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Early-Onset Alzheimer's Disease Symptoms Delayed by Rare Gene Variant

NEW YORK – Members of an international research team have discovered a protective genetic variant that appears to stave off the onset of cognitive symptoms in an individual carrying a risk variant for early-onset Alzheimer's disease.

"We have characterized about 1,200 individuals carrying the presenilin 1 (PSEN1) E280A mutation from the world's largest known kindred with autosomal dominant Alzheimer's disease (ADAD)," co-senior and co-corresponding authors Joseph Arboleda-Velasquez and Yakeel Quiroz, researchers with Mass General Brigham, and Diego Sepulveda-Falla, an investigator at University Medical Center Hamburg-Eppendorf in Germany, and their colleagues wrote in Nature Medicine on Monday, noting that a "genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia."

For their study, the researchers focused on a male patient who remained free of cognitive impairment until the age of 67 years, despite carrying the PSEN1 E280A mutation, which has been implicated in an early-onset form of AD that typically includes cognitive symptoms arising at age 43 to 45 and progression to dementia by the age of 49.

The individual did eventually develop dementia, the team explained, but not until he had reached age 72 — much later than the onset of similar symptoms in most PSEN1 E280A mutation carriers. The symptoms progressed in the following year, and he died of aspiration pneumonia at 74.

Using a combination of clinical profiles, neuropathology and neuroimaging studies, exome sequencing, whole-genome sequencing, and single-cell RNA sequencing, the investigators narrowed in on a rare variant in RELN, a gene encoding the reelin signaling protein.

The variant, dubbed COLBOS based on its discovery in the Mass General Colombia-Boston biomarker study, appeared to delay cognitive symptoms in a RELN-COLBOS heterozygous Colombian individual. Based on neuroimaging, the man had high levels of tau protein "tangles" and amyloid-beta plaque in the brain at the age of 73, the team reported, but lower-than-expected tau tangles in a memory-related part of the brain called the entorhinal cortex.

Prior analyses on the same extended family had led to another rare protective variant, known as the Christchurch (ch) variant, which falls in the APOE3 gene. In particular, a woman from the ADAD cohort with an early-onset AD-linked PSEN1 E280A mutation who carried two copies of the APOE3ch variant remained free of mild cognitive impairment until her late 70s.

"Extreme protection against the most aggressive form of Alzheimer's is very rare, so the Christchurch and COLBOS cases are extraordinary," Arboleda-Velasquez said in an email, adding that "the COLBOS case shows it's possible to remain cognitively unimpaired in the face of high amyloid and tau burden."

There have been relatively few studies focused on variants that protect against, or delay, AD symptoms, Arboleda-Velasquez explained, prompting the investigators to take a closer look at the genetic, neurological, and clinical features for individuals with outlying AD trajectories.

"Extraordinary cases like this one illustrate how individuals and extended families with Alzheimer's disease can help advance our understanding of the disease and open new avenues for discovery," Quiroz said in a statement.

When they looked more closely at the RELN-COLBOS variant through follow-up analyses and mouse model experiments, the researchers found that homozygous versions appeared to boost the activity of reelin and downstream proteins, while diminishing tau phosphorylation — insights that may ultimately help in tracking down protective pathways that might be exploited to develop new AD treatments.

Arboleda-Velasquez and coauthor Leo Kim, a researcher with Mass Eye and Ear and Harvard Medical School, are cofounders of a firm called Epoch Biotech, which is developing new AD therapies based on factors offering protection in clinical cases.

"Regulation of this RELN-protective pathway, particularly in the [entorhinal cortex], may have a profound therapeutic impact on the resistance to tau pathology and neurodegeneration, and resilience against cognitive decline and dementia in AD," the authors suggested.