Advances in Non-Pharmacological Interventions for Subjective Cognitive Decline: A Systematic Review and Meta-Analysis

Abstract

Background:

Subjective cognitive decline (SCD) is considered the earliest symptomatic manifestation of preclinical Alzheimer’s disease (AD). Currently, given the lack of effective and curable pharmacological treatments for AD, non-pharmacological interventions (NPIs) for individuals with SCD may provide a valuable opportunity for the secondary prevention of AD.

Objective:

This systematic review and meta-analysis, conducted in accordance with the PRISMA guidelines, aimed to investigate the benefits of current NPIs in the population with SCD.

Methods:

The online electronic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, PsycInfo, and CINAHL, were searched to identify randomized controlled trials of NPIs for SCD. Intervention strategies were psychological and health-related education interventions, mind-body therapy, lifestyle modification, cognitive training, and multidomain interventions. Outcomes included subjective memory, objective memory, global cognitive function, psychological well-being, and mood. Study quality was determined using the criteria of the Cochrane collaboration’s tool. The Hedges’ g of change was analyzed.

Results:

Eighteen studies were included in this review and meta-analysis. Overall, psychological and health-related education interventions exhibited a medium effect on objective memory function (Hedges’ g = 0.53, p = 0.01). Cognitive training led to a small effect on objective memory, which was marginal statistically (Hedges’ g = 0.19, p = 0.05). In addition, cognitive training also significantly improved subjective memory performance (Hedges’ g = 0.49, p = 0.0003) and psychological well-being (Hedges’ g = 0.27, p = 0.03).

Conclusion:

Overall, the psychological intervention and cognitive training may be beneficial to cognitive function and psychological well-being. NPIs may be effectively implemented in older adults with SCD.

Keywords

Alzheimer’s disease cognitive training intervention lifestyle non-pharmacological psychological subjective cognitive decline

INTRODUCTION

Alzheimer’s disease (AD) is considered a pathophysiological continuum with a long preclinical phase, during which AD-related pathological abnormalities, such as elevated amyloid-β (Aβ) deposition and neurofibrillary tangle formation, have been apparent [1]. This pathological process begins decades before the emergence of AD clinical symptoms [2]. The prevalence of AD is projected to rise dramatically over the next 40 years, and there is an urgent need for strategies to maintain cognitive function in older adults. Given the lack of effective treatments at the stage of AD dementia, early intervention may offer the best chance for therapeutic success.

Subjective cognitive decline (SCD), which is characterized by a self-perception of decline in cognitive performance without objective impairment in neuropsychological tests, is considered a risk factor for accelerated cognitive decline and for incident mild cognitive impairment (MCI) and AD [3, 4]. Initially, there were various descriptions for this concept, such as subjective cognitive impairment, subjective memory decline, subjective memory impairment, and subjective memory complaints. The lack of common terminology has resulted in numerous study conclusions. Thus, the international working group of the Subjective Cognitive Decline Initiative (SCD-I) proposed a conceptual framework for research on SCD in 2014 [5]. The unified definition of SCD highlights the self-reported cognitive decline from the perspective of individuals without the need of confirmation by others. SCD may serve as a first symptomatic indicator of AD [5]. Individuals with SCD exhibit similar pathophysiological characteristics as those with AD, with increased Aβ deposition [6, 7], disruption of white matter [8, 9], and loss of gray matter volume in certain brain regions, such as the hippocampus, entorhinal, precuneus, and posterior cingulate cortex [10]. Based on the biological definition of AD, cognitively normal adults with AD-related pathologic biomarkers are considered preclinical AD [11]. Longitudinal studies showed that SCD with amyloidopathy had a risk of progressing to either MCI or dementia between 40% and 62% within 3 years [12], suggesting that SCD may represent an impactful “window of opportunity” for modifying the disease course.

