To better assist with the design of future clinical trials for Alzheimer’s disease (AD) and aid in our understanding of the disease’s symptomatology, it is essential to clarify what roles β-amyloid (Aβ) plaques and tau tangles play in longitudinal tau accumulation inside and outside the medial temporal lobe (MTL) as well as how age, sex, apolipoprotein E (APOE) ε4 (APOE-ε4), and Klotho-VS heterozygosity (KL-VShet) modulate these relationships. This evidence concerns the gene APOE and Alzheimer disease.