For decades, most cases of dementia in the elderly were treated as Alzheimer’s. Today, it is known that up to one in five cases has another biological basis: LATEa condition linked to advanced aging that affects areas of the brain associated with memory.
Formally described in 2019 by researchers at the University of Kentucky, in the United States, — whose acronym in English means “TDP-43 Age-Related Encephalopathy with Limbic Predominance” — began to clarify a recurring impasse in medical practice: despite typical symptoms, patients did not present positive results in specific Alzheimer’s tests.
“Clinically, LATE usually causes a condition of progressive cognitive decline, with a predominance of episodic memory deficits, very similar to LATE’s disease”, explains neurologist Iron Dangoni, from Einstein Hospital Israelita in Goiânia.
At the origin of the problem, however, the two conditions are not equal. While Alzheimer’s is marked by the accumulation of beta-amyloid and tau proteins, LATE involves the abnormal deposition of the TDP-43 protein in limbic regions of the brain, such as the hippocampus and amygdala, structures directly involved in the formation and consolidation of memory.
Recognizing LATE is essential to avoid inaccurate diagnoses, align expectations of clinical evolution and adapt therapeutic decisions. “Identifying this condition helps explain why some patients do not respond as expected to therapies targeting Alzheimer’s,” says Dangoni.
Diagnostic challenges
Detecting LATE in life, however, is still difficult. Currently, the definitive diagnosis of the condition is neuropathological, made from the analysis of the brain after the patient’s death. Unlike Alzheimer’s, for which imaging exams and laboratory tests already allow the identification of specific biomarkers, LATE does not yet have direct diagnostic tools in clinical practice.
“This is still a very important challenge. As the symptoms are very similar to Alzheimer’s disease, it is currently not possible to know whether an individual who has an accumulation of amyloid and tau also has a deposit of TDP-43”, reports neuroscientist Eduardo Zimmer, professor of pharmacology at the Federal University of Rio Grande do Sul (UFRGS).
There are ongoing attempts to change this scenario. One scheduled for completion in November 2026 investigates a molecule capable of detecting the accumulation of the TDP-43 protein in imaging tests. Developed by Swiss pharmaceutical company AC Immune, the molecule showed promising results in tests with primates, published in . Efficacy and safety in humans are still under evaluation.
The most concrete advance was the publication of clinical criteria to distinguish probable and possible cases of LATE, published in January 2025 in Alzheimer’s & Dementia. The model combines clinical symptoms, imaging tests and the presence or absence of Alzheimer’s biomarkers. In practice, these criteria attempt to deal with common situations in the office. In elderly patients with progressive memory loss, imaging tests can show changes in areas of the brain linked to memory, such as the hippocampus. When these patients do not present typical Alzheimer’s biomarkers, the condition is considered a probable case of LATE.
In Brazil, this recognition is still indirect. “In the Brazilian clinic, it is syndromic, based on advanced age, the clinical profile and the exclusion of Alzheimer’s by biomarkers when available”, explains Dangoni. “Our healthcare system still faces important limitations in accessing advanced biomarkers, but there is growing awareness among specialists, especially in tertiary and academic centers.”
Although it faces similar challenges as other countries in diagnosing and treating LATE, Zimmer assesses that the country is well positioned to contribute to understanding the impact and prevalence of the disease. He highlights the work of the University of São Paulo (USP), which analyzes changes associated with different proteins involved in dementia, such as amyloid, tau and TDP-43. “We will still have a lot of information about the Brazilian population from this work carried out at USP. Obviously, it would be very important to have brain banks in other regions, to have an idea of regional prevalence”, he states.
Treatment options
In patients with isolated LATE, cognitive decline tends to be slower than in Alzheimer’s. Memory loss progresses gradually, and symptoms usually appear later. The scenario worsens when the two conditions coexist, a situation in which progression is faster and cognitive impairments are broader and more severe.
Evidence gathered in a , based on clinical and neuropathological data, indicates that people with LATE without association with Alzheimer’s have better cognitive performance over time. In cases where the two diseases overlap, the decline is more accelerated, resulting in some of the most serious cases of dementia in old age.
There are still few therapeutic options under investigation. The one specifically targeting LATE is underway at the University of Kentucky and is testing the possible effects of nicorandil, a medication used in Europe and Asia to treat angina. The hypothesis is that, by improving circulation in small blood vessels, the drug may help prevent aging hippocampal sclerosis, one of the changes associated with this dementia. The study, which involves 64 participants, is expected to be completed in November this year.
Given the frequent overlap between LATE and Alzheimer’s, researchers are also considering the possibility that medications already approved to treat Alzheimer’s have some effect on symptoms associated with the “new” disease. To date, however, there is no clinical evidence to confirm this hypothesis.
For the neurologist at Einstein Goiânia, recognition of the condition has changed the interpretation of brain aging. “For the patient, this means more accurate diagnoses and more honest communication about prognosis and therapeutic expectations,” says Iron Dangoni. “It also paves the way for the development of new biomarkers and specific treatments, in addition to improving the design of clinical studies, avoiding the inclusion of patients with LATE in research focused exclusively on Alzheimer’s.”