Unfortunately, most clinical trials of pharmacological interventions targeting AD-related pathology have failed [13]. Additionally, current authorized pharmacological treatments mainly focus on alleviating clinical symptoms of dementia without treating or reversing the progression of AD. Thus, non-pharmacological interventions (NPIs) for preventing cognitive decline and dementia are increasingly raising the broad interest of researchers. Based on the theory of neuroplasticity, NPIs may contribute to the cognitive maintenance and improvement by modifying the structure, electrophysiology, and glucose metabolism of the human brain [14 –16]. There may also be potential gains from NPIs for adults with SCD. First, non-pharmacological treatments may alleviate the burden of AD with few adverse events. Second, due to the heterogeneous etiologies of SCD [17], the effects of current drugs targeting AD may be uncertain. Third, previous studies have reported the close relationship between several vascular and lifestyle-related risk factors and increased risk of dementia [18 –21]. Approximately one-third of AD patients worldwide may be attributable to nine modifiable risk factors, such as low education, midlife obesity, midlife hypertension, diabetes, smoking, less of exercises, low social contact, hearing ability declined, and depression, which provide us a potential prevention strategy for individuals at risk for AD [20]. For instance, Lourida et al. reported that a favorable lifestyle, including no current smoking, regular physical activity, healthy diet, and moderate alcohol consumption, was associated with a lower dementia risk, even among participants with high genetic risk [22]. Therefore, individuals with SCD may benefit from NPIs focusing on dementia risk reduction and prevention. Finally, underlying mechanisms of AD remain unclear, and currently, various hypotheses, such as amyloidosis, neuroimmune, neuroinflammation, and oxidative stress, have been considered to be associated with the pathogenesis of AD [23, 24]. Owing to its complex and multifactorial etiologies, the effect of pharmacological treatments targeting single neurotransmitter or pathological change may be limited. Thus, multi-target therapies against risk factors and mechanisms may be advantageous to SCD.

Four systematic reviews evaluating NPIs for SCD have been published. Metternich and colleagues [25] conducted a systematic review and meta-analysis for individuals with subjective memory complaints. They found that expectancy change was most efficient in subjective memory, while memory training was the only efficient intervention for objective memory. However, the main limitation was that subjects in several included studies were not SCD. Another systematic review included six studies to evaluate the effect of cognitive interventions [26]. Although most interventions showed improved cognitive performances, there was a relevant heterogeneity concerning the characteristics and feasibility of implementation. Moreover, Smart et al. [27] evaluated the efficacy on cognitive, behavioral, and psychological function, and found a small effect size for all types of NPIs on cognitive outcomes. However, both RCT and non-RCT were included in this review. The most recent meta-analysis included sixteen RCTs. This study exhibited that psychological interventions could improve psychological well-being and may also improve metacognition [28]. Nevertheless, in addition to NPIs, pharmacological interventions were also studied.

Purpose of this systematic review

SCD may serve as an optimum target for early intervention. The evidence from prior reviews suggests that NPIs may have positive effects on cognitive function in individuals with SCD. However, not all the systematic reviews specify randomized controlled trials (RCTs), which limits the rigor of conclusions. In addition, previous reviews of NPIs focused specifically on single-domain interventions, neglecting the effects of multidomain interventions on cognition. Here, the primary objective is to evaluate the benefits of all types of NPIs, including psychological and healthy education, mind-body therapy, lifestyle modification (e.g., physical exercise, nutrients, and functional food supplementation), cognitive training, and multidomain interventions, on subjective memory, objective memory, global cognitive function, psychological well-being, and mood (depression and anxiety) outcomes in SCD. We would like to summarize the recent researches in the context of RCTs to produce an updated systematic review and meta-analysis. Then, we will forecast the possible future directions for clinical trials of NPIs in the population with SCD.

METHODS

This systematic review and meta-analysis aligned with the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [29].

Search strategy

Three authors, CS, YS, and XW (a library science specialist), independently performed the literature search and selected the relevant studies until May 2020. A literature search was performed in MEDLINE (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, PsycInfo (Ovid), and CINAHL (EBSCO). The search strategy was conducted on the aforementioned databases based on the following combinations of terms: (memory OR subjective OR self-report OR cognitive complaint) AND (training OR intervention OR therapy OR treatment) AND (physical OR meditation OR music OR lifestyle OR diet OR nutrient) AND (randomized controlled trial OR controlled clinical trial). Further details on the search strategy are provided in the Supplementary Material. Google Scholar was also used to search for potential articles. The search was limited to RCTs, English language, and human studies. The aforementioned procedures were performed with no limitation on publication date, region or country to prevent the omission of related articles from selected databases. The references listed in related research articles and systematic reviews were manually scanned for additional relevant studies. For included studies without sufficient data, necessary data were obtained by sending emails to the authors.

