Beyond Alzheimer’s
Emerging Dementia Research Redefines Perspectives on Aging Brains.
Dr. David Jones, a behavioural neurologist at the Mayo Clinic, remembers the patient who made him rethink his understanding of Alzheimer’s disease (AD).
A highly intelligent older woman, the patient had experienced subtle memory problems for years but otherwise didn’t seem to be having cognitive difficulty. Tests confirmed mild memory issues, but Dr. Jones wasn’t too concerned. Then, he saw an MRI scan of her brain.
“It was striking,” he recalled.
What he saw was that the limbic system, an area of the brain strongly associated with memory, was severely deteriorated. “I thought, ‘You only see this in end-stage Alzheimer’s disease, but clinically, she’s nowhere near that stage, she’s doing very well.’”
He then performed an FDG-PET scan, a type of CT scan that can detect brain changes associated with AD.
UNLIKE THE LIMBIC SYSTEM, THE SCAN SHOWED THE WOMAN’S CEREBRAL CORTEX, AN AREA OF THE BRAIN INVOLVED IN THINKING AND REASONING, WAS PERFECTLY HEALTHY.
“The brains of Alzheimer’s patients don’t look like that,” Dr. Jones said. “I thought, ‘This is very interesting.’”
More than a dozen years later, after seeing similar patients and studying affected brains, Dr. Jones and his colleagues laid out new criteria for diagnosing the condition, calling it Limbic-predominant Amnestic Neurodegenerative Syndrome, or LANS, in a 2024 paper published in the journal Brain Communications.
LANS is often linked to a disorder called Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE.
While LATE and LANS are frequently connected, they are not the same thing, Dr. Jones said. He explained that LANS describes a clinical syndrome that involves the degeneration of the limbic system in the brain. Meanwhile, LATE is a disorder in which the TDP-43 protein turns into a sticky plaque. When this plaque clogs up the limbic system, it can lead to LANS. However, plaques derived from other proteins, like those from AD, can be involved as well, and a mix of different types of plaque is the most common scenario, he said.
This distinction is important for several reasons, including potential future treatments, he noted. For example, a drug that treats the limbic system directly, rather than targeting the TDP-43 protein, could be effective for everyone with LANS, regardless of which protein caused their condition.
“Understanding these nuances is crucial for accurately diagnosing and treating these conditions,” Dr. Jones said.
THE IMPACT
The good news is that dementia caused by LANS tends to be milder and progresses more slowly than AD. Symptoms tend to be limited to memory problems – without the personality changes, impaired reasoning, trouble thinking, loss of language ability, and debilitating cognitive decline seen in AD.
Neurodegenerative diseases involve “normal proteins that turn into glop,” said Dr. Pete Nelson, a neuropathologist at the University of Kentucky Sanders-Brown Center on Aging, and a co-author on the paper.
Because the brain can’t cope with this toxic sludge, it responds by killing the affected cells. Over time, this causes the brain to shrink, sometimes losing a third of its mass.
Because it impacts the limbic system, it affects short-term memory consolidation, Dr. Nelson explained.
It’s not necessarily where the memories are stored, but it’s where the organization of memories being laid down occurs.
That’s one reason behind a telltale symptom of the condition: a peculiar loss of ability to remember “emotionally charged historical facts,” said Dr. Jones. For example, American patients could not identify a photo of Osama bin Laden or recall details of the Sept. 11, 2001 terrorist attacks.
“In extreme cases, people could not give me details of World War II, like who the leader of Germany was,” Dr. Jones said. “These are striking losses of memories that you don’t see in other conditions.”
THINKING OUTSIDE THE ALZHEIMER’S BOX
Scientists and doctors have understood for at least three decades that not all cases of age-related dementia are the same, said Dr. Soo Borson, professor of clinical family medicine at USC’s Keck School of Medicine and Co-Lead of BOLD Public Health Center of Excellence on Early Detection of Dementia.
While AD used to be a catch-all diagnosis applied to any older person with dementia, there’s been a growing recognition that many don’t actually meet the criteria for the disease.
Previously, researchers could only spot these differences when they examined patients’ brains after death. But with advances in imaging technology and other diagnostic tools, it is now becoming possible to analyze brain changes and make a diagnosis while the patient is alive, Dr. Borson said.
“The ability to differentiate between different forms of degenerative brain disease is a fairly new phenomenon,” she noted.
