While Alzheimer’s is the most widely studied form of dementia, a newly identified condition can easily be confused with the disease.
Peter Nelson, MD, PhD, an experimental neuropathologist at the University of Kentucky’s Sanders-Brown Center on Aging recently coined the name for the condition: LATE, or limbic-predominant age-related TDP-43 encephalopathy. TDP-43 is an amino-acid protein that regulates RNA splicing and other cellular functions.
Before the 2019 discovery, researchers were seeing a history of people with evidence of dementia unexplained by autopsy results. A new autopsy protocol developed by the team led to the discovery and classification of LATE and subsequent publication of a definitive paper in 2022.
The motivation driving the work of Nelson is personal. His grandmother, Sylvia Becker, died of Alzheimer’s.
“It is every researcher’s dream to help identify and classify a disease, and then to go on and help beat it,” he said. “LATE can often be mistaken for Alzheimer’s disease as it also causes memory loss – a predominant symptom of Alzheimer’s – but it tends to progress more slowly and only shows up in seniors over 80 years old.”
Scientists had suspected something like LATE for years, especially among older patients who didn’t seem to fit an Alzheimer’s diagnosis. The initial research linked the TDP-43 protein with two forms of dementia: amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and frontotemporal lobar degeneration.
“This may help explain why when we autopsied some of the brains of people whom we thought had Alzheimer’s, we didn’t see any signs of the disease,” said Nelson.
Autopsy reports show that up to half of people over age 80 have some form of LATE in their brain, with about a quarter having enough of it to affect memory and cognition.
“By reaching a consensus on what LATE actually is, scientists can start working on identifying biomarkers (measurable signs of a disease process—like protein levels in the blood or structural abnormalities seen on brain scans) for the disease and potential treatments. Perhaps more importantly, it means they can better discern which patients may be suited for clinical trials for other types of dementia.”
Alzheimer’s vs. LATE: Differences and diagnosis
Symptoms of LATE are similar to Alzheimer’s—memory impairment is typically the first indication.
“What differentiates LATE is age: It’s much more prevalent in people older than 85,” Nelson said. “Further, when present alone, it can have a slower progression over time. However, when LATE is combined with Alzheimer’s, the resulting disease is more swift and severe than either alone.”
Although it’s currently almost impossible for clinicians to distinguish between LATE and Alzheimer’s disease, there are some key differences. Rather than buildups of amyloid plaques and clumps of tau (proteins that appear normally in brains) characteristic of Alzheimer’s disease, LATE shows up in misshapen TDP-43 proteins in specific regions of the brain and damages many of the same areas affected by Alzheimer’s, including:
- Amygdala (involved in emotional regulation)
- Hippocampus (involved in learning and memory)
- Temporal lobe (involved in words and their meanings)
- Portions of the frontal lobes (involved with keeping information in mind and manipulating it)
Scientists are still studying what causes TDP-43 to clump outside of cell nuclei.
“We are currently relatively poor at diagnosing LATE specifically in live persons, though we have good diagnostic methods for Alzheimer’s, so it can be a ‘diagnosis of exclusion,’” said Nelson.
He added that researchers do not currently see evidence that any ethnic, racial or other sub-population group is at higher or lower risk.
What are the symptoms of LATE?
Because LATE affects many of the same brain regions as Alzheimer’s, it often presents with similar symptoms, including:
- Memory loss
- Trouble finding and understanding words
- Trouble keeping information in mind
New LATE clinical trials are underway
Effective drug treatment for Alzheimer’s has been elusive, but the discovery of LATE may help explain why drug therapy has been so difficult and has failed in previous clinical trials.
“People who actually had LATE, not Alzheimer’s, may have been included in previous clinical trials and thus may not have responded to treatment,” Nelson said. “Even more confusing, it’s possible to have LATE and Alzheimer’s at the same time, making it harder to figure out which disease is causing which symptom. While we now have brain imaging tools such as PET scans that allow us to find out if someone has high levels of beta-amyloid that indicate Alzheimer’s, there’s no test right now to diagnose LATE.”
Because the number of people with dementia is expected to skyrocket over the next few decades, experts say better diagnostic and treatment methods are essential.
“This group of older adults is expanding at the fastest rate of any demographic,” Nelson said. “We need to have strategies that enable us not only to identify the various forms of dementia but ways to both treat and, hopefully, even prevent them.”
No FDA-approved treatment exists for LATE, but Nelson’s group – in partnership with the National Institute on Aging – is spearheading the first-ever clinical trial using a drug that seeks to prevent disease progression in at-risk individuals. A study commenced in December 2021 is testing the safety and efficacy of nicorandil, a vasorelaxant drug used to treat angina and heart disease in the elderly (but that has not been tested in humans for the prevention or treatment of dementia).
The potential success of this trial (which will conclude in November 2024) will not only help with immediate treatment for their condition but may also reduce the economic burden of dementia-related health care costs.
The most important next step is to develop a test that can measure levels of TDP-43 in a living patient.
“We’ll want to be able to measure that during the earlier years of a person’s life, to get a sense of how much TDP-43 they have at baseline and then how much they develop later in life if they start showing signs of dementia,” explained Keith Fargo, director of scientific programs and outreach at the Alzheimer’s Association.
Fargo said the hope is that dementia patients can be offered a cocktail of dementia drugs, similar to the approach with HIV, targeting whatever combination of brain disorders they have.
Action steps to help prevent LATE and other forms of dementia
While there aren’t any definitive ways to tell if you or a loved one has LATE, you can take steps now to help lower your risk of developing any kind of dementia, said Gary Small, MD, director of the UCLA Longevity Center. He stressed that approximately one-third of dementia cases can possibly be prevented with lifestyle changes:
- Lose weight
- Control high blood pressure
- Eat better following the Mediterranean diet, which focuses on fruits, vegetables, healthy fats (such as olive oil), fish, legumes and whole grains and lowers the risk of developing cognitive impairment in older adults by a third
- Check hearing loss (which can be tied to dementia)