Inclusion and exclusion criteria

In this review, eligible criteria were: 1) participants with a diagnosis of SCD. The definition of SCD was in accordance with the criteria proposed by Jessen et al. [5], which were self-experienced decline in cognitive capacity (unrelated to an acute event), normal performance on standardized cognitive tests, failure to meet the criteria for MCI or dementia; 2) SCD subjects aged 55 years or older [27], without gender and race restrictions; 3) subjects from health care, memory clinics or community settings; 4) intervention strategies focused on all types of NPIs, including single-domain and multidomain interventions. The psychological or healthy education, mind-body therapy (e.g., meditation, music), lifestyle (e.g., physical exercise, diet, nutrients, or functional food supplementation), and cognitive training were considered as single-domain interventions. The strategies combining two or more treatments were regarded as multidomain interventions. Two authors (CS and YH) independently assigned the included studies to one type of these interventions; 5) only RCTs with any kind of control condition (e.g., active control, wait-list control); 6) included studies need to be published in a peer-reviewed journal.

Exclusion criteria were: 1) interventions targeting patients with MCI or AD; 2) subjects with objective impairment in neuropsychological tests; 3) subjects without cognitive complaints; 4) history of stroke, systemic diseases, other central nervous system diseases (e.g., Parkinson’s disease, tumors, encephalitis, and epilepsy), major depression, psychosis and medical causes that may cause cognitive impairment; 5) pharmacological intervention studies; 6) qualitative studies, systematic reviews, and duplicate publications.

Outcome measures

The outcome measures were subjective memory performance, objective memory performance (immediate recall, delayed recall, recognition, and total memory score), global cognitive function, psychological well-being, and mood (depression and anxiety). Given that SCD is characterized by a self-report decline in cognitive function, subjective memory performance was selected as the main outcome in this meta-analysis. In previous studies, objective memory and global cognitive function have been identified as the important outcomes in intervention studies for SCD [30 –32]. In addition, psychological well-being and mood were also chosen as outcome measures because distress and mood disturbances are considered to be common in adults with SCD [33]. The outcome measures were presented as mean scores and standard deviation.

Assessment of trial quality

All the included studies were evaluated by all the authors. The trial quality was evaluated by the Cochrane collaboration’s tool for assessing risk of bias (ROB) using RevMan 5.3 software. This tool included the following ROB items: 1) random sequence generation (selection bias); 2) allocation concealment (selection bias); 3) blinding of participants and personnel (performance bias); 4) blinding of outcome assessment (detection bias); 5) incomplete outcome data (attrition bias); 6) selective reporting (reporting bias); and 7) other bias. For each included study, two authors (CS and YL) independently rated the quality level (i.e., “low risk,” “high risk,” or “unclear”) across above six domains. When a discrepancy occurred in the rating for ROB, a third rater (XnW) evaluated the discrepancy and made a final decision through discussion.

Data extraction

For each study retained for the present review, two authors (CS and XW) independently abstracted the following data: demographic details, study design, characteristics of interventions (e.g., duration, organization), outcomes of interest (including assessment tools), information of follow-up period, main findings, and conclusions. Two authors discussed the collected data and reached a consensus to resolve the disagreements.

Statistical analysis

Assessment of heterogeneity

The heterogeneity across the studies was tested by performing the I-squared (I²) statistic, to quantitatively measure the inconsistency across studies. Studies with an I² statistic from 25% to 50%, 50% to 75%, and >75% were considered to have mild, moderate and high levels of heterogeneity, respectively. If there was high level heterogeneity, exploratory subgroup and meta regression analyses were conducted to examine the possible sources of heterogeneity. In addition, sensitivity analyses were performed to assess whether the robustness and stability of the meta-analyses were influenced by the quality of included studies.

Assessment of pooled effect estimates

If there was high level heterogeneity, due to the diversity among research designs, statistical methods, sample characteristics, and the length of interventions, random effects estimation was adapted. Otherwise, estimation was concluded by the fixed effects model.

Data synthesis

Meta-analyses were performed where three or more studies investigated a comparable intervention and outcome. When a study reported multiple measures reflecting the same outcome indicator (e.g., within subjective memory performance), we calculated a composite measure for the meta-analysis, the detail equations are provided in the Supplementary Material.

