1. Introduction
An estimated 50 million individuals are currently living with Alzheimer’s disease and related dementias (ADRD) globally [
1], with a significant increase projected over the next one (~75 million by 2030) and two decades (~130 million by 2050). ADRD is one of the world’s most expensive health conditions. Lifetime costs of care for individuals with ADRD are estimated at US
$350,000 in 2018 dollars [
2]. In the US, costs of ADRD are projected to grow from
$290 billion in 2019 to more than
$1 trillion in 2050 [
2]. This number is doubled when estimating the global cost [
3]. Given the magnitude of the problem in terms of individuals affected and the costs associated with ADRD, the World Health Organization recently asserted that prevention and treatment of ADRD is a public health priority [
4].
Currently, no pharmacological disease modifying therapies (DMT) exist for the prevention or treatment of ADRD [
5]. The past three decades have seen repeated failures in clinical trials of pharmacological therapies targeting beta amyloid, one of the pathologies present in individuals with Alzheimer’s disease. Currently, over 100 drug compounds are in some stage of clinical evaluation. Nevertheless, the failure rate to date has tempered the enthusiasm of current compounds in the clinical trial pipeline. While sobering, these failures have resulted in greater understanding and appreciation of the heterogeneity of ADRD, and the numerous genetic, biological, and behavioral factors associated with ADRD. At the same time, a growing body of research demonstrates the possibility for enhancing cognitive reserve and reducing risk of ADRD. These studies have consistently shown that ADRD are multifactorial in nature, with numerous genetic, environmental, and behavioral factors conferring protection or risk for ADRD. Given the large number of modifiable risk factors, including physical inactivity, poor diet, smoking, low education, midlife hypertension, midlife obesity, diabetes mellitus, depression, and education and occupational attainment [
6], delay or prevention of ADRD through enhancing cognitive reserve and reducing modifiable risk factors offers a potential non-pharmacological DMT to reduce the growing number of individuals living with ADRD.
From Single-Domain to Multi-Domain Interventions
Non-pharmacological trials aimed at ADRD risk factor reduction emerged in the early 2000s. These clinical trials focused on single domain interventions such as physical exercise [
7], cardiovascular health [
8], and cognitive training [
9]. While some of these studies provided positive results, the heterogeneous nature of ADRD rendered many single-domain interventions ineffective when deployed in large randomized control trials [
10,
11,
12,
13]. The development of non-pharmacological interventions for reducing risk of delirium among older adults provides a useful analogy. Non-pharmacological interventions evolved from single-domain interventions—Originally deployed to treat older adults with delirium and later investigated for risk reduction—Into multidomain non-pharmacological risk reduction interventions for delirium [
14]. This evolution came from the recognition that single-domain treatments were not efficacious, in combination with an understanding that multiple factors contribute to the onset of delirium and prevention is the most effective strategy for reducing the occurrence of delirium [
15]. Given the heterogeneous nature of pathological cognitive decline and ADRD, several modifiable risk and protective factors exist at different points across the lifespan (
Figure 1). Multidomain non-pharmacological interventions provide an opportunity to address the multiple risk factors simultaneously present among older adults at risk of ADRD. Over the past decade, the first large randomized control trials deploying multidomain non-pharmacological lifestyle interventions have been completed and have provided an initial evidence base for the efficacy and potential of these types of interventions to effectively enhance cognitive reserve and reduce risk of ADRD in specific older adult populations [
16,
17,
18].
This study provides a comprehensive overview of completed and prospective non-pharmacological multidomain lifestyle interventions that aim to enhance cognitive reserve and reduce risk of ADRD. The review summarizes participant and intervention characteristics, study length and intervention frequency, primary and non-primary outcomes, adherence, and attrition. It also synthesizes studies completed to date and discusses how current and prospective studies are incorporating data reported from completed studies to further refine and optimize FTF and digital multidomain interventions.
