An Agenda for Addressing Multimorbidity and Racial and Ethnic Disparities in Alzheimer’s Disease and Related Dementia

Abstract

Advancements in Alzheimer’s disease and related dementias (ADRD) research on the U.S. population acknowledge the importance of the high burden of ADRD on segments of the population and yet-to-be characterized risks attributable to the burden of multiple chronic diseases (multimorbidity). These realizations suggest successful strategies in caring for people with ADRD and their caregivers will rely not only on clinical treatments but also on more refined and comprehensive models of ADRD that take its broad effects on the whole-person and the whole of society into consideration. To this end, it is critical to characterize and address the relationship between ADRD and multimorbidity combinations that complicate care and lead to poor outcomes, particularly with regard to racial and ethnic disparities in the occurrence, course, and effects of ADRD. Several research and policy recommendations are presented to address the intersection of ADRD, multimorbidity, and underrepresented populations most at risk for adverse outcomes.

A recently published 2020 Alzheimer’s Disease Facts and Figures report ¹ identifies several marked racial and ethnic disparities in the incidence of dementia in the United States, including a roughly double incidence among older black, and about a 1.5 times incidence among older Hispanic, compared to older white Americans. The magnitude of these disparities is reflected in other studies that also document high dementia incidence among black and American Indian/Alaska Native populations, intermediate dementia incidence among Hispanic, Pacific Islander and white Americans, and low dementia incidence among Asian Americans. ² These studies highlight the important and substantial gaps that still remain in our understanding of the epidemiology of ADRD, namely the interplay between socioeconomic factors—such as race—and existing chronic disease burden that disproportionately affects racial/ethnic minority groups and may confer additional risks for onset and worsening of ADRD. At the same time, a host of research recognizes that differences in ADRD may not be due to any inherent or immutable characteristics of minority ethnic populations, but may be attributable to lower quality of education, greater exposure to racial discrimination and related stress, ^3,4 and early life experiences that accumulate throughout the lifecourse.

Such findings attest to the importance of considering more than just biology in the nation’s strategy for addressing dementia. Despite decades of research, there has been no “silver bullet” for preventing or curing ADRD. Successful strategies in caring for ADRD on individual and population levels will depend not only on treatments developed through basic and clinical sciences, but also on more refined models of ADRD and its broad effects on health and society. Within the framework of the socioecological model, ⁵ the effects of ADRD are best understood as multiple levels of influence comprising personal or clinical, familial, community, and societal factors that are intricately interconnected, where these factors are shaped by one another. Two issues demand specific attention and form the main objective of this paper: (1) discussing the relationship between ADRD and co-existing, multiple chronic health conditions (multimorbidity) and, (2) elaborating on the disparities in the occurrence, course, and effects of ADRD across different racial and ethnic groups. At first glance, these 2 issues may seem somewhat unconnected, but we argue that they involve the same fundamental challenges, and can both be addressed by more focused and persistent attention to contextual factors in ADRD.

Addressing these issues is timely and critical in light of the COVID-19 pandemic where greater levels of multimorbidity burden among underserved and underrepresented racial/ethnic groups as well as considerations of socioeconomic status and cultural circumstances are crucial determinants of survival. In addition, older adults living in long-term care settings—many of whom have ADRD and are less likely to be from disadvantaged backgrounds ⁶ —are also particularly vulnerable to the current health crisis given the potential for rapid spread of a highly infectious disease in congregate settings.

ADRD: A Complex Syndrome Contingent on Multiple Factors

While ADRD may be caused by multiple differing or co-existing pathologies, it is clear that the greatest risk factor is advancing age. ADRD has, on the basis of its complex pathophysiology, multifaceted interrelationships with other disease conditions and sociodemographic factors. It occurs consistently throughout the world, in various racial and ethnic groups, and it may develop in individuals who have no apparent health problems. Research has, however, identified strong associations with several health conditions, including diabetes, hypertension, vascular disease (including stroke and transient ischemic attack), traumatic brain injury, and Down syndrome. In addition, certain medications or interventions appear to increase the risk of diminished cognitive performance. Nevertheless, none of this research has established any single cause or definitive causal pathophysiologic pathway for ADRD and has not led to any novel treatments or preventative strategies. ⁷ Instead, the indication of multiple pathways and pathologies highlights the need to model more thoroughly the relationship between ADRD, co-morbidities with ADRD (that may inflect course), morbidities that may precede ADRD (and inform risk), and the implications for racial and ethnic populations. The interrelationships among ADRD, concomitant disease, and racial and ethnic populations are not well understood and have critical implications for disease course (both comorbid and ADRD), treatments, and caregiving needs.