For all comparisons, standardized mean differences (SMD) were calculated, through estimated mean difference between the two groups divided by the mean SD. Hedges’ g was applied to adjust for small sample bias. According to effect size criteria, the values of Cohen’s d were 0.2, 0.5, and 0.8, representing small, medium, and large effect sizes, respectively. The results were presented in Table 3.

Assessment of publication bias

Publication bias was assessed by scrutinizing the protocols of the included studies. Potential publication bias was assessed by visually inspecting the funnel plots in which the estimates were plotted against their standard errors. Begg’s test was performed to evaluate the presence of publication bias.

All analyses were 2-tailed and a p value < 0.05 was considered statistically significant. Publication bias assessment was conducted using STATA 15.0 software. Other analyses were performed with RevMan Software (version 5.3, Stata Corp, College Station, TX, USA).

RESULTS

Description of included studies

The database search yielded 10,229 articles. Additional studies (n = 4) were supplemented by manual retrieval of references from four prior systematic reviews and meta-analysis. After the omission of duplicate articles (n = 4,402) and articles that did not meet the eligibility criteria, a total of 22 articles were deemed appropriate for the systematic review. However, only 18 studies had sufficient outcome data for inclusion in the meta-analysis. The selection process flowchart is shown in Fig. 1.

Fig. 1

PRISMA Flow diagram of the literature search.

Among the 18 selected studies, one was classified as mind-body therapy (mindfulness training) [16]. Five studies were categorized as lifestyle modification, with one as physical exercise [34] and four as functional foods or nutrients supplementation interventions [35 –38]. Nine studies investigated the cognitive training [30–32 , 39–44] and two focused on the multidomain interventions (i.e., combined physical and mental activity, combined exercise and memory training) [45, 46]. There was one study involving psychological and health-related education [47]. Of the 9 cognitive training interventions, one study reported two separate forms of intervention (i.e., integrated psychostimulation program and computerized cognitive training) [42], while another evaluated three separate forms of intervention (i.e., ACTIVE memory training, health promotion, and a participation-centered course) [30]. These two studies also included psychological or health-related education interventions. Thus, a total of three studies were classified as psychological and health-related education interventions.

The control group was divided into active control groups (n = 9) and wait-list control groups (n = 9). The interventions varied in terms of length (i.e., 4 to 24 weeks). Only three studies of the cognitive training interventions had longitudinal follow-up data (i.e., 4 to 9 months) [31 , 43]. Ten studies reported subjective memory performance among their outcomes. Sixteen studies reported objective memory function, of which six had immediate recall, six provided delayed recall, four had recognition, and eleven included total memory score. Six studies included global cognitive function. Four studies reported psychological well-being, and three had mood (depression and anxiety) outcomes. Participants were recruited mainly through health care facilities, memory clinics, community-based centers and widespread advertisements. The characteristics of the included studies are summarized in Table 1.

Quality assessment of studies

To assess the quality of the studies, we used the criteria of the Cochrane collaboration’s tool. Half of the studies showed low risk in random sequence generation. Regarding the unclear sequence generation in other studies, the random assignments were adopted without detailed information. Only five studies specified the use of allocation concealment [32 , 47]. Most studies (n = 12) were blind for the participants and personnel, and only seven were blind for the outcome assessment. One was rated as high risk due to the unblinded outcome data analysis described in the article [38]. Three studies did not report the reasons for the number of participants included in the final analysis. Only a few articles presented an intent-to-treat analysis (n = 5) [32 , 43–45]. Owing to the lack of main outcome results, two studies were regarded as high risk in the reporting bias [31, 42]. In this review, the quality assessment of included studies is shown in Table 2 and Supplementary Figs. 1 and 2.

Table 1

Overview of the NPI studies in adults with SCD (n = 18)

