For one woman, later life was all but scripted. She had mutations in multiple genes predisposing her to early-onset Alzheimer’s disease, and it was all but expected that she would develop the disease in her 40s or 50s. Instead, Aliria Rosa Piedrahita de Villegas, from Colombia, lived healthily until her 70s with no sign of neurological disease – and scientists want to know why.
Alzheimer’s disease (AD) has a complex history and our understanding is limited at best. Scientists believe that some cases are caused by a buildup of misfolded protein, called β-amyloid, that results in neurotoxicity. Current AD treatments focus on the prevention of these plaques. This hypothesis has been around for decades and treatments targeting it seem to work wonders in animal models, but invariably fail when reaching human trials. This disconnect has puzzled scientists and continues to call into question the original amyloid hypothesis, with some even going as far as to say AD isn’t even a disorder of the brain.
This brings us to the woman in question who, despite carrying all the hallmarks of early-onset AD, appears to be protected from it in some way. Scientists were following this woman throughout her life and retrieved her body for an autopsy following her death from cancer, in hopes of understanding exactly what was keeping her brain healthy.
She carried a mutation in the risk gene PSEN1, as well as two mutations in the gene APOE3, also known as the Christchurch mutation. These mutations are heavily implicated in the development of AD and raise the risk by multiple factors – variants of PSEN1 are found in 70 percent of early-onset AD, and APOE3 is one of the leading risk genes.
As expected, the PSEN1 mutation resulted in the development of amyloid plaques, but they behaved differently in this case. Typically, amyloid plaques form clusters around important regions of the brain involved in memory and cognitive processing, but in Aliria’s brain, they weren’t. Instead, there were increased numbers tau tangles (another hallmark of AD) in her occipital cortex, which is responsible for visual processing, and her overall disease progression differed from other PSEN1 carriers.
So, why was it that she was able to dodge AD for so many years? The scientists remain unsure, though they believe it to be something to do with the Christchurch mutations. According to a statement to Being Patient, this was the only genetic trait they could link the resilience to. When they took animal cells and modified the APOE3 gene in a similar fashion, they found it influenced how the tau tangles were dispersed and stunted the progression of the disease.
Now, they hope this unprecedented brain can help lead to new treatments against AD, which remains one of the greatest medical problems of modern times.
The study was published in the journal Springer Acta Neuropathologica.