Here, we report a case of a 63-year-old woman (at the time of death) with the clinical history consistent with Alzheimer D, an autopsy with brain histopathology supporting Alzheimer disease (AD), congophylic angiopathy, and Lewy Body pathology, and whose medical genetic testing reveals a novel PSEN2 mutation of adenosine replacing cytosine at codon 222, nucleotide position 665 (lysine replacing threonine) that has never been previously reported. The gene discussed is PSEN2; the disease is early-onset autosomal dominant Alzheimer disease.