Author	Subjects	Intervention types	During	Follow-up	Outcomes	Main Findings
Psychological and health-related education intervention
Hoogenhout et al., 2012 [47]	SCD (n = 60)	E: Psychoeducation interventionC: Waiting-list control	4 weeks	NA	(1) Subjective memory: MMI;(2) Objective memory: MQ;(3) Psychosocial well-being: PWQ	Psycho-education intervention could reduce negative emotional reactions toward cognitive functioning.
Mind-body therapy
Smart et al., 2016 [16]	SCD (n = 15);NC (n = 23)	E: Mindfulness trainingC: Psychoeducation (active control)	8 weeks	NA	Subjective memory: CCI	(1) There was a selective increase in the P3 component and in percent volume brain change for SCD.(2) SCD participants reported a decrease in cognitive complaints.
Lifestyle modification
Physical exercise
Boa Sorte Silva et al., 2020 [34]	SCD (n = 127)	E: Exercise interventionC: Active control	24 weeks	NA	Objective memory: Monkey Ladder, Spatial Span, Digit Span, Paired Associates	Multiple modality exercise with mind–motor training resulted in greater improvements in memory compared to an active control group.
Functional foods and nutrients supplementation
Wirth et al., 2018 [35]	SCD (n = 30)	E: SpermidineC: Placebo	12 weeks	NA	Objective memory: MST-mnemonic discrimination, MST-recognition memory	Memory performance was moderately enhanced in the spermidine group compared with placebo group.
Boespflug et al., 2016 [36]	SCD (n = 27)	E: Fish oilC: Placebo (corn oil)	24 weeks	NA	Objective memory: working memory	Dietary fish oil supplementation increases red blood cell omega-3 content, working memory performance, and BOLD signal in the posteriorCingulate cortex during greater working memory load.
Brautigam et al., 1998 [37]	SCD (n = 241)	E1: Ginkgo biloba alcohol/water extract-high dose group;E2: Ginkgo biloba alcohol/water extract-low dose groupC: Placebo	24 weeks	NA	(1) Subjective memory: a 5- point Likert scale for the subjective perception of memory and/or concentration;(2) Objective memory: Benton Test of Visual Retention-Revised, 15 Words of Rey (part 1 and 2)	The increase of the visual short-term memory was more significant in the low dose group.
Macpherson et al., 2012 [38]	SCD (n = 56)	E: Multivitamin supplementation C: Placebo	16 weeks	NA	Objective memory: SUCCAB, CVLT-II	Supplementation with a combined multivitamin, mineral and herbal formula may benefit working memory in elderly women at risk of cognitive decline.
Cognitive training
Valentijn et al., 2005 [43]	SCD (n = 139)	E1: Collective training;E2: Individual training;C: Wait-list control	8 weeks	4 months	(1) Subjective memory: MSE, CFQ;(2) Objective memory: VVLT, the short-story test	(1) Compared with the control group, the collective training group and individual training group showed a consistent decrease in stress and anxiety in memory related situations.(2) Compared with the other two groups, the collective training group had an improved recall of a previously learned word list.
Youn et al., 2011 [39]	SCD (n = 40)	E: Multistrategic memory trainingC: Wait-list control	/	NA	(1) Subjective memory: SMCQ;(2) Objective memory: 5 times of immediate recall of the learning word list, SRFT;(3) Mood: SGDS	Multistrategic memory training with the metamemory concept may improve memory ability and other cognitive functions which are not trained.
Cohen-Mansfield et al., 2015 [30]	SCD (n = 44)	E1: ACTIVE memory training;E2: Health promotion;C: Active control	10 weeks	NA	(1) Subjective memory: the self-report of memory difficulties;(2) Objective memory: GCS domains-memory;(3) Global cognitive function: GCS (global);(4) Psychosocial well-being: ULS-8	(1) All three interventions resulted in significant improvement in cognitive function.(2) The cognitive training group participants reported greater improvement in the self-report of memory difficulties than the other groups.(3) All approaches seemed to decrease loneliness.
Pereira-Morales et al., 2018 [42]	SCD (n = 49)	E1: Integrated psychostimulation program;E2: A computerized cognitive training;C: Wait-list control	8 weeks	NA	(1) Subjective memory: SMCQ;(2) Objective memory: the Grober and Buschke test (short-term and long-term memory)(3) Mood: STAI State anxiety	Cognitive training could lead to significant improvements in cognition and psychological well-being.
Kwok et al., 2013 [41]	SCD (n = 200)	E: The Active Mind cognitive-training program;C: Active control	8 weeks	NA	(1) Objective memory: total adjusted CDRS-memory;(2) Global cognitive function: total adjusted CDRS;(3) Psychosocial well-being: SF12	(1) The intervention group showed greater improvement in the cognitive function and quality of life;(2) Subjects with lower education level were associated with better cognitive response to the cognitive-training program.
Kwok et al., 2013 [31]	SCD (n = 223)	E: Cognitive trainingC: Health-related educational control (active control)	12 weeks	9 months	(1) Objective memory: CDRS memory;(2) Global cognitive function: CDRS global score	(1) Cognitive training was effective in enhancing the overall cognitive functioning of less educated older adults with SCD; (2) The positive effect was durable for at least nine months in conceptualization and memory.
Cheng et al., 2018 [32]	SCD (n = 93)	E: Integrated attention training program;C: A health-related education program (active control)	12 weeks	6 months	(1) Subjective memory: MIC;(2) Objective memory: a 10 min assessment of delayed recall;(3) Global cognitive function: CMMSE, ADAS-Cog;(4) Mood: HAMD	This program showed domain-specific effects but had no effects on global cognition or functioning.
Youn et al., 2019 [40]	SCD (n = 275)	E: Multi-strategic metamemory trainingC: Wait-list control	10 weeks	NA	(1) Subjective memory: SMCQ;(2) Objective memory: EVLT, SRFT	This program has a positive impact on enhancing cognitive performance, improving white matter integrity in the anterior and posterior cerebrum and increasing cortical thickness of prefrontal regions.
Fairchild et al., 2010 [44]	SCD (n = 53)	E: A memory enhancement condition;C: A minimal social support condition (active control)	6 weeks	NA	(1) Subjective memory: MMQ;(2) Objective memory: the Names and Faces Task (immediate recall and delayed recall)(3) Psychosocial well-being: PANAS-Positive affect	Those in the memory enhancement condition reported being more content with their memory, having fewer lapses in memory, greater use of mnemonic strategies, and were less bothered by memory complaints.
Multidomain intervention
Barnes et al., 2013 [45]	SCD (n = 126)	E1: MA-I/EX-I;E2: MA-I/EX-C;E3: MA-C/EX-I;C: MA-C/EX-C (active control)	12 weeks	NA	Global cognitive function: a composite cognitive score	Physical plus mental activity was associated with significant improvements in global cognitive function with no evidence of difference between intervention and active control groups.
McEwen et al., 2018 [46]	SCD (n = 59)	E: Simultaneous exercise and memory training C: Sequential exercise and memory training (active control)	4 weeks	NA	Objective memory: composite memory	This program is sufficient to improve memory, attention, and reasoning abilities.

