Alzheimer’s-defying brain offers clues to treatment, prevention

Good news! Exciting research! A very unusual case!

"... As researchers at Massachusetts General Hospital and other centers first described in 2019, the woman, from Medellin, Colombia, was a member of an extended family with a mutation in a gene labeled PSEN1. The PSEN1 E280A mutation is autosomal dominant, meaning that only a single copy of the gene is required to cause disease. Carriers of the mutation typically exhibit symptoms of Alzheimer’s in their 40s or 50s, and die from the disease soon after, but this woman did not begin to show signs of Alzheimer’s until her early 70s. She died in 2020 from metastatic melanoma at the age of 77.

The key difference in the Colombian woman’s ability to fend off the disease for three decades appeared to be that in addition to having the PSEN1 E280A mutation, she was also a carrier of both copies of a mutation known as APOE3 Christchurch. ...

The APOE family of genes control production of apolipoproteins, which transport lipids (fats) in blood and other bodily fluids. The APOE2 variant is known to be protective against Alzheimer’s dementia, while the APOE4 variant is linked to an increased risk for the disease.

APOE3, the most common variant, is not typically associated with either reduced or increased risk for Alzheimer’s. ...
the woman did, in fact, have pathologic features of Alzheimer’s disease in her brain, but not in regions of the brain where the hallmarks of Alzheimer’s are typically found. ...
“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,” ...
In this case, the tau pathology largely spared the frontal cortex, which is important for judgment and other “executive” functions, and the hippocampus, which is important for memory and learning. Instead, the tau pathology involved the occipital cortex, the area of the brain at the back of the head that controls visual perception. ...
“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,” ..."

From the 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, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies."

Alzheimer’s-defying brain offers clues to treatment, prevention – Harvard Gazette Genetic mutation found that could shed light on mechanism for disease resistance, lead to new therapies

Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (open access)