An Alzheimer’s-Proof Brain: Ground-Breaking Case Provides Clues to Treatment and Prevention of Dementia

The woman's brain, according to the experts, may hold crucial clues for treating dementia.

The woman appears to have been protected by the APOE3 Christchurch mutation.

Aliria Rosa Piedrahita de Villegas should have had Alzheimer's disease in her 40s and died from it in her 60s due to a rare genetic abnormality.

Since she remained free of dementia into her 70s, her brain is now supplying crucial information on the pathophysiology of dementia and potential treatments for Alzheimer's disease.

According to initial study from Massachusetts General Hospital (MGH) and other institutions in 2019, the woman, from Medellin, Colombia, was a member of an extended family with a mutation in the PSEN1 gene.

One copy of the gene is all that is required for illness to manifest due to the autosomal dominant nature of the PSEN1 E280A mutation.

When carriers of the mutation typically show symptoms of the disease in their 40s or 50s and succumb to it soon after, this woman did not begin to show symptoms until she was in her early 70s. She died in 2020 from malignant melanoma at the age of 77.

This is an important instance for Alzheimer's disease, and it has already opened up new avenues for prevention and therapy that we are actively exploring with some partners. According to researcher Yakeel T. Quiroz, Ph.D., "this work is now shedding light on some of the processes of resistance to Alzheimer's disease."

Paul B. and Sandra M. Edgerley MGH Research Scholar 2020–2025 Quiroz is the director of the Multicultural Alzheimer Prevention Program (MAPP) at Mass General and an Associate Professor of Psychology in the Department of Psychiatry at Harvard Medical School.

The Colombian woman's ability to resist the disease for three decades seems to be mostly due to the fact that she also carried the APOE3 Christchurch mutation in addition to the PSEN1 E280A mutation.

The APOE gene family regulates the synthesis of apolipoproteins, which move lipids (fats) through the blood and other body fluids.

While the APOE4 variant has been associated to an elevated risk for the disease, the APOE2 variant is known to be protective against Alzheimer's dementia.                 

The most prevalent version of APOE3, however, is rarely linked to either a lower or higher risk of developing Alzheimer's disease.

The woman did in fact show pathologic signs of Alzheimer's disease in her brain, according to a new paper by Quiroz and colleagues in the neuropathology journal Acta Neuropathologica, but not in areas of the brain where these signs are generally found.

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

A specific pattern of aberrant tau "clumping" or aggregation, a protein known to be changed in Alzheimer's disease and other neurologic illnesses, was discovered in Aliria's brain by researchers.

The frontal cortex, which is crucial for decision-making and other "executive" processes, as well as the hippocampus, which is crucial for memory and learning, were essentially spared in this case by the tau disease.

Instead, the occipital cortex, a region of the brain near the back of the head that regulates vision, was affected by the tau disease.

Only the occipital cortex, a crucial part of the brain, exhibited typical Alzheimer's symptoms like lower levels of APOE expression and persistent inflammation of the brain's defense cells called microglia.

Accordingly, the Christchurch variant may have an effect on the distribution of tau pathology, affect the age of onset, severity, development, and clinical presentation of [autosomal dominant Alzheimer's disease], and provide potential therapeutic approaches, the researchers write.

"We rarely get pleasant surprises while examining the brains of individuals with familial Alzheimer's disease. An impressively distinct protective phenotype was evident in this case. Our molecular and pathologic discoveries, I'm confident, will at the very least point to some potential research directions and inspire optimism for an effective approach to treating this condition. - says Diego Sepulveda-Falla, MD, co-first author and research lead at Hamburg, Germany's University Medical Center Hamburg-Eppendorf.

Francisco Lopera, MD, director of the Neuroscience Group of Antioquia in Medelln, Colombia, says, "This rare example is an experiment planned by nature that teaches us a way to prevent Alzheimer's: let's observe, learn from, and mimic nature. Lopera, a senior author who also found this family and has been following them for 30 years, is a neurologist.

An APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia has distinct tau neuropathology and cellular profiles, according to a study by Diego Sepulveda-Falla, Justin S. Sanchez, Maria Camila Almeida, Daniela Boassa, Juliana Acosta-Uribe, Clara Vila-Castelar, Liliana Ramirez-Gomez, Ana Baena, David Aguillon, and Nelson Villalba-Moreno, David Jessica The following research was published in Acta Neuropathologica on July 15, 2022: Lisa Littau, Andres Villegas, Thomas G. Beach, Charles L. White III, Mark Ellisman, Susanne Krasemann, Markus Glatzel, Keith A. Johnson, Reisa A. Sperling, Eric M. Reiman, Joseph F. Arboleda-Velasquez, Kenneth S. Kosik, Francisco Lopera, and Yakeel T.

The German Federal Ministry of Education and Research, the Alzheimer's Association, the MGH Executive Committee on Research (MGH Research Scholar Award), the Deutsche Forschungsgemeinschaft, the Universidad de Antioquia, the Werner Otto Stiftung, and the National Institutes of Health all provided funding for the study.

By MASSACHUSETTS GENERAL HOSPITAL