ADRD and Multimorbidity Combinations

The absence of any overt associations between ADRD onset and progression with single predictors encourages considering the relationship between combinations of factors that may act in synergistic ways. ⁸ This requires more sophisticated analytic strategies than are typically applied. Most analyses of multimorbidity in ADRD have considered chronic conditions as largely uniform, assessed mainly by means of the number of conditions. Such work has consistently found that people with ADRD with multiple chronic conditions have a more rapid progression and worse outcomes than those with fewer conditions. ⁹ However, approaching multimorbidity as a homogeneous predictor, varying only in magnitude, overlooks key nuances related to specific combinations of chronic conditions and common physiological pathways.

For instance, our work with the National Health and Aging Trends Study data established that certain combinations, such as those including cognitive impairment with depressive symptoms, were greatly associated with prospective impairments in activities of daily living (ADLs) and independent activities of daily living (IADLs). ^10,11 Indeed, other studies have recommended screening for predementia syndromes characterized by slow gait in order to better identify individuals at-risk for dementia and mortality. ¹² Such findings encourage assessment of the individual’s cognitive, psychiatric, and somatic health status in making decisions about medical treatment and psychosocial support, and demonstrate that evaluating specific types of multimorbidity provides novel perspectives on ADRD and daily living.

Research about protective and risk factors for ADRD further illustrates the critical need to account for underlying health conditions. A striking example is seen in studies of the risk of ADRD after exposure to antidepressant medications. Using large health datasets that accounted for the indication of treatment, this work concluded that antidepressants had opposite risks depending on whether the medications were prescribed for depression or for migraine: SSRI antidepressants appeared to increase dementia risk when used to treat depression, but to decrease dementia risk when used to treat migraine. ¹³ This sort of “confounding by indication” complicates analyses of ADRD pharmacoepidemiology, and can only be resolved by careful attention to comorbid health factors. It seems prudent to ensure that studies about exposure to various other medication classes account for multimorbidity combinations.

The association between specific multimorbidity profiles on the risk for and trajectory of cognitive decline remains largely unknown in broad population-based samples with complex patterns of disease, although several recent studies have taken on this task and examine the risk attributable to specific cardiovascular or metabolic comorbidities. ^{14 -18} It will be especially important to better specify risk profiles associated with multimorbidity patterns, including mental health issues, ¹⁹ and identify predictive factors because of the high social costs involved in ADRD care. It is possible that improving the management of multimorbidity combinations, such as by clinical interventions or caregiver empowerment, could have significant impacts on the course of ADRD. Likewise, there may be certain addressable patterns of chronic disease, sociodemographic factors, and health behaviors that increase risk of developing ADRD. Critical gaps remain in understanding the relevance and temporal occurrence of such multimorbidity patterns for the onset and progression of the disease. Even the methodologies for carrying out these types of analyses are still nascent. ^20,21

ADRD Across Diverse Populations and Over Time

Although ADRD affects all populations, it occurs at different rates, and with different consequences in different groups. There is a dearth of research that assesses ADRD risk and progression in the presence and consideration of changing patterns of co-existing morbidities over time. While complex to study, longitudinal research of ADRD in the context of multimorbidity is critical. For example, few studies provide a lifecourse perspective detailing the risk of ADRD onset and progression, and the ways in which this risk is informed by early adulthood or midlife development of cardiovascular disease, or the importance of existing disease relative to and independent of socioeconomic factors. Disentangling the contribution of etiological risk from socioeconomic risk remains an important gap in our understanding. This is particularly salient given greater ADRD and multimorbidity burdens disproportionately falling on racial and ethnic minority populations in early midlife relative to non-Hispanic white peers. ²² If prevention strategies are to be effective and proactive, a lifecourse perspective to ADRD research is a logical step.