While it’s true that AD is the most common age-related neurodegenerative pathology seen in the brain, “it actually accounts for less dementia than most people think,” said
Dr. Claudia Kawas, professor of neurology at the University of California, Irvine, School of Medicine.
That means that many people who have the brain changes associated with AD don’t actually go on to develop symptoms, she explained.
At the same time, some people with dementia symptoms have overlapping pathologies.
They may have plaques associated with both AD and LATE or LANS.
“The question is, which one is contributing to what?” she said.
Dr. Nelson agreed it’s likely that LATE, LANS, and AD often overlap. People with one condition are at higher risk of the other, and having multiple conditions at the same time seems to predict a worse outcome. Dr. Kawas said they have more severe dementia and experience a faster decline.
And while some people with AD pathology never develop dementia, that changes if they also have a second pathology like LATE or LANS. Having multiple types of plaques makes it much more likely that someone will have dementia symptoms, she said.
“It almost seems like we can tolerate Alzheimer’s pathology in our brain until we get knocked over with another hit,” Dr. Kawas explained.
UNDERSTANDING RISK FOR WOMEN
So far, the biggest risk factor for LATE appears to be age, with risk increasing after age 75.
“LATE is very, very strongly age-related,” said Dr. Kawas, whose research focuses on the “oldest old” – people over age 90 and 100.
In fact, while research suggests that the accumulation of AD-associated plaques may start to level off after age 90, brain changes associated with LATE seem to increase in extreme old age, she noted.
And while it’s likely that women are at higher risk for LATE and LANS than men, as they are with other dementias, that’s probably not because of inherent sex differences but because they simply live longer.
“The biggest differences have to do with longevity,” Dr. Borson said. “Other than that, there are not huge gender differences across any of these disorders.” But she noted, sex differences should receive more study. “Those research areas are really important,” she added.
A LINK TO CARDIOVASCULAR HEALTH
Scientists still have much to learn about LATE and LANS and the factors that increase risk. But researchers have noticed a possible link to arteriosclerosis, or a hardening of blood vessels, including the blood vessels that permeate the brain.
“It’s possible that people with hypertension and diabetes who are also at risk for LATE or LANS should be careful in controlling these cardiovascular risk factors through risk factor reduction or medicines,” Dr. Nelson said.
And even though scientists don’t yet understand the details of what causes LATE and LANS, it’s well known that people’s vulnerability to neurodegenerative diseases tends to be influenced by how well-developed their brains are in the years and decades before they grow old, Dr. Borson noted.
EDUCATION, NUTRITION, PHYSICAL ACTIVITY, SOCIAL RELATIONSHIPS, AND OTHER HEALTHY BRAIN HABITS CAN ALL HELP BUILD UP THE BRAIN, POTENTIALLY FORTIFYING IT AGAINST DETERIORATION LATER IN LIFE.
In addition to taking steps to protect their own brain health, women can have a beneficial effect on future generations, such as by modelling healthy eating to their families, and encouraging grandchildren to stay in school, Dr. Borson said.
“Women have powerful roles in brain protection,” she noted.
THE VALUE IN GETTING DIAGNOSED
Unfortunately, there is currently no known treatment for LANS.
The key thing for people to know is that the pathology is not an Alzheimer’s pathology, so the new Alzheimer’s medications are not indicated in this condition.
But there’s still value in getting a clear diagnosis, Dr. Borson added, and other experts agreed.
For starters, finding out you have LANS might be reassuring. “For people who react with tremendous worry and fear if they get a diagnosis of Alzheimer’s, this disorder has a more benign course,” Dr. Borson said.
Having a clear diagnosis can empower people to understand their condition and make decisions for the future, and it can potentially help them access new treatments in the future when they do become available, Dr. Jones said.
It can also potentially make patients eligible to participate in clinical trials, giving them access to experimental treatments. Dr. Nelson noted that a clinical trial of a potential treatment for LATE is currently underway at the University of Kentucky.
“Consider participating in a clinical trial,” he said. “It can be fun, interesting, make you better, and help the world.”
But diagnosis is the first step. Because LANS is relatively new, many doctors may miss the signs or not have access to the advanced technologies needed to make a diagnosis.
Even if a provider tells someone they don’t have AD, that’s not enough, Dr. Nelson said. Patients and caregivers can advocate for themselves by asking about whether they fit the criteria for LANS, and whether any other types of dementia should be considered.
“If you don’t have answers, how can you make a plan?” Dr. Jones said. “A diagnosis is not just academic, it’s a key step to quality clinical care.”
Source: Mind Over Matter V21