Those who inherit one copy of the e4 form have about three times the risk of developing Alzheimer’s compared with those with two copies of the e3 form, while those who inherit two copies of the e4 form have an eight- to 12-fold risk.77-79 In addition, those with the e4 form are more likely to have beta-amyloid accumulation80 and Alzheimer’s dementia at a younger age than those with the e2 or e3 forms of the APOE gene.81 A meta-analysis including 20 published articles describing the frequency of the e4 form among people in the United States who had been diagnosed with Alzheimer’s found that 56% had one copy of the APOE-e4 gene, and 11% had two copies of the APOE-e4 gene.82 Another study found that among 1,770 diagnosed individuals from 26 Alzheimer’s Disease Research Centers across the United States, 65% had at least one copy of the APOE-e4 gene.83 However, a recent study84 found that individuals with the APOE-e4 risk gene had a decreased risk of developing dementia if they had more years of early life education, had mentally challenging work in midlife, participated in leisure activities in late life, and/or had strong social networks in late life. APOE Pair African Americans* European Americans* e3/e3 45.2 63.4 e3/e4 28.6 21.4 e3/e2 15.1 10.2 e2/e4 5.7 2.4 e4/e4 4.5 2.4 e2/e2 0.7 0.2 Created from data from Rajan et al.74 *Percentages do not total 100 due to rounding. Percentage of African Americans and European Americans with Specified APOE Pairs TABLE 3 14 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Studies of Alzheimer’s risk based on APOE status among Blacks have had inconsistent results. For example, some have found that having the e4 allele did not increase risk among Blacks,75-76,85 while other studies have found that it significantly increased risk.86-87 More research is needed to better understand the genetic mechanisms involved in Alzheimer’s risk among different racial and ethnic groups. Family History A family history of Alzheimer’s is not necessary for an individual to develop the disease. However, individuals who have a parent or sibling (first-degree relative) with Alzheimer’s are more likely to develop the disease than those who do not have a first-degree relative with Alzheimer’s.68,77 Those who have more than one firstdegree relative with Alzheimer’s are at even higher risk.71 A large, population-based study found that having a parent with dementia increases risk independent of known genetic risk factors such as APOE-e4.88 When diseases run in families, heredity (genetics) and shared non-genetic factors (for example, access to healthy foods and habits related to physical activity) may play a role. Modifiable Risk Factors Although age, genetics and family history cannot be changed, other risk factors can be changed or modified to reduce the risk of cognitive decline and dementia. Examples of modifiable risk factors are physical activity, smoking, education, staying socially and mentally active, blood pressure, and diet. In fact, the 2020 recommendations of The Lancet Commission on dementia prevention, intervention and care60 suggest that addressing modifiable risk factors might prevent or delay up to 40% of dementia cases. Modifiable risk factors have been the subject of much research. In addition to The Lancet Commission report,60 the 2019 World Health Organization (WHO) recommendations89 to reduce risk of cognitive decline and dementia, an Alzheimer’s Association article90 evaluating the effects of modifiable risk factors on cognitive decline and dementia, and a report from the National Academy of Medicine91 all point to the promising role of addressing these risk factors to reduce risk of dementia and cognitive decline. This section focuses on risk factors common to these reports. It is important to note that “reducing risk” of cognitive decline and dementia is not synonymous with preventing cognitive decline and dementia altogether. Individuals who take measures to reduce risk may still develop dementia, but they may be less likely to develop it or they may develop it later in life than they would have if they had not taken steps to reduce their risk. It is also important to note that factors that increase or decrease the risk of cognitive decline and dementia may not necessarily do so by directly affecting the brain changes associated with Alzheimer’s disease.85 For example, it is possible that smoking may contribute to cerebrovascular disease, which in turn increases the risk of dementia, but it may not directly contribute to the development of the amyloid plaques and tau tangles that characterize Alzheimer's disease. Cardiovascular Disease Risk Factors, Physical Activity and Diet Brain health is affected by the health of the heart and blood vessels. Although it makes up just 2% of body weight, the brain consumes 20% of the body’s oxygen and energy supplies.92 A healthy heart ensures that enough blood is pumped to the brain, while healthy blood vessels enable the oxygen- and nutrient-rich blood to reach the brain so it can function normally. Many factors that increase the risk of cardiovascular disease are also associated with a higher risk of dementia.