In a patient with delayed onset of the Alzheimer's disease despite having a genetic predisposition to its early-onset, researchers have identified a genetic mutation that could have helped him remain cognitively intact until his late 60s.
The international team of researchers, led by those at Massachusetts General Hospital (MGH) and Mass Eye and Ear, US, said that the variant occurred in a different gene than in a case from the same family reported in 2019 but that it pointed to a common disease pathway, locating a brain region that could provide an optimal treatment target in the future.
Their findings are published in the journal Nature Medicine.
"The genetic variant we have identified points to a pathway that can produce extreme resilience and protection against Alzheimer's disease symptoms," said co-senior author Joseph F. Arboleda-Velasquez, an associate scientist at Mass Eye and Ear.
A family member of the world's largest-known kindred with a genetic variant called the "Paisa" mutation (Presenilin-1 E280A) first caught the investigators' attention. Carriers of this mutation have been known to develop mild cognitive impairment at a median age of 44, dementia at age 49, and die from complications of dementia in their 60s.
Francisco Lopera, director of the Neuroscience Group of Antioquia in Medelln, Colombia, discovered this family and has been following them for the last 30 years. This team of investigators previously studied a woman from this family who remained unimpaired until her 70s and whose case was reported in 2019.
In this paper, the investigators describe a case of a male carrier of the Paisa mutation who remained cognitively intact until age 67. He progressed to mild dementia at age 72 and died at 74 - decades after most people with the Paisa mutation typically do.
The male patient was enrolled in the Mass General Colombia-Boston biomarker study (COLBOS), which brought members of an extended family group of 6,000 individuals with the known Paisa mutation to Boston for advanced neuroimaging, biomarker and genetic examinations.
Performing genetic and molecular analyses to identify other variants that could have been rendering him protection, the team's most promising candidate was a new and rare variant, never before reported in the Reelin gene, which they named Reelin-COLBOS. The team further verified the protective role of the Reelin-COLBOS variant in mouse models and neuropathological studies led by co-senior author Diego Sepulveda-Falla, a principal investigator at the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf, Germany.
"Each of the protected cases shows a distinctive protective pattern in the postmortem analyses, one global and the other very localised," said Sepulveda-Falla. "They are forcing us to revise our previous concepts about neurodegeneration and cognitive decline."
The researchers described Reelin as a "cousin" of the more famous APOE, a protein heavily implicated in Alzheimer's disease, both of which compete to bind to similar cellular receptors. While the binding of Reelin diminishes the phosphorylation of tau, a protein known to form pathological tangles in brains with Alzheimer's disease, binding of APOE with the receptor has the opposite effect.
While mutations in Reelin have been linked to diseases like autism, schizophrenia, epilepsy, and bipolar disorder by diminishing the tau protein's function, Reelin-COLBOS has been found to increase the function of the protein.
"The fact that the first case showed us a variant affecting APOE and the second case affects Reelin tells us that this signalling pathway that controls the phosphorylation of tau, among other effects, may be key to understanding why these patients were protected. This is critical to guide therapies because it clearly tells us that more Reelin could potentially have beneficial effects," said Arboleda-Velasquez.
The neuroimaging scans of the most recent patient, at age 73, revealed that while his amyloid-beta plaque burden was high and he had tau tangles in some regions of his brain, his entorhinal cortex, playing a critical role in memory and learning, had notably very limited tau pathology, a finding further verified in mouse models. The degeneration of the entorhinal cortex is known to lead to cognitive impairment and dementia.
As investigators pursue gene therapies that may in the future deliver treatments that can modify or manipulate gene expression, understanding what region of the brain to focus on for delivery will become increasingly important, the study said.