Because Aβ deposition triggers or accelerates additional pathogenic events including microglia-mediated immune response and tau tangle spread, effective strategy targeting Aβ will likely be primary prevention prior to plaque development. ...APOE genotype also has differential effects on age-related cognitive decline and Lewy body dementia parallel to their risk profile for AD. Preclinical studies using animal models and cellular models are needed to address specific effects of this variant on neuropathological features (i.e., amyloid plaques and tau tangles), immune response, lipid metabolism, vascular integrity and function, and other AD-related pathways. ...the R251G mutation could potentially change the apoE4 structure such that it either reduces its harmful effects or enhances its physiological functions 1.