More Alzheimer's Research Trouble

This is a new investigation here at Science that suggests some serious problems in an area of Alzheimer’s work that’s had a lot of attention in recent years. It’s been known for decades that there are mutations in some families and populations that predispose people towards Alzheimer’s-like pathology. I talked about these most recently in this 2023 post, but the subject there was actually on the other side of things: mutations that seemed to be having a protective effect.

That’s obviously of great interest. Don’t get me wrong - the mutations that cause extra harm are also very important to learn about, because we need all the clues we can get. But a protective mutation (be it in Alzheimer’s, cardiovascular disease, or whatever) immediately suggests working on its mechanism to see if can be replicated as a therapy in others. It’s intrinsically interesting just as a window into the (still murky) pathology of the disease as well, naturally.

This story is about a family in a particular region of Colombia that carries a mutation in the PSEN1 gene, which codes for presenilin-1, a key part of the gamma-secretase enzyme complex that processes the “amyloid precursor protein” (APP) and others. That mutation, E280A, is a terrible thing to carry, because it leads to cognitive decline and full-scale dementia in a persons 40s and 50s. But the reports in 2019 and 2023 report (blogged about above) was about patients that had this mutation along with others that seemed to allow them to partially or completely avoid that fate (!) These mutations implicated pathways involving the reelin and APOE3 proteins, both of which are plausible candidates for involvement in Alzheimer’s pathology. Another report in 2024 showed that only one copy of one of these mutations could be protective as well. The APOE3 one is also known as the Christchurch mutation, since it had shown up in an earlier New Zealand study.

This all set off a lot of press coverage, and many readers may well recall seeing some of these articles. It’s set off a lot of research ideas in the Alzheimer’s field as well, up to the point of planning human gene therapy trials and development of potential therapeutic antibody treatments. And such results certainly should get people moving. The idea of a intrinsic protective mutation against Alzheimer’s is extremely compelling, as mentioned above. But the Alzheimer’s research community has been getting worried about how well these reports are holding up.