Dementia, including the most common cause, Alzheimer’s disease (AD), and related neurodegenerative disorders, is a rapidly increasing worldwide problem related to increased longevity and decreased fertility. The impact is not just due to the increasing number of cases but also to the increased proportion of affected individuals. Dementia will have an increasingly profound impact on many populations of Europe, Asia, and the Americas, as well as many developing nations, particularly those with limited health resources. Dementia is a condition that is personally devastating and creates a tremendous burden on caregivers and society. An important consideration is evidence that many AD contributing factors are modifiable and can be prevented. AD pathology starts long before its hallmark clinical symptoms appear. The earliest established brain alteration is the development of neurofibrillary changes composed of hyper-phosphorylated microtubule-associated protein tau (TAU) in the locus coeruleus, then in the midbrain raphe and the nucleus basalis of Meynert, followed by accumulation of the beta-amyloid protein (Abeta) in the neocortex, which accumulates over decades. With progression, there is synaptic loss, which becomes massive and corresponds most closely to the cognitive decline, particularly memory dysfunction, from mild cognitive impairment to profound dementia. ApoE-ϵ4 is the predominant risk factor, genetic or environmental, for this disease, and the AD process is substantially more prevalent and has a younger age-of-onset in ApoE-ϵ4 carriers relative to noncarriers. This chapter summarizes the current literature on the role of ApoE4 and its deleterious effects on brain synaptic function and provides recommendations for improving healthy aging practices to prevent or slow AD pathology, which may be important for several other causes of AD and dementia as well.