It remains unclear precisely how APOE-mediated risk for AD is related at a biochemical level to the pathologic cascade driven by disease-causing variants in APP, PSEN1, and PSEN2. However, a rare patient that belongs to a large Colombian mEOAD kindred of PSEN1 p.E280A carriers—who showed symptom onset nearly 30 years later than expected—may hold important insights. Here, PSEN1 is linked to Alzheimer disease.