SCD, subjective cognitive decline; NC, normal control; E: Experimental group; C: Control group; NA, not available; ACTIVE, the Advanced Cognitive Training for Independent and Vital Elderly; MMI, Maastricht Metacognition Inventory; MQ, Memory Quotient; PWQ, Psychological Well-being Quotient; CCI, Cognitive Complaints Index; MST, Mnemonic similarity task; MMSE, Mini-Mental State Examination; SUCCAB, Swinburne University computerized cognitive assessment battery; CVLT-II, California Verbal Learning Task II; MSE, ‘Memory Self-Efficacy’; CFQ, the Cognitive Failure Questionnaire; VVLT, Visual Verbal Learning Test; SMCQ, Subjective Memory Complaints Questionnaire; SRFT, Simple Rey Figure Test; SGDS, Geriatric Depression Scale, short form; GCS, Global Cognitive Score; ULS-8, the UCLA Loneliness Scale; STAI, State-Trait Anxiety Inventory; CDRS, Chinese version of Mattis Dementia Rating Scale; SF12, psychological well-being of the 12-item Short-Form Health Survey; CMMSE, the Cantonese version of the Mini-Mental State Examination; MIC, the Memory Inventory for the Chinese; ADAS-Cog, the Chinese version of the Alzheimer’s Disease Assessment Scale–Cognitive Subscale; HAMD, Hamilton Depression Rating Scale (HAM-D); EVLT, Elderly Verbal Learning Test; MMQ, Multifactorial Memory Questionnaire; PANAS, the Positive Affect and Negative Affect Schedule.

