The Silent Mimic: Millions Potentially Misdiagnosed with Alzheimer’s May Actually Have LATE
A growing concern is emerging within the medical community: a form of dementia that closely imitates Alzheimer’s disease may have led to millions of misdiagnoses among seniors, significantly complicating treatment and care strategies. This condition, known as Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE, is a common, age-related dementia that affects a substantial portion of the elderly population. Given that over 6.5 million individuals in Singapore are aged 65 and above, the implications of wider recognition for LATE are considerable. It is now understood that among the millions already living with dementia, a significant number might have been incorrectly identified.
While both Alzheimer’s and LATE impact similar critical brain regions, such as the hippocampus and amygdala, their underlying causes differ. Alzheimer’s is characterised by the build-up of amyloid proteins, whereas LATE is associated with the accumulation of TDP-43 protein. LATE is typically a distinct disease, generally less severe than Alzheimer’s. However, they present with remarkably similar symptom profiles, including memory loss, difficulties with language, and challenges in focusing and complex thought processes. It is estimated that LATE is responsible for approximately 15 percent of all dementia cases, a figure that translates to roughly 1 million individuals.
Furthermore, LATE frequently coexists with other brain pathologies. This means many individuals previously diagnosed solely with Alzheimer’s dementia may have, in fact, been experiencing LATE all along, or a combination of both conditions. Studies suggest that around 40 percent of individuals diagnosed with dementia exhibit LATE pathology in addition to other conditions like Alzheimer’s disease or vascular damage. This highlights LATE’s dual role: it can be a standalone condition and is also a very common component of mixed dementia.
The advent of new dementia drugs, such as Leqembi, which are designed to target the amyloid plaques characteristic of Alzheimer’s disease, raises a critical issue. Since LATE is caused by TDP-43 protein accumulation leading to brain atrophy, patients with LATE might be receiving treatments aimed at the wrong underlying problem. Currently, there are no specific drugs approved for treating LATE. However, researchers are actively exploring potential therapies. For instance, a drug called nicorandil, which is already approved in Europe and Asia for treating chest pain, is being investigated by University of Kentucky researchers. They hypothesise that it may enhance blood flow in the brain’s small vessels and offer protection to the hippocampus, a vital region for memory that is significantly affected by LATE.
Understanding LATE: Symptoms, Diagnosis, and the TDP-43 Protein
LATE typically manifests in individuals aged 85 and older. The cognitive decline associated with LATE is generally more gradual than in typical Alzheimer’s, affecting memory and thinking processes progressively. Similar to Alzheimer’s, the primary impact is on memory, leading to difficulties in retaining new information, misplacing objects, and disorientation, such as getting lost.
For a long time, researchers were perplexed by the observation that many elderly individuals exhibiting dementia symptoms did not display the amyloid plaques or tau tangles that are the hallmarks of Alzheimer’s disease. This scientific enigma spurred a search for alternative causes, and mounting evidence began to point towards the accumulation of a different protein: TDP-43.
In 2019, a significant breakthrough occurred when an international team, led by neurologist Dr. Peter Nelson at the University of Kentucky, formally defined this condition as LATE. While a definitive diagnosis of LATE can only be confirmed post-mortem through the examination of brain tissue, medical professionals are developing methods to identify it during a patient’s lifetime. This involves a comprehensive evaluation process that includes a thorough review of the patient’s medical history, detailed memory and cognitive assessments, standard blood tests, and advanced brain imaging techniques such as Magnetic Resonance Imaging (MRI). In certain situations, Positron Emission Tomography (PET) scans or cerebrospinal fluid analysis may also be employed to rule out other potential causes of memory loss.
It is noteworthy that approximately half of individuals diagnosed with Alzheimer’s disease pathology, characterised by amyloid protein clumps in the brain, also exhibit LATE pathology marked by TDP-43 accumulation. The specific characteristics of LATE can vary depending on the presence of Alzheimer’s, potentially leading to a more pronounced and rapid decline in cognitive function.
A Personal Journey: Ray Hester’s LATE Diagnosis and Clinical Trial Participation
The challenges of misdiagnosis are vividly illustrated by the case of Ray Hester, a 79-year-old retired Air Force officer and biomedical technician from Versailles, Kentucky. Initially, Hester was believed to be in the early stages of Alzheimer’s disease, experiencing worsening memory and difficulties with word retrieval. However, subsequent testing revealed no signs of the amyloid plaques that define Alzheimer’s.
Instead, Hester was diagnosed with LATE, a recently defined form of dementia, last year. For both Ray and his wife, Sandy, this revised diagnosis brought a unique blend of comfort and challenge. Having witnessed her mother and aunt experience rapid declines due to Alzheimer’s, Sandy had feared a similar distressing trajectory for her husband. Learning that Ray had LATE, a condition that often progresses more slowly, provided a measure of emotional relief, even as they confronted the reality of an incurable illness.
Currently, Ray Hester is participating in the first-ever clinical trial for LATE at the University of Kentucky. He takes two pills daily, unaware whether he is receiving the experimental drug nicorandil or a placebo. His approach to managing his condition involves focusing on manageable tasks, such as changing lightbulbs at his church and meticulously organising family photo albums. Yet, the daily challenges persist; he struggles with complex home repairs that were once straightforward and frequently battles to recall common words, a task his wife gently assists him with. For Hester, the precise nomenclature of his condition is less significant than the lived experience of navigating its daily realities. “I still have problems, right?” he shared in a recent interview.
The Kentucky trial involves 64 participants experiencing mild memory issues. Each participant receives two heart-shaped pills daily, either nicorandil or a placebo, over a two-year study period, which is scheduled to conclude next year. Dr. Greg Jicha, a neurologist at the University of Kentucky’s Sanders-Brown Center on Aging and the lead investigator of the study, explained that nicorandil, while a heart medication, appears to influence genetic abnormalities linked to LATE.
The most significant known genetic risk factor for developing LATE is the ε4 variant of the APOE gene (APOE4), which also elevates the risk of Alzheimer’s disease. Possessing one copy of the APOE4 allele increases LATE risk, while having two copies further amplifies it. By improving blood flow in small vessels, thereby addressing vascular dysfunction associated with APOE4, nicorandil may help protect brain cells and slow the processes that contribute to TDP-43 accumulation and hippocampal shrinkage.
Dr. Jicha aptly described the diagnostic challenge: “It can look like Alzheimer’s clinically — they have a memory problem. It looks like a duck, walks like a duck, but then it doesn’t quack, it snorts instead.” This analogy underscores the subtle yet crucial differences that necessitate a more nuanced diagnostic approach for dementias.
