC and the University of California, San Diego, the recently created Epstein Family Alzheimer’s Research Collaboration is driving Alzheimer’s research at both universities, accelerating the search for better treatments and a cure.

At the heart of this effort, USC Dornsife physicist Peter Chung, Robert D. Beyer (’81) Early Career Chair in Natural Sciences and assistant professor of physics and astronomy and chemistry, has been exploring one of the hallmarks of Alzheimer’s — the brain’s tau protein formations. When tau proteins, which typically support and maintain neuron structure, become defective, they form into “tangles.” These tangles are harmful as they lead to nerve cell damage and inflammation, laying the groundwork for Alzheimer’s symptoms.

Until now, the only methods available to study tau tangles have presented researchers with significant challenges. To better understand these abnormal protein accumulations within brain neurons, Chung and his colleagues are engineering synthetic versions that precisely replicate the tangles’ structure as seen in Alzheimer’s patients. They are also creating a laboratory model that will enable the rapid evaluation of numerous chemical compounds. Their goal? To discover groundbreaking treatments capable of dissolving tau tangles, offering hope to Alzheimer’s patients by potentially slowing the progression of the disease — or even stopping it in its tracks.

Movement for the Brain
As director of USC Dornsife’s Evolutionary Biology of Physical Activity Laboratory, David Raichlen is interested in many issues relating to physical activity and brain health. Curious about modifiable lifestyle behaviors — changes that might be more attractive to people than physical activity — he recently finished a study of time spent sitting. After all, sedentary time was already linked to cardiovascular disease risk and type 2 diabetes; it made sense that it might affect the brain as well. “The impetus was to find out whether behaviors that are easier to modify — like sitting — could have an impact on brain health,” he explains.

Raichlen, professor of biological sciences and anthropology, used data from the UK Biobank and from wrist-worn accelerometers to classify peoples’ sitting behaviors and discovered something rather surprising: The risk of dementia didn’t respond linearly to the time spent sitting. Instead, he and his colleagues found that there was little risk in sitting up to about 9.5 hours each day — but after that, the risk of developing dementia increased significantly.

While sitting is one of the most natural and common postures for humans, it significantly alters numerous body systems. Weight is taken off the lower limbs and triglycerides build up, which has an impact on the heart. Sitting also reduces blood flow to the brain, which could increase the likelihood of dementia.

The key is to sit less and move around more, Raichlen says. “If people can find ways to reduce sedentary time and increase the amount of time they are active, the payoff may be a delay in the onset of dementia,” he says. “And fortunately, standing up and walking around the house may be easier for people than increasing exercise.”

Because people who sit for long periods of time may have dietary or lifestyle changes that weren’t captured by the accelerometers but could also impact their brain health, Raichlen is continuing his research.

Following on his lab’s previous studies suggesting that passive activities, like watching television while sitting, are worse for the brain than active behaviors such as using a computer, he also hopes to conduct randomized control trials to understand the mechanisms through which physical activity benefits the brain, amidst a backdrop of various sedentary behaviors.

The relationship between air pollution and dementia is something else Raichlen is actively engaged in researching. Breathing in poor-quality air seems to negate the beneficial impacts of exercise on brain health. Small particles of pollution in the air can enter the body, causing inflammation and stress-induced damage to the brain.

Clues from Indigenous People
In the search for clues to dementia, answers may lie deep in the traditions of preindustrial societies. Exploring this possibility, an international team of experts has been working in the Bolivian Amazon rainforest, studying the Tsimane and Moseten Indigenous groups. For more than two decades the team has sought insights into the groups’ cognitive health. Seven years ago they were joined by USC Dornsife’s Margaret Gatz, professor of psychology. Together, they are uncovering how the prevalence of dementia among these groups could inform a broader understanding of the disease.

The low incidence of heart disease in the groups suggests the potential for low rates of dementia, given its link to the cardiovascular system. Driven by this hypothesis, Gatz and the team employed an array of tools: CT brain scans, cognitive tests, neurological assessments and culturally appropriate questionnaires, all facilitated by a local team of trained translators and Bolivian physicians, to diagnose dementia and cognitive impairment.

Their findings were striking. Dementia prevalence among the groups’ elderly was around 1% — a stark contrast to 11% among older adults in the United States. With such a significant disparity, Gatz’s research is focused on determining the factors that contribute to the groups’ remarkably low dementia rates.

The low rates may be partly due to vascular health, she says, because there are many aspects of the Tsimane and Moseten lifestyles that contribute to both good heart health and good brain health, including diet and high levels of physical exercise.

Mild cognitive impairment is alarmingly underdiagnosed: Among Americans 65 and older, 7.4 million are unknowingly living with the condition. Even more startling, half of these individuals are silently battling Alzheimer’s disease.

Yet, Gatz cautions against over-simplification. “It’s an Indigenous population that is beset by many infections and has low educational levels,” she says, noting the complexity of dementia risk factors. Both inflammation and limited education are, paradoxically, known contributors to increased dementia risk.

One of the challenges in studying Indigenous groups is determining what it means to be cognitively successful in a different society. For the Tsimane, that means fishing, hunting and farming with hand tools and gathering food from the forest throughout their lives. For the Moseten, it means also engaging in agricultural work.

“We are meeting people who are incredibly intelligent in their own environment,” Gatz says. “The challenge is understanding the culture and trying to develop assessment methods that take into account the context in which people live.”

In some ways, she says, these studies are also an example of history in action. “It’s an incredible privilege to be able to look at lifestyles of Indigenous people as a snapshot of what might historically have been true of people living in more developed countries,” Gatz says. “You get to be able to compare that snapshot simultaneously with what we’ve learned from studies in the U.S. and Europe. So, this is an amazing opportunity.”

Gatz’s work also sheds light on the complex relationship between familial genetics and environmental factors in the context of dementia. Analyzing data from the Swedish Twin Registry, she and colleagues uncovered compelling evidence that an Alzheimer’s diagnosis in one sibling correlates with a shortened lifespan for other family members, including those who don’t develop dementia. This suggests that the risks associated with developing dementia may be a delicate balance of genes and environmental factors that affect the entire family’s health.

Increasing our knowledge about the causes and underlying factors of dementia can also help to empower those who are managing it today, like Jean and Mike Bland. For Mike, the future is still unknown — he worries about his own health since he is now a full-time caregiver to his wife. Both he and Jean hope the medication will slow the onset of her dementia, and that research will yield more therapies in the future. With the passage of time, Jean has become a little more confused about following recipes, shopping for groceries, and making decisions. But Mike is sure of one thing: Wherever he goes, Jean will go with him.

“We probably hug and kiss more than we ever have,” he says. “Because we know that our time is limited now.”