Table 2

Quality assessment of the studies (risk of bias) (n = 18)

Studies	Random sequence generation	Allocation concealment	Blinding			Incomplete outcome data	Selective report	Other bias
			Participants	Personnel	Assessors
Hoogenhout et al., 2012 [47]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Smart et al., 2016 [16]	Unclear	Unclear	Low risk	Low risk	Unclear	Unclear	Low risk	Low risk
Boa Sorte Silva et al., 2020 [34]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Wirth et al., 2018 [35]	Unclear	Unclear	Low risk	Low risk	Unclear	Low risk	Low risk	Low risk
Boespflug et al., 2016 [36]	Unclear	Unclear	Low risk	Low risk	Unclear	Low risk	Low risk	Low risk
Brautigam et al., 1998 [37]	Low risk	Unclear	Low risk	Low risk	Unclear	Low risk	Low risk	Low risk
Macpherson et al., 2012 [38]	Low risk	Low risk	Low risk	Low risk	High risk	Low risk	Low risk	Low risk
					(data analysis was unblinded)
Valentijn et al., 2005 [43]	Low risk	Unclear	Low risk	Low risk	Unclear	Low risk	Low risk	Low risk
Youn et al., 2011 [39]	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk	Low risk	Low risk
Cohen-Mansfield et al., 2015 [30]	Unclear	Unclear	Low risk	Unclear	Low risk	Low risk	Low risk	Unclear
Pereira-Morales et al., 2018 [42]	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk	High risk	Low risk
							(lack of main outcome results)
Kwok et al., 2013 [41]	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear	Low risk	Unclear
Kwok et al., 2013 [31]	Unclear	Unclear	Unclear	Unclear	Low risk	Unclear	High risk	Unclear
							(lack of main outcome results)
Cheng et al., 2018 [32]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Youn et al., 2019 [40]	Low risk	Unclear	Unclear	Unclear	Unclear	Low risk	Low risk	Low risk
Fairchild et al., 2010 [44]	Low risk	Unclear	Unclear	Unclear	Unclear	Low risk	Low risk	Low risk
Barnes et al., 2013 [45]	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk	Low risk	Low risk
McEwen et al., 2018 [46]	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk

