Alzheimer's Progression Delayed by Rare Genetic Variant

The world's second case of ascertained extreme resilience to autosomal dominant Alzheimer's disease was reported, suggesting a new way Alzheimer's progression might be delayed.

A rare genetic variant of RELN, which encodes the signaling protein reelin, was associated with 20 years of resilience to autosomal dominant Alzheimer's disease in a Colombian man, reported Diego Sepulveda-Falla, MD, of the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf in Germany, and co-authors.

Despite an extremely elevated amyloid plaque burden, the man had limited tau pathology in the entorhinal cortex. The case "suggests a role for RELN signaling in resilience to dementia," the researchers wrote in Nature Medicine.

The first case of extreme resilience to Alzheimer's was reported in 2019. Both cases were from the world's largest known kindred of about 1,200 people with autosomal dominant Alzheimer's disease who carried the PSEN1 E280A mutation. Carriers of this mutation develop mild cognitive impairment by a median age of 44 and dementia by age 49, with rare exceptions. Most belong to a large kindred from the Colombian state of Antioquia.

In the 2019 case, a Colombian woman had two copies of the APOE3 Christchurch gene variant; she remained cognitively unimpaired for nearly 30 years after the expected age at clinical onset.

The new case involved a man from the same population who carried a variant termed RELN-COLBOS. He remained cognitively intact until age 67, had mild cognitive impairment at age 70 that progressed to mild dementia at age 72, and died at age 74. He was enrolled in the Colombia-Boston biomarker research study (COLBOS) of autosomal dominant Alzheimer's disease and had neuroimaging at Massachusetts General Hospital when he was 73.

The RELN finding highlights a novel molecular pathway that could be targeted therapeutically to potentially increase resilience across all forms of Alzheimer's disease, the researchers suggested.

"In general, hereditary Alzheimer's disease is considered to be a model for the study of this type of dementia," Sepulveda-Falla told MedPage Today. "We recently learned that the Christchurch mutation in the APOE gene conferred extreme resistance to hereditary Alzheimer's disease."

"With the current study, we learned that another gene, Reelin, can be also mutated in a way that protects against the disease to the same degree," he continued. "This means that there are at least two different ways in which Alzheimer's can be stalled several decades, and that gives us hope for possible therapies."

In the woman with the APOE3 Christchurch variant, protection against tau aggregation was extended globally in a dose-dependent manner, Sepulveda-Falla noted. "This makes sense because APOE is highly expressed and produced in the brain," he said.

"On the other hand, the effect of the RELN-COLBOS mutation seems to be more localized, for instance protecting entorhinal cortex neurons," Sepulveda-Falla pointed out. "In adulthood, Reelin is only expressed by some specific cells in the brain; it's very localized."

"With the RELN-COLBOS case, we have learned that it is possible to be cognitively protected against Alzheimer's disease as long as some specific areas are protected, despite severe pathology," he added. "This challenges our previous assumptions about the disease."

The results identify the entorhinal cortex as a brain region that may be an Alzheimer's treatment target in the future, Sepulveda-Falla and colleagues said. RELN-COLBOS also appeared to be protective of the entorhinal cortex in a mouse model, they added.

The findings are not definitive but could be helpful to generate hypotheses, the researchers acknowledged. Other factors, including additional variants, may have contributed to the Alzheimer's resilience seen in the RELN-COLBOS carrier.

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