[Reading Science] Discovered Rare Mutation That Prevents Dementia

Shaking Up Conventional Wisdom on Dementia Causes and Treatments
Could Become a Catalyst for Developing New Therapies

Scientists have discovered new clues that could accurately identify the causes and treatments for the onset and progression of Alzheimer's dementia. While studying cases of 1,200 families with genetically inherited early-onset dementia, they found a single exceptional case. Through the rare mutant gene this individual possessed, they saw hope for overcoming the limitations that previous dementia research had revealed.

The research team from Antioquia University in Colombia published this study on the 15th in the international journal Nature Medicine. The team analyzed the genes and medical histories of about 1,200 Colombian residents carrying the 'paisa mutation,' which causes early-onset dementia between ages 45 and 50. Surprisingly, they found one individual with this genetic mutation who maintained a normal state with only mild cognitive impairment until the age of 67. Brain examinations of this individual showed that the concentrations of amyloid and tau proteins?known causes of dementia?were similar to those of other severe dementia patients. However, the tau protein concentration in the entorhinal cortex, a brain region related to memory and navigation abilities, was found to be at a low level.

In particular, the research team discovered through genetic analysis that this individual had a mutation in the reelin protein, which is known to be associated with brain disorders including schizophrenia and autism. Until now, the role of reelin protein in dementia had been largely unknown. When the same mutation was experimentally introduced in mice, even more surprising findings emerged. It was observed that the mutated reelin protein chemically modified tau protein, preventing it from attaching to brain cells.

Detailed observations revealed that the mutated reelin protein binds to the same receptor as the APOE protein, which is associated with causing Alzheimer's dementia in people without the paisa mutation. The research team had previously published a study in 2019 analyzing the genes of a woman with the paisa mutation who developed dementia 30 years later than average, finding that she had a mutation in the APOE protein. It was also confirmed that a large amount of amyloid protein had accumulated in the brain cells of this woman.

These findings challenge the existing consensus on the causes of Alzheimer's dementia. Recently, Alzheimer's researchers have primarily targeted amyloid protein, believing that the disease occurs because amyloid protein kills brain cells. However, amyloid-targeting dementia drugs, even those approved by the U.S. Food and Drug Administration (FDA), have only shown modest effects in slowing cognitive decline.

Yadong Huang, a neuroscientist at the Gladstone Institutes in San Francisco, explained, "The fact that this patient was able to maintain mental health for so long despite amyloid protein deposits in brain cells suggests that the causes of Alzheimer's may be more complex. There are multiple causes of Alzheimer's dementia, and amyloid protein is just one of them."

This research is also expected to aid in the discovery of new dementia treatments. When combined with previous studies, it supports the hypothesis that strengthening reelin protein or weakening APOE protein could protect the brain from dementia. The research team explained, "Targeted therapies for reelin or APOE proteins may be more effective for sporadic Alzheimer's patients, who experience slower progression and milder symptoms, rather than for large-scale familial early-onset cases found in Colombia."