In a patient with late-onset Alzheimer’s disease, despite having a genetic predisposition to early onset, researchers have identified a genetic mutation that may have helped him remain cognitively intact into his late 60s.
An international team of researchers, led by staff from Massachusetts General Hospital (MGH) and Mass Eye and Ear, USA, said the variant occurred in a different gene than the case from the same family reported in 2019, but that it pointed to a common disease pathway, localization brain regions that might provide an optimal target for treatment in the future.
“The genetic variant we identified points to a pathway that can produce extreme resistance and protection against Alzheimer’s disease symptoms,” said co-author Joseph F. Arboleda-Velasquez, a Mass Eye and Ear scientist.
A family member of the world’s largest relative with a genetic variant called the “Paisa” (Presenilin-1 E280A) mutation first caught the attention of investigators. Carriers of this mutation are known to develop mild cognitive impairment at a median age of 44, dementia at age 49, and die of dementia complications at age 60.
Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellin, Colombia, discovered this family and has been following it for the past 30 years. This team of investigators previously studied a woman from this family who remained unharmed into her 70s and whose case was reported in 2019.
In this article, the investigators describe the case of a male Paisa mutation carrier who remained cognitively intact until age 67. He progressed to mild dementia at the age of 72 and died at the age of 74 – a decade after most people with the Paisa mutation usually 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 a known Paisa mutation to Boston for advanced neuroimaging, biomarker and genetic testing.
Carrying out genetic and molecular analyzes to identify other variants that might provide him with 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-author Diego Sepulveda-Falla, principal investigator at the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf, Germany.
“Each of the protected cases shows a distinct pattern of protection in the postmortem analyses, one global and the other very localized,” Sepulveda-Falla said. “It forces us to revise our previous concepts about neurodegeneration and cognitive decline.”
The researchers described Reelin as a “cousin” to the more famous APOE, a protein strongly implicated in Alzheimer’s disease, with the two competing to bind to similar cellular receptors. While Reelin binding reduces the phosphorylation of tau, a protein known to form pathological tangles in Alzheimer’s brains, APOE binding to the receptor has the opposite effect.
While mutations in Reelin have been linked to diseases such as autism, schizophrenia, epilepsy and bipolar disorder by reducing the function of the tau protein, Reelin-COLBOS was found to increase the protein’s function.
“The fact that the first case showed us a variant affecting APOE and the second case affecting Reelin tells us that this signaling pathway, which controls tau phosphorylation among other things, may be the 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.
Neuroimaging scans of the last patient, aged 73, revealed that while his amyloid-beta plaque burden was high and he had tau tangles in some brain regions, his entorhinal cortex, which plays a critical role in memory and learning, had remarkably limited tau pathology, a finding further validated in mouse models. Degeneration of the entorhinal cortex is known to lead to cognitive impairment and dementia.
As researchers develop gene therapies that may in the future yield treatments that can modify or manipulate gene expression, understanding which brain region to target for delivery will become increasingly important, the study said.
Written by: Vaishali verma
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