Understanding Disparities Associated with Alzheimer Disease and Related Dementias

Alzheimer disease and related dementias (ADRDs), including their prodrome, mild cognitive impairment, affect nearly 7 million Americans and >55 million people worldwide.¹ Nearly all the research into the features, statistics, and risk factors of ADRD has been conducted in largely White populations in North America, Europe, and Australia. Between 2000 and 2010, the mortality rate for people with ADRD increased by 68%, in contrast to a decline in mortality rates for cardiovascular disease, cancer, and stroke over the same period.² Over the next 20 years, the number of people age >65 and >85 years is expected to grow by 62% and 84%, respectively.³ The older adult population in the United States is also becoming more racially diverse. In 2006, 19% of adults age ≥65 years were non-White, and the White population has decreased by 8.6% since 2010.³ By 2050, the proportion of non-White older Americans will increase to 39%, with approximately 14 million Hispanic individuals, 8.6 million Black individuals, and 5.8 million adults from other ethnoracial groups.³

Disparities in prevalence estimates, diagnoses, and health outcomes persist in many non-White communities that bear a disproportionate burden of disease. The Alzheimer’s Association reports that Black or Hispanic individuals are estimated to have a 1.5 to 2 times increased risk of developing dementia and that rural populations have a 1.3-fold increased risk of developing dementia; they also report that two thirds of people with ADRD are women.¹ Little is understood regarding ADRD risk in Indigenous (eg, American Indian, Pacific Islander)⁴ or LGBTQIA+ (lesbian, gay, bisexual, transgender, queer/questioning, intersex, asexual, and other gender identities and sexual orientations) communities.⁵ Individuals with lower education levels or fewer economic resources have poorer aggregate outcomes, including in brain health and ADRD. Whereas the Lancet Commission identified 12 modifiable risk factors accounting for 40% of the population-attributable risk of ADRD, nearly all studies have been conducted in non-Hispanic White individuals.⁶

The associated paucity of biomarker data in minoritized populations is striking. Even with the recent approval of disease-modifying medications (ie, lecanemab [Leqembi; Eisai, Nutley, NJ; Biogen, Cambridge, MA]), the clinical effects are modest, the treatments are expensive, and not everyone may benefit. This is especially problematic given that the populations at highest risk for ADRD are often left out from ADRD clinical trials because of exclusion criteria that involve comorbid medical conditions that place these same populations at highest risk for developing cognitive decline or dementia or because thresholds for AD biomarker evidence of disease have been determined largely in White populations.⁷ This has resulted in an unacceptably high screen fail rate for Black or Hispanic individuals in ADRD clinical trials, largely because of lower amyloid burden when matched for level and severity of cognitive impairment with non-Hispanic White individuals.⁸

Genetic risk factors add another layer of complexity. The APOE4 allele is frequently cited as the strongest single genetic risk factor for ADRD, with the risk of developing dementia increasing with the presence of none to 1 to 2 copies of the APOE4 allele. However, nearly all studies have been conducted with largely White European samples. In Black individuals, APOE4 alleles are common, and a recent report suggests a nonsignificant relationship between APOE4 and amyloid accumulation in Black individuals compared with non-Hispanic White individuals.⁹ Instead, the phospholipid-transporting ATPase ABCA7 gene has stronger associations with ADRD risk in individuals with African ancestry than in individuals with European ancestry.¹⁰ Although ABCA7 has been shown to have a stronger effect size than the APOE4 allele in Black individuals, this is rarely reported or discussed in the news or at scientific conferences. Furthermore, the literature suggests that APOE4 is not associated with dementia in Native Americans¹¹ or the Chamorro people of Guam.¹² The strength of association of APOE4 in Hispanic individuals is more complex because of ancestry admixtures among European White, African, and Native American lineages.¹³ Thus, disparities in ADRD outcomes need to be examined taking into account both biologic and social factors.

Health Disparities vs Health Care Disparities

There are a number of factors underlying the differential risk of ADRD in minoritized communities. Differences in symptom presentation, language, literacy, and education barriers, perceptions and expectations of care, and structural obstacles (eg, locale, transportation, number of providers and specialists) may impede case ascertainment, delay diagnoses and treatment, and lead to poorer outcomes. Cultural barriers may lessen participation in research, including mistrust of medical institutions, health beliefs that “senility” represents a normal stage of aging, and the legacy of the Tuskegee Syphilis Study and related phenomena.¹⁴ Ethnoracial identity and socioeconomic status affect numerous aspects of the health care experience, including stigma, cultural differences in perception of disease and care, awareness and understanding of ADRD, ability to obtain a diagnosis, disease management, and access to care and support services.

