Higher levels of long-term exposure to fine particulate matter air pollution is associated with worse cognitive function and cognitive decline.200-207 Uncommon Genetic Changes That Greatly Increase Risk Certain genetic mutations and the extra copy of chromosome 21 that characterizes Down syndrome are uncommon genetic factors that greatly influence Alzheimer’s risk. Genetic Mutations A small percentage of Alzheimer’s cases (an estimated 1% or less)208 develop as a result of mutations to any of three specific genes. A genetic mutation is an abnormal change in the sequence of chemical pairs that make up genes. These mutations involve the gene for the amyloid precursor protein (APP) and the genes for the presenilin 1 and presenilin 2 proteins. Those inheriting an Alzheimer’s mutation to these genes are virtually guaranteed to develop the disease if they live a normal life span.209 Symptoms tend to develop before age 65, sometimes as young as age 30, while the vast majority of individuals with Alzheimer’s have late-onset Alzheimer’s. Trisomy in Down Syndrome In Down syndrome, an individual is born with three copies of chromosome 21 (called trisomy 21) instead of two. People with Down syndrome have an increased risk of developing Alzheimer’s, and this is believed to be related to trisomy 21. Chromosome 21 includes the gene that encodes for the production of APP, which in people with Alzheimer’s is cut into beta-amyloid fragments that accumulate into plaques. Having an extra copy of chromosome 21 may increase the production of beta-amyloid fragments in the brain. Overall, people with Down syndrome develop Alzheimer’s at an earlier age than people without Down syndrome. By age 40, most people with Down syndrome have significant levels of beta-amyloid plaques and tau tangles in their brains.210 As with all adults, advancing age increases the likelihood that a person with Down syndrome will exhibit symptoms of Alzheimer’s. According to the National Down Syndrome Society, about 30% of people with Down syndrome who are in their 50s have Alzheimer’s disease.211 About 50% of people with Down syndrome who are in their 60s have Alzheimer’s disease.211 Looking to the Future With the discovery that Alzheimer’s may begin 20 years or more before the onset of symptoms, a substantial window of time has been opened to intervene in the progression of the disease. During this window of time, advances in the identification of biomarkers for Alzheimer’s will enable earlier detection of the disease, giving those affected the opportunity to address modifiable risk factors that may delay cognitive decline and participate in clinical studies of potential new treatments. Biomarker advances will also accelerate the development of these new treatments by enabling clinical trials to specifically recruit individuals with the brain changes experimental therapies target. In addition, biomarker, basic science and other research advances offer the potential to expand the field’s understanding of which therapies may be most effective at which points in the Alzheimer's disease continuum. However, a fuller understanding of Alzheimer's — from its causes to how to prevent it, how to manage it and how to treat it — depends on other crucial factors. Among these is the inclusion of participants from diverse racial and ethnic groups in all realms of Alzheimer's research. Most of the research to date has not included sufficient numbers of Blacks, Hispanics, Asian Americans/ Pacific Islanders and Native Americans to be representative of the U.S. population. Moreover, because Blacks and Hispanics are at increased risk for Alzheimer’s (see Prevalence section, page 18), their underrepresentation hampers the conduct of rigorous research to understand factors that may contribute to their increased risk. Improving inclusion also increases the diversity of lived experiences of participants (and investigators), which opens the door to discovering environmental and societal factors that may influence health behaviors and other factors that increase risk. It is important that researchers identify risk factors that can be addressed to alter the disparate burden of Alzheimer's. Only by improving representation in clinical trials, observational studies and other investigations will everyone have the potential to benefit from advances in Alzheimer’s science. Overview 17 By 2050, the number of people age 65 and older with Alzheimer’s dementia is projected to reach 12.7 million. Prevalence 19 Prevalence of Alzheimer’s and Other Dementias in the United States Based on updated calculations, an estimated 6.2 million Americans age 65 and older are living with Alzheimer’s dementia in 2021.A1,216 Seventy-two percent are age 75 or older (Figure 2).216 Of the total U.S. population: • More than 1 in 9 people (11.3%) age 65 and older has Alzheimer’s dementia.216 • The percentage of people with Alzheimer’s dementia increases with age: 5.3% of people age 65 to 74, 13.8% of people age 75 to 84, and 34.6% of people age 85 and older have Alzheimer’s dementia.216 People younger than 65 can also develop Alzheimer's dementia, but it is much less common and prevalence is uncertain.