2. Methods
A literature search utilizing PubMed, PsycInfo, ClinicalTrials, and NIH RePORTER was conducted from inception to August 1, 2019. Following previously utilized criteria, to be considered in the current review the study or protocol was required to meet a set of inclusion criteria associated with qualification as a multidomain lifestyle intervention to enhance cognition and reduce risk of ADRD [
19]. First, the use of a control group was required to ensure scientific rigor. While many of the lifestyle behaviors that make up interventions in these studies have shown to be beneficial, the use of a control group is clinically important in discerning the true effects of the intervention. Second, interventional studies were required to contain 3 or more separate active lifestyle behavior components. This criterion was developed utilizing the FINGER protocol study design [
17]. The FINGER protocol multidomain intervention included active behavior change across the domains of diet (healthy Nordic diet), physical activity (aerobic and strength training), and cognitive engagement (computerized cognitive training). In addition to these three active intervention components, intervention participants also received clinician feedback and motivation on the importance of managing vascular risk factors, as well as organic social engagement with other study participants. Given the difficulties in demonstrating significant and sustained cognitive outcomes in previous single-intervention studies [
10,
11,
12,
13,
20,
21,
22], the FINGER protocol design provides a plausible heuristic for multidomain intervention development. Third, the intensity, frequency, and duration of intervention implementation in combination with maintenance and tracking was required to be at least 6 months. Studies exploring lifestyle change have noted that 6 months is generally the minimum length of time for participants to benefit from a positive lifestyle intervention due to the inherent difficulty of integrating these changes into daily practices and the nature of the behaviors being that are addressed [
23]. This time frame also allows for the detection of possible cognitive benefits from the intervention, as changes to cognition are mostly seen over long periods of time [
24]. Fourth, interventional studies were required to include measures of cognition as a primary or secondary outcome. Completed and prospective studies—Both face-to-face (FTF) and digital—Are also investigating the effects of multidomain behavioral interventions and monitoring on aspects of physical health and validated dementia risk measures [
25,
26]. While these studies are valuable in their own right, changes in cognitive performance between intervention and control participants strengthen the outcomes by which the efficacy of multidomain interventions can be evaluated. Furthermore, given that measurement of cognition is a requirement in the clinical determination of pathological cognitive decline (e.g., MCI or dementia), measures of cognition are needed to allow for the objective measurement of stability or change (either positive or negative).
4. Conclusions
Alzheimer’s disease and related disorders (ADRD) pose population health risks to virtually every society around the world. The health, societal, and economic burdens associated with ADRD have transformed ADRD into a global health priority [
1,
4,
63,
64]. The lack of pharmacological-based disease-modifying therapies (DMT) to date [
65], combined with the low likelihood of effective pharmacological DMTs in the near future [
5], has brought increased focus to non-pharmacological reserve and risk reduction (RRR) interventions [
66,
67]. Over the past three decades, mounting evidence has linked multiple lifestyle factors with increased risk of pathological cognitive decline, including ADRD [
68,
69,
70,
71,
72,
73,
74]. This evidence has been complemented by epidemiological data, indicating that declines in dementia incidence are likely due to better management of lifestyle behaviors [
75,
76,
77].
The existing evidence base from completed multidomain RCTs points to the clinical utility of non-pharmacological, lifestyle-based interventions for enhancing cognitive reserve and reducing risk of ADRD. At the same time, these studies point to the necessity of multidomain interventions to successfully address the multiple risk factors associated with ADRD in aging populations. One of the enduring challenges in the development of pharmacological DMTs for ADRD has been intervening at the point in disease progression that is clinically efficacious [
78]. To date, trials targeting individuals with detectable cognitive or cognitive and functional impairment have failed [
65]. Given the underlying pathological processes at work that can precede readily observable clinical symptoms, current pharmacological trials are now targeting pre-clinical populations [
79,
80]. Owing to the multifactorial etiology of ADRD that occurs dynamically across different life stages, multidomain non-pharmacological lifestyle interventions also need to utilize a life-course approach. Cardiovascular health factors provide an example of the dynamism involved. Vascular risk in ADRD, often focused on SBP and blood cholesterol, are targets for middle-aged individuals with risk for ADRD. Among older adults, less is known with respect to optimization of these factors [
81]. Similarly, social isolation has been associated with Alzheimer’s disease pathology and MCI [
82,
83]. Interventions that target social engagement, however, may not be optimal until past middle age.
The unique use cases for non-pharmacological multidomain interventions also warrant consideration. Within clinical research contexts, the use of clinical diagnostic criteria such as the recently adopted NIA-AA criteria for asymptomatic or pre-clinical Alzheimer’s disease [
80] provide for highly characterized study populations. At the same time, Alzheimer’s disease pathology rarely occurs in isolation from other forms of pathological burden (e.g., vascular pathology) [
84] with interactions between pathologies posited in the initiation and accumulation of pathological burden [
85]. Given this heterogeneity, SCD and subtle, measurable changes in cognitive performance reported by patients remains a critically important signal for initiation of reserve building and risk reduction interventions.
