Doctors are growing concerned that a dementia mimicking Alzheimer’s has led to millions of misdiagnosed seniors, complicating treatment and care.
LATE (Limbic-predominant Age-related TDP-43 Encephalopathy) is a common, age-related dementia that affects a significant portion of the elderly population, particularly the 6.5 million people 65 and older.
Now, its wider recognition means that among the more than 6.7 million Americans already living with dementia, there could be millions that have been misdiagnosed.
While Alzheimer’s and LATE damage the same critical brain regions, like the hippocampus and amygdala they are caused by a build up of different proteins, amyloid and TDP-43, respectively. LATE is a distinct disease typically less severe than Alzheimer’s.
Each causes a nearly identical profile of symptoms, including memory loss, language impairment and difficulty with focus and complex thought. LATE is also believed to be the cause of around 15 percent of dementia cases, roughly 1 million people.
It also frequently coexists with other brain pathologies. Many people previously diagnosed with Alzheimer’s dementia may actually have had LATE dementia all along, or a mix of both.
About 40 percent of people diagnosed with dementia have LATE in addition to conditions like Alzheimer’s disease or vascular damage. Not only is it a standalone condition but also a very common component of mixed dementia.
The latest generation of dementia drugs such as Leqembi target the amyloid plaques that define Alzheimer’s disease. LATE, however, is caused by the buildup of the protein TDP-43, which causes brain atrophy. This means LATE patients may be prescribed a drug that targets the wrong problem.
There are currently no drugs to treat LATE, but University of Kentucky researchers are testing a drug called nicorandil that has been approved in Europe and Asia for chest pain. They believe it may improve small blood vessel flow in the brain and help protect the hippocampus, a key memory region damaged in LATE.
LATE tends to occur in seniors 85 and older. The mental decline is generally slower than in typical Alzheimer’s, affecting memory and thinking gradually.
Like Alzheimer’s, it primarily affects memory, causing issues with new information, misplacing items and getting lost.
Researchers were puzzled when they found that many individuals who died at an advanced age with dementia symptoms often did not show the amyloid plaques or tau tangles that define Alzheimer’s disease.
This led scientists to search for another cause, and mounting evidence pointed to the accumulation of a different protein, TDP-43.
In 2019, an international team spearheaded by Dr Peter Nelson, a neurologist at the University of Kentucky formally defined this condition as LATE.
A definitive diagnosis of LATE can only be made after death by examining brain tissue, doctors may be able to identify it during a patient’s lifetime through a comprehensive evaluation.
This includes reviewing the patient’s history, conducting memory and cognitive tests, performing basic blood work and obtaining brain imaging such as an MRI.
In some cases, a PET scan or spinal fluid analysis may also be used. This process can effectively rule out other causes of memory loss.
Approximately one-half of people with Alzheimer’s disease pathology, including clumps of amyloid protein in their brain, also have LATE pathology marked by an accumulation of TDP-43. LATE’s characteristics change depending on whether Alzheimer’s is also present, causing more significant, rapid decline.
Ray Hester, a 79-year-old retired Air Force officer and biomedical technician from Versailles, Kentucky, was thought to be in the early stages of Alzheimer’s disease and had worsening memory and word-finding difficulties.
But further testing showed no signs of the amyloid plaques that define Alzheimer’s.
Instead, Hester, 79, was diagnosed with LATE last year, a then-newly defined form of dementia. For him and his wife, Sandy, the revised diagnosis was slightly comforting.
Having watched her mother and aunt decline rapidly from Alzheimer’s, Sandy had feared a similar heartbreaking trajectory.
Learning her husband had LATE, which often progresses more slowly, offered a measure of emotional relief, even as they faced the reality of a similar incurable condition.
Now a participant in the first-ever clinical trial for LATE at the University of Kentucky, Hester takes two pills daily, not knowing if they are the experimental drug nicorandil or a placebo.
His approach to his diagnosis involves taking on manageable tasks like changing lightbulbs at his church and meticulously organizing family photo albums.
Yet the challenges are ever-present; he struggles with complex home repairs that were once easy and often battles to retrieve common words, a task where his wife gently assists.
For Hester, the specific name of his condition matters less than the daily reality of living with it.
‘I still have problems, right?’ he told the New York Times.
The Kentucky trial includes 64 participants experiencing mild memory issues, each of whom takes two heart-shaped pills daily, either nicorandil or a placebo, over a two-year study period, which is set to conclude next year.
Dr Greg Jicha, a neurologist at the University of Kentucky’s Sanders-Brown Center on Aging and study leader, told the New York Times: ‘It is a heart pill, but it seems to work on the genetic abnormalities that have been linked to LATE.’
The strongest known genetic risk factor for developing LATE is the ε4 variant of the APOE gene (APOE4), the same variant that increases the risk of developing Alzheimer’s disease. Having one copy of the APOE4 allele increases the risk for LATE; having two copies increases it further.
By improving blood flow in small vessels, which addresses vascular dysfunction linked to APOE4, nicorandil might help protect brain cells and slow the processes that lead to TDP-43 buildup and hippocampal shrinkage.
‘It can look like Alzheimer’s clinically — they have a memory problem,’ Dr Jicha said.
‘It looks like a duck, walks like a duck, but then it doesn’t quack, it snorts instead.’