With regard to ADRD, Black and American Indian/Alaska Native racial groups and Hispanic immigrants have higher age-specific ADRD prevalence and incidence than non-Hispanic white groups. ² Further, Black Americans appear to be diagnosed later in the course of ADRD than white patients, likely due to cultural factors and normalization of ADRD symptoms as part of the usual aging process. ^23,24 Compounding issues of later ADRD presentation, underrepresented racial/ethnic groups also suffer greater cognitive decline throughout the course of their disease, ^25,26 which may be related to socioeconomic resources, such as educational quality, the development of cognitive reserve, financial means, as well as early and midlife stressors. ^3,27,28 Further complicating our understanding, heterogeneity within racial and ethnic groups is well documented, with wide differences by country of origin and by foreign-born and US-born individuals, likely shaped by exposure to changing socioecological conditions and available resources during the lifecourse. ²⁹ Despite some research in these interconnected areas, large gaps remain in the scientific understanding of ADRD prevalence and incidence in diverse US populations. ³⁰

Even though they appear to face greater burden from ADRD, racial and ethnic minority groups are considerably less likely to participate in clinical research compared to their white peers ³¹ a likely result from a long history of discrimination and systemic exclusion from accessing care that fuels distrust in the ADRD clinical and research enterprise. ³² A recent review found that “a striking minority of enrolled patients [in ADRD clinical trials] was constituted of blacks and Hispanics,” and that many publications from trials failed to report racial and ethnic status. ³³ Importantly, lower participation does not derive from a lack of willingness on the part of underrepresented groups. Racial and ethnic minorities consistently report high levels of willingness to participate—even in studies that require biological specimen collection ³⁴ —but also note important barriers to participation which are often unaddressed. More efforts are needed to foster trust between research teams and minority participants, and to address barriers such as linguistic differences, lack of transportation, and competing life demands in the form of time and financial constraints. ^35,36

Taken all together, these observations mean that findings from much of our existing research base may not apply to the population groups that are most severely affected by ADRD. For instance, researchers have found that optimal cutoffs for detecting ADRD differ by racial and ethnic status, and may result in misdiagnosis or overdiagnosis among these groups. ³⁷ Failure to consider racial and ethnic and cultural context ³⁸ in the design and conduct of research, failure to involve broader communities of understudied minority ethnic groups, and failure to engage insufficient numbers of racial and ethnic minority participants will ultimately limit the generalizability and applicability of findings of the most promising interventions to treat and manage ADRD. ³⁹

ADRD and Other Health Conditions

Most chronic diseases require some degree of self-management, and ADRD can undermine this capacity. Individuals with ADRD have difficulty in keeping medical appointments, following behavioral recommendations, and refilling and taking pills on schedule. ⁴⁰ Some tasks, such as diabetes self-management, involve complex reasoning and planning which may prove too difficult even for those with mild cognitive impairment who do not have reliable formal or informal caregiver support. ⁴¹ Suboptimal management of chronic conditions diminishes health, well-being, and functioning, and has profound negative consequences on not only patients’ own lives, but also on the health care system, such as through costly and avoidable hospitalizations and the need for more aggressive medical treatments. Costs for potentially modifiable health conditions are considerably higher for patients with than without ADRD. ⁴² Health systems have started to identify ways to adapt clinical interventions for those with cognitive impairments, ⁴³ but a key challenge remains that the task of chronic disease management typically falls to informal caregivers, for which they may not be trained and which may trigger or exacerbate their own stress. It remains unclear how the effects of ADRD differ based on family, cultural, economic, and community factors.

ADRD and Communities

With the socioecological model in mind again, the impact of ADRD extends to the interrelationships between caregivers and families to broader communities—neighborhoods, municipalities, and societal structures—that dictate the availability of resources and supports. Most of the attention in ADRD research has focused on the patients and caregivers, and less on the effects of the condition on family systems and communities. Numerous studies have demonstrated the profound, life-altering consequences of providing unpaid, informal ADRD care, often falling to spouses and adult children. Caregivers may forego continued workforce participation, decrease leisure or self-care activities, and limit social participation. Further, there are substantial racial differences in the type and degree of physical and emotional strain among ADRD caregivers. ⁴⁴ Yet research to date has not been particularly sensitive to potential racial or ethnic differences in caregiving patterns: 67% of published studies of ADRD caregiver support interventions did not report any results by racial and ethnic group. ⁴⁵ The consequence is the absence of tested, evidence-based ADRD supports and services that are tailored to the needs of various diverse communities. Among studies that have focused on the needs of diverse families, these suggest substantial heterogeneity both within and between racial and ethnic groups in the social and cultural factors that influence caregiving role expectations, experienced caregiver burden, and coping and stress-reduction strategies. ^46,47 Additional work is still needed to understand and address unmet needs and mobilize culturally-acceptable efforts to avoid adverse caregiver outcomes.