As multidomain intervention studies are now being implemented across the globe, effective localization of these interventions will grow in importance. To date, the evidence base for these studies has occurred in high-income countries, with substantial infrastructure and clinical workforce for the deployment of these programs. Yes, it is clear that middle- and lower-income countries will be adversely affected by ADRD in the coming decades [
86,
87,
88]. Tailoring of multidomain interventions across geographic, cultural, and economic factors will be increasingly important to maintain efficacy and adoption across diverse contexts.
A unique opportunity exists for digitally-mediated multidomain intervention programs to reach populations in low- and middle-income countries in ways that physical infrastructure and clinical work forces cannot [
89,
90]. Digitally deployed interventions, in combination with support through health coaching, remove geographical barriers and offer opportunities for individuals to participate with others even in remote or isolated contexts. Moreover, digital deployments of these programs are uniquely positioned to augment FTF programs as a means of reinforcing intervention components, maintain engagement, and support effective adherence for optimal dosing of unique lifestyle behaviors. Given the rise of digital therapeutics to address chronic disease, digital multidomain intervention programs to enhance cognitive reserve and reduce risk of ADRD are well-positioned to effect lifestyle change in at-risk individuals with both short- and longer-term health benefits [
38,
39,
40].
A common challenge to both FTF and digital multidomain intervention programs is adherence. The FINGER study reported high engagement (7% dropout at 12-months) with variable adherence across individual intervention components (e.g., >90% for cardiovascular monitoring, <50% for cognitive training). Similarly, adherence in the MAPT study was variable (e.g., >75% for Omega-3/placebo tablets, ~60% adherence to multidomain sessions and cardiovascular consultations) [
35]. Adherence to digitally delivered programs is an important area of current research [
91,
92], with evidence supporting the role of content and intervention tailoring to specific populations and individuals to improve adherence [
93,
94]. Additionally, the use of health coaching within digitally delivered programs can further influence motivation, engagement, and adherence [
95]. Multidomain interventions targeting the enhancement of cognitive reserve and reduction of risk factors associated with ADRD enjoy a unique position due to the numerous non-dementia specific outcomes that these programs can effectively address in older adult populations. A “top-down” approach to lifestyle interventions, beginning with cognitive health, has demonstrated improvements in cognition [
36], health-related quality of life [
37], self-perceived physical function and general health [
39], and chronic disease risk reduction [
38].
The public health relevance of these non-pharmacological approaches is an important consideration. A shift in mindset from pharmacological cure to lifestyle care is needed in order to embrace the significant potential benefits of enhancing cognitive reserve and reducing risk of ADRD. Even small reductions in ADRD incidence will have outsized public health impacts. Given that as much as many as half of all cases of ADRD may be attributable to modifiable risk factors [
96], non-pharmacological multidomain interventions provide a viable opportunity to effect population level health. Microsimulation models such as the Future Elderly Model have shown total societal savings of more than
$100 billion from delaying disease onset by just one year in the US [
97]. Similarly, epidemiological studies have reported that a large portion of the years lived with ADRD are amenable to population level risk reduction interventions, with even minor risk reduction yielding significant public health benefits [
76,
98] and may be cost-effective [
99].
In the near future, the measurement and management of cognitive health from mid-life onwards will provide for proactive intervention to enhance cognitive reserve, reduce risk factors associated with pathological cognitive decline including ADRD, and optimize cognitive aging at the societal and population levels. For this to be achieved, a combination of FTF, brick and mortar multidomain lifestyle interventions, and digitally delivered multidomain interventions are needed. Digital interventions and digital therapeutics such as those reviewed here are critical adjuncts to FTF interventions that support engagement and adherence, while simultaneously serving as an effective stand-along delivery mechanism for evidence-based enhancement of cognitive reserve and risk reduction. In a similar way to how cardiovascular disease and diabetes mellitus are currently addressed at a population health level—With non-pharmacological lifestyle interventions as the first line intervention for both prevention and treatment—Multidomain lifestyle interventions are poised to be the first line intervention for prevention and treatment. Additionally, as effective repurposed or novel pharmacological DMTs emerge, drug-based interventions can be used in combination with lifestyle interventions to complement or increase efficacy utilizing a precision medicine approach. A dual therapy approach, including both pharmacological and non-pharmacological interventions, may represent the most optimistic future for the prevention and treatment of ADRD. However, while this optimistic future is not a reality, the reality of FTF and digital multidomain lifestyle interventions to enhance cognitive reserve and reduce risk of pathological cognitive decline provides much needed optimism and offers the potential to slow the growing number of individuals living with ADRD.