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Experts propose new definition and recommendations for Alzheimer’s-like disorder

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A continuously evolving spectrum of age-related cognitive decline

Alois Alzheimer’s original patient was 51 years old, and for roughly 70 years Alzheimer’s disease was considered a rare disease that caused presenile dementia. In the 1970s, Robert Katzman, MD, and Robert D. Terry, MD, equated the neuropathologic features of Alzheimer’s disease with the more common senile dementia, and since then we have recognized Alzheimer’s disease as the most common form of dementia. Autopsy studies of patients dying in their 80s and 90s, however, has revealed that far more common than pure Alzheimer’s disease is a mixed neuropathologic picture. In addition, with the advent of biomarker studies a substantial number of individuals have “suspected non-Alzheimer pathology.”

Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and associate director and clinical core director of Mayo’s Alzheimer’s Disease Center.

Dr. Richard J. Caselli

Adding to this is a primary age-related tauopathy and now an age-related TDP-43 proteinopathy, all of which appear to present with an amnestic dementia syndrome. The current consensus working group recommendations on limbic-predominant age-related TDP-43 encephalopathy (LATE) make the important point that clinical trials in elderly dementia patients must be more careful to screen out those who do not have Alzheimer’s disease but instead a mimic, among which, in essence, LATE can be considered.

Interestingly, the authors identify the apolipoprotein E epsilon 4 (APOE4) allele as a predisposing factor for LATE, although given the advanced age of the LATE patient population, one could argue that a certain degree of resilience extended their lives into the LATE age range.

In contrast, in the Alzheimer’s Disease Sequencing Project, among those with autopsy confirmation, the prevalence of APOE4 in Braak stage 5-6 declines with succeeding decades so that, by the 80s and 90s, the prevalence of APOE2 is actually higher at 7.3% vs. 4.1% with APOE4 for ages 80 to younger than 85 years, 9.3% with APOE2 vs. 8.6% with APOE4 for 85 to younger than 90 years, and 16.7% with APOE2 vs. 6.9% with APOE4 for ages 90 years and above.

Our understanding of age-related cognitive decline, from the normal to the pathological ends of the spectrum, continues to evolve, and LATE is simply the latest addition to our growing knowledge base that will further inform clinical diagnosis, research, and experimental therapeutics.

Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.



An international group of experts has proposed a new name, staging criteria, and recommendations for a recently recognized brain disorder that mimics Alzheimer’s disease and is marked by a proteinopathy caused by malformed transactive response DNA-binding protein of 43 kDa (TDP-43).

The term limbic-predominant age-related TDP-43 encephalopathy (LATE) was coined in an effort to raise awareness and kick-start research into this “pathway to dementia,” the experts wrote in a report appearing in Brain.

“As there is currently no universally agreed-upon terminology or staging system for common age-related TDP-43 proteinopathy, this condition is understudied and not well recognized, even among investigators in the field of dementia research,” wrote the authors of the report, led by Peter T. Nelson, MD, PhD, of the University of Kentucky, Lexington.

LATE neuropathologic changes, associated with a progressive amnesia syndrome that mimics Alzheimer’s, are seen in more than 20% of individuals past the age of 80 years, according to large, community-based autopsy series. It coexists with Alzheimer’s disease in many patients, lowering the threshold for developing dementia, authors said.

The term LATE is designed to encompass several other terms related to TDP-43 pathology, including hippocampal sclerosis and cerebral age-related TDP-43 with sclerosis, Dr. Nelson and coauthors noted in their report.

The TDP-43 protein is encoded by the TARDBP gene and provides several functions related to the regulation of gene expression, the authors wrote.

Misfolded TDP-43 was known to play a causative role in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, the authors noted, and then was also identified in the brains of older individuals with hippocampal sclerosis or Alzheimer’s disease neuropathologic changes.

The authors proposed a three-stage classification system for LATE neuropathologic change based on TDP-43 immunohistochemistry performed during routine autopsy evaluation of the amygdala, hippocampus, and middle frontal gyrus.

The amygdala is an area affected early in the course of the disease (Stage 1), whereas involvement of the hippocampus represents a more intermediate stage (Stage 2), and the middle frontal gyrus is more affected in advanced stages of the disease (Stage 3), according to the schema.

Five genes have been identified with risk alleles for LATE neuropathologic changes, authors said. Of note, several groups have found that the apolipoprotein E epsilon 4 (APOE4) allele, known to be a risk factor for Alzheimer’s disease neuropathologic changes and Lewy body disease, is also linked to increased risk of TDP-43 proteinopathy.

There are no established biomarkers specific to TDP-43 proteinopathy yet, which hampers development of clinical trials designed to test interventions to treat or prevent LATE, Dr. Nelson and colleagues said in their report.

LATE could also obscure the effects of potentially disease-modifying agents being tested in Alzheimer’s disease clinical trials, which can complicate the interpretation of study results, they added.

“Until there are biomarkers for LATE, clinical trials should be powered to account for TDP-43 proteinopathy,” they wrote.

Dr. Nelson and coauthors of the report in Brain reported no competing interests.

SOURCE: Nelson PT, et al. Brain. 2019 Apr 30. doi: 10.1093/brain/awz099

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