APP and Alzheimer disease: Established risk factors for AD include the APOE4 allele [19, 55]; genetic variants of amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) [54]; metabolic diseases or conditions such as diabetes and obesity [30, 50]; and vascular conditions such as cardiovascular disease, stroke, and hypertension [15, 21, 32].