Researchers studied a woman's 'Alzheimer’s-proof brain' to prevent the disease

The PSEN1 E280A mutation is autosomal dominant, which means that only one copy of the gene is required for the disease to occur.

Because the PSEN1 E280A mutation is autosomal dominant, the disease can be caused by only one copy of the gene.

This woman did not exhibit symptoms of Alzheimer's until she was in her early 70s. She died in 2020 at the age of 77 from metastatic melanoma.

"This is a ground-breaking case for Alzheimer's disease and has already opened new paths for treatment and prevention, which we're currently pursuing with some collaborators. This work is now bringing light into some of the mechanisms of resistance to Alzheimer's disease," says investigator Yakeel T. Quiroz, Ph.D. — director of the Multicultural Alzheimer Prevention Program (MAPP) at Mass General, an Associate Professor of Psychology in the Department of Psychiatry at Harvard Medical School, and Paul B. and Sandra M. Edgerley MGH Research Scholar 2020-2025.

She was also carrying APOE3 Christchurch

According to research published July 15, Aliria Rosa Piedrahita de Villegas was also a carrier of both copies of the APOE3 Christchurch mutation.

According to Quiroz and colleagues in the neuropathology journal Acta Neuropathologica (a monthly peer-reviewed scientific journal), the woman did have pathologic features of Alzheimer's disease in her brain, but not in the areas of the brain where the hallmarks of Alzheimer's are typically found.

"This exceptional case is an experiment designed by nature that teaches us a way to prevent Alzheimer's: let's observe, learn, and imitate nature," said Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellín, Colombia.

"This patient gave us a window into many competing forces — abnormal protein accumulation, inflammation, lipid metabolism, homeostatic mechanisms — that either promote or protect against disease progression, and begin to explain why some brain regions were spared while others were not," says Justin Sanchez, AB, co-first author, and an investigator at MGH Neurology.

Clumping or abnormal aggregation of tau

Researchers discovered a distinct pattern of abnormal aggregation or "clumping" of tau, a protein known to be altered in Alzheimer's disease and other neurologic disorders, in Aliria's brain.

"Thus, the Christchurch variant may impact the distribution of tau pathology, modulates age at onset, severity, progression, and clinical presentation of [autosomal dominant Alzheimer's disease], suggesting possible therapeutic strategies," the researchers write.

"It is seldom that we have nice surprises while studying familial Alzheimer's disease brains. This case showed an amazingly clear protected phenotype. I am sure our molecular and pathologic findings will at least suggest some avenues of research and elicit hope for a successful treatment against this disorder."- says co-first author, Diego Sepulveda-Falla, MD, Research Lead at University Medical Center Hamburg-Eppendorf in Hamburg, Germany.

"This exceptional case is an experiment designed by nature that teaches us a way to prevent Alzheimer's: let's observe, learn and imitate nature," concludes Francisco Lopera, MD, director of the Neuroscience Group of Antioquia in Medellín, Colombia. Lopera is a co-senior author and the neurologist who discovered this family and has been following them for the last 30 years.

The study was published in the journal Springer Link.

Abstract:

We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer's disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer's symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes, and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, and modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.