Unraveling the Genetic Armor Against Alzheimer’s Disease: A New Hope Unfolds

May 25, 2023

One of the most intriguing mysteries is Alzheimer's disease, a neurodegenerative disease that steals away memory, cognition, and eventually life. The scariest part? We don't yet fully understand it.

But, as with all good puzzles, every once in a while, we find a piece that fits.

Enter our heroes: two individuals who, against all odds, have displayed extraordinary resilience to autosomal dominant Alzheimer's disease (ADAD).

The first case, a woman, is homozygous for a unique variant, APOE3 Christchurch (APOECh). Our new champion, a male, who remained cognitively intact until 67 years despite carrying a PSEN1-E280A mutation, a variant typically associated with early-onset Alzheimer's. Just like a Sherlock Holmes plot twist, he didn't carry the APOECh variant, but rather a rare variant in RELN (H3447R, now fondly known as COLBOS).

The Genetic Superheroes

Both these cases, like superheroes with their unique powers, presented an extraordinary biological event – a high amyloid plaque burden (the hallmark of Alzheimer's), but limited Tau tangle (another Alzheimer’s hallmark) in the entorhinal region of the brain. Imagine your body dealing with an overwhelming amount of garbage (amyloid plaques) but not letting it clutter the living room (entorhinal cortex), a pivotal area for memory. Amazing, right?

However, the man's superhero power seemed to spring from a different source - the RELN-COLBOS variant. RELN, like apolipoprotein E, binds to specific receptors, VLDLr and APOEr2, and is linked to the modulation of memory and cognition. The COLBOS variant has shown a stronger ability to activate its canonical protein target, Dab1, and reduce human Tau phosphorylation in a knockin mouse model. It's like having a fancy new tool that not only cleans the garbage more efficiently but also prevents the production of future waste.

Dancing with Philosophy, Psychology, and Genetics

You may ask, "What's the big deal about this genetic stuff?" Well, remember the philosophic doctrine of Determinism? It's the belief that all events are predetermined and therefore inevitable. In a way, genetics has often been seen through this deterministic lens - we are bound by the DNA we inherit. But these cases of resilience against ADAD challenge this idea, bringing a ray of hope to an otherwise grim scenario.

There's a peculiar interplay of biology and psychology at work here. It's a testament to the innate resilience of the human spirit, finding its mirror in the resilience of the human body. It seems our genetic warriors are fighting Alzheimer's on the battlefield of our brains, holding the line against cognitive decline.

A New Hope and Future Perspectives

This research doesn't just add a piece to the Alzheimer's puzzle; it opens a whole new avenue of exploration. Could we harness the power of these genetic variants to develop new treatments, or better yet, a cure?

It also adds to the growing body of evidence supporting the "amyloid hypothesis" in Alzheimer's disease, suggesting that amyloid buildup is a significant factor, but not the sole determinant of the disease. After all, our genetic superheroes had a considerable amyloid buildup but limited Tau tangles and delayed cognitive decline.

The Unseen Resilience

As a future doctor and an eternal student of medicine, it's awe-inspiring to witness these novel discoveries. The resilience of these individuals to ADAD feels like nature's way of whispering its secrets to us, shedding light on the resilience we all carry within us, unseen and unacknowledged.

As we continue to delve into the mysteries of Alzheimer's, I'm reminded of the words of Rollo May, a prominent existential psychologist, "In order to be open to creativity, one must have the capacity for constructive use of solitude. One must overcome the fear of being alone." In the quest for understanding Alzheimer's, we are, in a sense, overcoming our fear of confronting the solitude of our minds, opening avenues to creativity and hope, and in the process, getting closer to deciphering this devastating disease.

So, here's to hope, resilience, and the unending quest for knowledge. Here's to a future where Alzheimer's is but a memory of the past.

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