It is also important to consider the distinction between health disparities and health care disparities and how sociodemographic and cultural factors contribute to differences in health outcomes.¹⁵ Health disparity describes a higher burden of illness, disability, or mortality rates in one group relative to another. For example, women are at a higher risk of breast cancer than men. Health care disparity refers to differences between groups in access to and use of health care, insurance coverage, and quality of care received. For example, people from ethnoracial minority groups with low income are more likely to be uninsured or underinsured and receive fewer services than individuals with greater financial resources. These disparities reach beyond clinical care to include uneven representation (and sometimes no representation) of Black, Hispanic, Asian, or Indigenous individuals in ADRD clinical research, biomarker studies, and clinical trials.

Black individuals and Hispanic individuals experience delays in ADRD diagnosis (approximately 3 months for Black individuals and approximately 12 months for Hispanic individuals)¹⁶; have poorer cognitive performance, particularly in vocabulary and semantic memory¹⁷; and have more functional disability at time of diagnosis compared with White individuals.¹⁶ In a study of 111,125 electronic health records, ethnoracially minoritized patients and those with lower socioeconomic status had less documentation of cognitive testing, suggesting that delivery of medical care was different, despite the fact that Black and Hispanic older adults have a higher risk of mild cognitive impairment and ADRD compared with White individuals, even after correcting for age and educational differences.¹⁸ Although the risk for cognitive impairment is higher in Black or Hispanic older adults compared with non-Hispanic White individuals, dementia prevalence has increased over the past 2 decades in non-Hispanic White individuals from 40% in 2000 to 44% in 2016, but has remained steady in non-Hispanic Black individuals during the same period (from 37% in 2000 to 38% in 2016).¹⁹ Black, Asian, and Hispanic Medicare beneficiaries without cognitive deficits have lower total health care expenditures than White individuals without cognitive deficits, and higher total health care expenditures after ADRD diagnoses.²⁰ Costs differ for older adults from minority groups, with lower out-of-pocket expenditures (possibly because of differences in insurance coverage), lower prescription drug expenditures, and higher home health expenditures.²⁰

The Role of Social Determinants, Environmental Exposures, and Intersectionality

Multilevel analyses of cognitive decline and ADRD development have the potential to reap rewards by exploring exposures and mechanisms that may explain differential risk across different ethnoracial, sociodemographic, and culturally distinct groups and subgroups. However, the traditional grouping of individuals by race or ethnicity may not provide answers to disparities in health outcomes. Ethnoracial identity is self-identified based on common ancestral background, language, or culture, but there is little evidence that the inherent biology of ADRD differs by race or ethnicity; all cases of Alzheimer disease involve amyloid deposition, although the amount of amyloid may differ. Instead, integrating the exposome with intersectionality may provide a more accurate understanding of ADRD disparities.

The exposome encompasses the entirety of an individual’s environmental exposures, including social, structural, behavioral, clinical, and life course determinants^21,22; intersectionality examines how overlapping sociodemographic characteristics, such as ethnoracial and gender identity, sex, and socioeconomic status, interact to influence health outcomes.^23,24 This combined approach moves beyond simplistic categorizations (eg, Black vs White, Hispanic vs non-Hispanic, rural vs urban), acknowledging that these social determinants may interact with environmental factors to differentially contribute to ADRD risk, presentation, diagnosis, biomarker expression, and disease progression over the life course of an individual. Rethinking our approach to studying disparities in ADRD outcomes offers a nuanced understanding of the ADRD variability across different populations and accounts for the complexity of ADRD risk factors, acknowledging that both internal biologic processes and external social circumstances play key roles in mechanisms underlying disparities (Figure).

Stark disparities have been established in structural and social determinants of health (SDOH) and ADRD based on ethnoracial group, sex, gender, and other aspects of an individual’s identity that are socially patterned and may result in socioeconomic disadvantage. SDOH encompass the “conditions in the environments where people are born, live, learn, work, play, worship, and age” that affect a wide range of health-related outcomes, including ADRD.²⁵ Upstream from the social determinants are the structural determinants, which are the “social and political mechanisms that generate stratification and social class divisions in society and that define individual socioeconomic position within hierarchies of power, prestige and access to resources.”^26,27 Downstream of the influence of SDOH are medical determinants of health representing the direct effects of early SDOH challenges on accumulation of risk factors and comorbid medical conditions that may differentially place one group at a higher risk of disease compared with another group.²⁸ Many of the comorbid conditions are overrepresented in ADRD, especially in minoritized individuals. SDOH occurring in early and midlife could have a later influence on medical determinants of health, supporting the need to consider both to fully understand health disparities associated with ADRD (Figure). SDOH have been increasingly recognized as an important contributor to ADRD disparities, and limited studies have assessed how SDOH differ by the intersectionality of social identities (eg, racial group x gender) or how SDOH associations with ADRD vary by intersectional identities. This is a critical gap that needs to be addressed to further elucidate ADRD disparities and how various interventions may differentially affect individuals with compounding disadvantaged identities.

