Thread by @liminalcries

“The results look very promising, but it would be useful to see replication in more samples,” says neurologist Rudolph Tanzi of @harvardmed

https://twitter.com/ScienceNews/status/1659952130063577095

"Both the man and woman were members of a Colombian family who have a mutation in the PSEN1 gene that causes the rare inherited variety of Alzheimer’s."

"People with “familial” Alzheimer’s usually start showing signs in their 40s. The woman stayed sharp into her 70s, while the man described in the new study was still mentally healthy at 67."

"The woman had a protective mutation in a gene closely linked to Alzheimer’s, APOE. This mutation is known as the Christchurch variant, after the city in NZ where it was first found. The mutation identified in the new study was in a gene called RELN."

"Researchers named this new mutation RELN-COLBOS, after a joint Colombia-Boston study that the man participated in."

"Amyloid plaques were abundant in both patients’ brains. But the woman had low levels of tau tangles. The researchers think this is what spared her from dementia for decades, as tau is more tightly linked to symptoms than amyloid, researchers suspect."

"In the Colombian man’s brain, the researchers found a different picture for tau. Some brain regions, notably the entorhinal cortex, which is important for memory and one of the earliest areas affected in Alzheimer’s, had been spared from the tau buildup."

"The difference in tau between the 2 cases is due to where the 2 protective genes are active in the brain. In adults, RELN is active in only a few places, including the entorhinal cortex. APOE is active everywhere."

"Since APOE is ubiquitous, in one patient you get protection all around. In this other, the protection is localized to [certain] neurons, and by chance, they happen to be the neurons that are key for preserving cognition."

"Despite affecting different genes, both mutations produce proteins that attach to the same molecules on cells, and, ultimately, appear to reduce the formation of tau tangles. Introducing the RELN-COLBOS mutation into mice prevented tau buildup."

"This mechanism, common to both mutations, could be targeted by new treatments aiming to stave off all types of Alzheimer’s." 🧠

Characterizing the 2nd case of extreme resilience to #Alzheimer's. Despite a PSEN1-E280A mutation, this male remained cognitively intact until 67. A rare RELN variant hints at the potential role of RELN signaling in protecting against dementia.
nature.com/articles/s4159…