Prevailing reported unmet needs of patients with ADRD—such as support with transportation services, home modifications for personal safety, assistance with daily activities, and legal and financial planning services—are largely non-medical and related to patient and caregiver characteristics, and non-white race is a strong predictor of unmet needs. ⁴⁸ In order better to address the needs of both ADRD patients and their caregivers, it is essential to build the understanding of how ADRD affects different groups. Attention to such issues has already promoted the development of culturally-appropriate caregiving interventions, ⁴⁹ but many more are needed.

A Proposed Agenda for Future Inquiry and Policy

The many disparities and gaps in knowledge identified above will require attention before America can formulate a detailed plan for managing the large-scale effects of ADRD on individuals, the health care system, and communities. We propose that, as a critical first step, the next wave of research and clinical interventions in ADRD must, at every level, account for both the “whole person” and also the “whole community”—that is, on the ways in which ADRD affects families, neighborhoods, and societal structures. This means that all segments of the U.S. population should be included and adequately represented, particularly those who are disproportionately burdened by ADRD. Because many groups remain severely underrepresented in the ADRD research enterprise, remediation involves several specific courses of action by funders, researchers, and policymakers:

1. Solicit input and maintain involvement from diverse groups with regard to priorities for ADRD research and interventions. This recommendation is different from recruiting and retaining greater numbers of racial and ethnic minorities to investigator-designed trials and instead involves a more rigorous process of addressing misconceptions and mistrust of the research enterprise in underrepresented communities by developing and maintaining trusted partnerships and integrating this mutual learning iteratively. This approach may initially slow the process of research, and will most certainly add to the cost of programs, but in the long run these investments will ensure that all Americans stand to benefit from scientific advances, not just the select few who customarily agree to participate in ADRD research.

2. Hold taxpayer-funded investigators accountable to the expectation that their research will apply to America’s many population groups , not just those more likely to volunteer for research studies. ADRD research, in its design and execution, must be participatory and inclusive, and its findings must be applicable to our entire population. Developing systems and metrics designed to hold programs of research accountable should be prioritized.

3. Promote and fund research that addresses health equity in ADRD. Encourage greater knowledge generation around the epidemiology, natural history, cultural and family experience of ADRD in diverse groups, and drive efforts to disseminate beyond the scientific community. Refine our understanding of mechanisms by which age, social, behavioral, and medical factors account for racial and ethnic differences in cognitive decline, ADRD onset, and course of ADRD.

4. Develop and apply nuanced approaches to assessing multimorbidity combinations in the context of ADRD, particularly in the longitudinal follow-up and evaluation of ADRD and multimorbidity trajectories. Use novel and nuanced statistical methodologies rather than a simple enumeration of chronic conditions. Design research studies to account for combinations and patterns of chronic conditions, their relationship to one another and over time, and in particular, mood and cognitive impairments.

5. Develop and test interventions in diverse groups of people with ADRD. The end goal is for wide applicability and generalizability of evidence based interventions to improve health maintenance, connection to supports and services, and chronic disease management for all people with ADRD. There is a critical and unacceptable gap in our knowledge base of evidence based interventions that are applicable to, and effective in, underrepresented groups.

6. Develop and test innovative models of support that coordinate health and social care. Coordinating across community-based supports, care facilities, housing, and voluntary services to provide broad and comprehensive care for people with ADRD. It will be important to develop and test interventions and programs to build the evidence base for all population groups affected by ADRD.

7. Train and enable an inclusive workforce to support the care needs of vulnerable populations such as racial and ethnic minority groups and those without family or caregiver support. Facilitate and encourage an increased pipeline of a diverse and representative workforce to maximize the potential for engaging with people with ADRD and their care partners in a receptive, culturally-responsive and linguistically-inclusive manner.

The effects of ADRD in America permeate personal, family, and social experience, and many of these effects would not be dissipated even if successful curative or preventative treatments become available in the next several years. Addressing the causes, mechanisms, and consequences of ADRD with consideration of multimorbidity burden, its progression, and the social conditions that occur alongside ADRD will involve considerable research efforts. In turn, these efforts will provide important insights into any reorganization or offering of services that better support all people living with ADRD, their myriad needs, and the needs of their care partners. This charge is ever more important for disproportionately affected racial and ethnic groups, who are greatly affected by ADRD yet continue to be largely excluded from the ADRD research enterprise and subsequent therapeutic innovations. The best way to improve the quality of life for people and families living with ADRD, and reduce racial disparities in ADRD care and outcomes, is to understand the varied experiences and engage people with ADRD and their care partners to tailor services and social supports that best meet their needs.