Life Course Factors

The exposome encompasses all environmental, nongenetic exposures across a person’s life course that influence health and disease, including SDOH, internal factors such as metabolism and the microbiome, general external factors such as social status and neighborhood environments, and specific external factors such as occupation and pollutant exposures. Many components of the exposome have been included in the model of ADRD risk proposed by the Lancet Commission.⁶ SDOH are key components that can affect all aspects of the exposome (eg, behaviors, exposures, biologic functioning, access to resources) throughout the life course, and are therefore thought to have a substantial influence on ADRD risk. SDOH also affects late-life ADRD outcomes, including time of diagnosis and quality of health care. Disparities in SDOH by social strata can contribute to ADRD disparities, although this has been minimally explored within the context of intersectionality, and few studies have investigated the causal and biologic mechanisms linking SDOH and ADRD.²⁹

When considering race and ethnicity, we previously reported that there was a higher burden of vascular comorbidities (ie, diabetes, heart disease, obesity, hypertension) in Black individuals and Hispanic individuals, which appeared to drive greater vulnerability.³⁰ In Black individuals, frailty was the strongest single contributor to ADRD risk; in Hispanic individuals, depression was a main driver. However, when we reclassified all participants by socioeconomic status, comorbid medical conditions played a less prominent role, suggesting that the participants’ available resources and access to care drives ADRD risk in the most vulnerable groups, such as ethnoracial minorities, women, rural populations, and individuals with low education.³¹ This suggests that lifelong challenges in securing adequate housing, nutrition, education and job opportunities, and access to quality and timely medical care may place ethnoracial and other minoritized groups at higher risk so that by midlife to late life, the accumulation of vascular comorbidities, frailty, and mood disorders may increase their overall risk of ADRD.

Little is known about ADRD risk factors in Indigenous populations, including Native Americans, Alaska Natives, Native Hawaiians, and Pacific Islanders. Although culturally diverse and geographically dispersed, many Indigenous populations share a high burden of ADRD risk factors, including low socioeconomic status, obesity, hypertension, type 2 diabetes, and dyslipidemia.^32,33 Increasing concern about ADRD among Indigenous groups is also fueled by their longer life expectancies over the past 5 decades, resulting in a 3-fold increase in people age >65, putting them at much higher risk for ADRD.³

Targets for Intervention

Although ADRD does not affect different racial and ethnic groups equally, underlying medical and social determinants associated with racial and ethnic groups may help explain differences in performance on cognitive testing.³⁴ The poorer cognitive functioning observed among older adults from minoritized ethnoracial groups may reflect differences in peak cognitive reserve as measured by educational and occupational attainment that could be affected by age-related medical comorbidities associated with higher ADRD risk (eg, diabetes, hypertension, obesity).³⁵ Increased cognitive reserve could offer protection from ADRD by providing resistance against effects of accumulating pathology and strengthening synaptic plasticity.

Whereas women have a greater lifetime risk of developing AD,³⁶ at least 1 study suggested that women are less likely to be symptomatic with neuropathologically confirmed AD,³⁷ and multiple studies demonstrated that older women perform better on cognitive tests than men.³⁸ Reasons for sex-based disparities in cognitive status may relate to biologic factors (eg, genetics, hormones) but also social factors, such as life course differences in social support and engagement, which can impart cognitive reserve, in which the brain uses alternative or compensatory approaches to complete a task that imparts resilience against brain injury or neurodegeneration, which delays cognitive decline onset.³⁹

Conclusions

The literature suggests that socioeconomic status, race, and ethnicity contribute to disparities in ADRD health outcomes, but in different fashions. Differences in economic resources may contribute to disparities in access to health care services; race and ethnicity may contribute to disparities in the types and extent of health care services received. Future studies need to take into account early-, mid-, and late-life medical, social, and structural factors to better explain disparities in ADRD health outcomes. Improving nutrition, housing, and educational opportunities and eliminating discriminatory practices in early life would have clear long-term benefits, but will require large-scale, systemic changes. However, increasing resilience by promoting risk reduction, healthful behavioral change, social support, and better management of comorbid conditions are viable options for biomedical intervention.⁴⁰