PSEN1 loss-of-function variants do not cause early-onset Alzheimer's disease

True null loss-of-function PSEN1 variants predicted to trigger nonsense-mediated decay do not associate with early-onset dementia in 45 carriers across AD sequencing and biobank datasets.

• Why it matters: The field debates whether PSEN1 drives familial early-onset Alzheimer’s disease via loss- or gain-of-function, and a reported duo with a predicted stop-gain variant raised uncertainty.
• What they did: The study compiled 45 PSEN1 LoF carriers from the Alzheimer's Disease Sequencing Project, UK Biobank, and BioVU, then checked for recorded early-onset dementia and re-analyzed p.K109*.
• The result: No carriers had early-onset dementia, and 17 were over 65 at last follow-up without dementia or Alzheimer’s reported; p.K109* was reclassified as a cryptic splice event yielding p.K109_L113del.

AI summary of the abstract · may contain errors · not medical advice · read the paper.