Twisting DNA strands highlighted to represent a recently discovered gene, offering a beacon of hope in the quest for ways to prevent Alzheimer's disease.

Unlocking the Mystery of Alzheimer’s: The Rare Gene Change Providing a New Path for Prevention

Alzheimer’s disease has long been an enigmatic adversary in the realm of modern medicine. Traditionally, it has been thought of as a cruel inevitability for those predisposed to it through genetic factors. However, recent breakthroughs hint that our understanding of this complex disease and how we combat it might be on the cusp of transformation. The discovery of a man who defied his genetic fate and staved off Alzheimer’s symptoms for decades has sparked a flame of hope in the scientific community, illuminating a promising path toward its prevention [1, 2].

This extraordinary case involves a man from a large family in Antioquia, Colombia, where many family members carry a mutated gene known as presenilin-1, or PSEN1. This mutation almost invariably ushers in the onset of Alzheimer’s disease at a relatively young age. Despite having the PSEN1 mutation, this man bafflingly maintained normal cognitive function into his seventies, a phenomenon that led scientists to dive deeper into the genetic mysteries protecting his brain [1].

The Role of Reelin

Upon examining his genetic profile, researchers discovered an unexpected hero: a rare gene change that enhanced the function of a protein called reelin, a vital player in nerve cell communication. Typically, reelin works to ensure that neurons, the information relay system in the brain, interact effectively. The man’s genetic alteration amplified the reelin’s efficacy, effectively counteracting the effects of the PSEN1 mutation [1].

This newfound knowledge about reelin’s defensive capabilities offers an enlightening perspective in the fight against Alzheimer’s. As Dr. Joseph Arboleda-Velasquez, the lead author of the groundbreaking study, suggests, this revelation underscores the potential of enhancing reelin activity as a therapeutic strategy [1].

A Targeted Approach

Interestingly, this protective gene change seems to work selectively, rather than broadly. A specific brain region known as the entorhinal cortex, which is particularly vulnerable to Alzheimer’s and aging, appears to be the primary beneficiary of this amplified reelin function. Positioned at the base of the brain behind the nose, this area communicates signals associated with the sense of smell. Loss of smell is often an early sign of Alzheimer’s, heralding the onset of memory and cognitive issues. The targeted protection offered by the reelin variant might thus point towards a more efficient, localized approach to preventing Alzheimer’s [1].

Linking the Genetic Clues

Intriguingly, this is not the first case where someone from this Colombian family has defied their genetic destiny. Back in 2019, scientists reported a woman from the same lineage who, despite having a predisposition to early Alzheimer’s, retained her cognitive faculties well into her seventies. This anomaly was attributed to two copies of a change in her APOE3 gene, known as the Christchurch mutation. This variant seemed to diminish the APOE3 protein’s activity, which, like reelin, serves as a signaling molecule influencing Alzheimer’s risk [1].

Remarkably, these seemingly disparate genetic changes — in reelin and APOE3 — may not be as disconnected as they initially seem. The cellular receptors for reelin and APOE are one and the same, suggesting a common pathway influencing Alzheimer’s progression and resilience. These two patients, through their exceptional genetic profiles, are essentially guiding researchers to a more profound understanding of Alzheimer’s and how to mitigate its effects [1].

Implications and Future Directions

This groundbreaking research is reshaping our approach towards preventing Alzheimer’s. The cases of these two family members serve as a testament to the powerful effects that even a single genetic variant can exert. As such, scientists are now tasked with exploring how to mimic these naturally occurring protective measures in others at risk for the disease.

As stated by Francisco Lopera, who identified and followed this unique family, “The most exciting thing is that nature has revealed to us both the cause of Alzheimer’s and the cure for it… the solution is to imitate nature by developing therapies that mimic the mechanism of protection of these genetic variants” [2].

While Alzheimer’s research has long been a challenging endeavor, the discovery of this rare gene variant has thrown open the door to new possibilities. If we can harness these naturally occurring protective mechanisms, we may be on the precipice of preventing Alzheimer’s on a scale previously deemed unthinkable.

1. Man who defied genetics for decades may hold a clue to preventing Alzheimer’s, scientists say
2. Newly identified genetic variant protects against Alzheimer’s

Image by Victoria_Regen from Pixabay