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

PSEN1 variants are the most common cause of familial early-onset Alzheimer's disease (EOAD), but it is debated whether they act through a loss- or gain-of-function. Following a recent report of a duo with EOAD carrying a predicted loss-of-function (LoF) stop-gain variant (p.K109*) in PSEN1, we sought to determine whether PSEN1 LoF variants, as a class, cause EOAD. We identified 45 carriers of PSEN1 LoF variants predicted to trigger nonsense-mediated decay in the Alzheimer's Disease Sequencing Project, UK Biobank, and BioVU databases. None of these carriers had a recorded case of early-onset de

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