While PSEN1-E280A carriers develop dementia at the median age of 49 years, carrying a mutation on the AD risk modifier ApoE3 (R136S) delayed dementia significantly, until the 7th decade (Arboleda-Velasquez et al., 2019), demonstrating that Aβ accumulation is not enough to develop AD. Here, PSEN1 is linked to Alzheimer disease.