Table 3

Results of the meta-analyses for NPIs

Study/outcome	Effect size		Heterogeneity		Publication bias
	Hedges’g (95% CI)	SE	I² (%)	Z	p	Begg’s test (p’)
Psychological and health-related education intervention
(1) Subjective memory (n = 3):	–0.52 (–1.22, 0.17)		62	1.48	0.14	1.00
Hoogenhout et al., 2012 [47]	–0.17 (–0.73, 0.38)	4.38
Cohen-Mansfield et al., 2015 [30]	–0.21 (–1.07, 0.66)	0.17
Pereira-Morales et al., 2018 [42]	–1.30 (–2.15, –0.46)	2.01
(2) Objective memory-total memory score (n = 3):	0.53 (0.12, 0.94)		<0.001	2.53	0.01*	0.30
Hoogenhout et al., 2012 [47]	0.69 (0.11, 1.27)	4.74
Cohen-Mansfield et al., 2015 [30]	0.09 (–0.78, 0.95)	3.44
Pereira-Morales et al., 2018 [42]	0.59 (–0.18, 1.37)	0.68
Functional foods and nutrients supplementation
(1) Objective memory-total memory score (n = 4):	0.12 (–0.11, 0.36)		<0.001	1.02	0.31	0.31
Wirth et al., 2018 [35]	0.15 (–0.59, 0.90)	0.12
Boespflug et al., 2016 [36]	0.24 (–0.62, 1.10)	0.04
Brautigam et al., 1998 [37]	0.12 (–0.17, 0.42)	0.30
Macpherson et al., 2012 [38]	0.07 (–0.49, 0.62)	3.81
(2) Objective memory-recognition (n = 3):	0.05 (–0.20, 0.29)		<0.001	0.38	0.71	0.30
Wirth et al., 2018 [35]	–0.27 (–1.01, 0.48)	0.10
Brautigam et al., 1998 [37]	0.10 (–0.20, 0.39)	0.32
Macpherson et al., 2012 [38]	0.04 (–0.51, 0.59)	2.72
Cognitive training
(1) Subjective memory (n = 8):
Assessment tools (higher score means better performance) (n = 3):	0.49 (0.22, 0.76)		<0.001	3.61	0.0003*	1.00
Valentijn et al., 2005 [43]	0.54 (0.08, 1.00)	0.07
Cheng et al., 2018 [32]	0.46 (0.05, 0.88)	0.86
Fairchild et al., 2010 [44]	0.47 (–0.08, 1.02)	3.84
Assessment tools (higher score means worse performance) (n = 5):	–0.11 (–0.32, 0.10)		<0.001	1.01	0.31	0.81
Cohen-Mansfield et al., 2015 [30]	–0.05 (–0.91, 0.82)	0.18
Pereira-Morales et al., 2018 [42]	–0.31 (–1.14, 0.51)	3.03
Valentijn et al., 2005 [43]	–0.15 (–0.61, 0.31)	1.93
Youn et al., 2011 [39]	–0.44 (–1.14, 0.27)	1.33
Youn et al., 2019 [40]	–0.03 (–0.30, 0.25)	0.45
(2) Objective memory-total memory score (n = 5):	0.19 (0.00, 0.37)		<0.001	1.98	0.05*	0.46
Cohen-Mansfield et al., 2015 [30]	–0.41 (–1.29, 0.47)	3.56
Kwok et al., 2013 [41]	0.12 (–0.17, 0.42)	0.40
Kwok et al., 2013 [31]	0.30 (–0.01, 0.61)	0.36
Pereira-Morales et al., 2018 [42]	0.00 (–0.82, 0.82)	0.85
Valentijn et al., 2005 [43]	0.30 (–0.15, 0.75)	1.50
Objective memory-immediate recall (n = 3):	0.04 (–0.21, 0.28)		<0.001	0.28	0.78	1.00
Valentijn et al., 2005 [43]	0.09 (–0.77, 0.95)	1.97
Youn et al., 2011 [39]	0.34 (–0.36, 1.04)	1.37
Youn et al., 2019 [40]	–0.02 (–0.30, 0.26)	0.81
Objective memory-delayed recall (n = 3):	0.18 (–0.16, 0.52)		43	1.04	0.30	0.30
Valentijn et al., 2005 [43]	0.20 (–0.25, 0.65)	1.14
Youn et al., 2011 [39]	0.70 (–0.02, 1.41)	0.69
Youn et al., 2019 [40]	–0.01 (–0.29, 0.27)	0.58
(3) Global cognitive function (n = 4)	–0.01 (–0.23, 0.20)		25	0.11	0.91	0.73
Cheng et al., 2018 [32]	0.04 (–0.37, 0.44)	1.97
Cohen-Mansfield et al., 2015 [30]	–0.89 (–1.80, 0.03)	2.84
Kwok et al., 2013 [41]	0.09 (–0.20, 0.39)	1.24
Youn et al., 2019 [40]	–0.01 (–0.29, 0.26)	0.31
(4) Psychological well-being (n = 3):	0.27 (0.03, 0.52)		<0.001	2.16	0.03*	1.00
Cohen-Mansfield et al, 2015 [30]	0.24 (–0.63, 1.10)	0.25
Fairchild et al., 2010 [44]	0.24 (–0.30, 0.79)	1.81
Kwok et al., 2013 [41]	0.29 (–0.01, 0.59)	1.38
(5) Depression and anxiety (n = 3):	–0.20 (–0.54, 0.14)		10	1.16	0.25	0.30
Cheng et al., 2018 [32]	0.00 (–0.41, 0.41)	0.62
Pereira-Morales et al., 2018 [42]	–0.58 (–1.29, 0.12)	3.15
Youn et al., 2011 [39]	–0.34 (–1.04, 0.35)	2.44

CI, confidence interval; SE, standard error.

Meta-analysis on outcome measures

Psychological and health-related education

Three studies investigated the effect of psychological and health-related education interventions on subjective memory and objective memory-total memory score [30 , 47]. The meta-analysis exhibited a significant improvement in objective memory-total memory score (Hedges’ g = 0.53, 95% confidence interval [CI] 0.12 to 0.94, Z = 2.53, p = 0.01, medium effect). There was no heterogeneity across the studies (I² <0.001). The results showed no statistical significance in subjective memory (Hedges’ g = –0.52, 95% CI –1.22 to 0.17, Z = 1.48, p = 0.14). However, the heterogeneity tests revealed a medium level of heterogeneity across the studies (I² = 62%). Given that only three studies were included in the meta-analysis, subgroup analysis and meta-regression analysis was not appropriate to further clarify the potential reasons for heterogeneity. When we deleted one study by Pereira-Morales et al. [42], the heterogeneity significantly decreased (I² < 0.001). The potential reason may be that this study adopted an integrated psychostimulation program, which might be more effective in improving the subjective memory performance. In addition, we also used a randomized effect model to assess the overall effect of the measurement indicators. Table 3 presents the analysis results, and the forest plot of objective memory-total memory score is shown in Supplementary Figure 3. For the outcome indicators, no publication bias was observed (Begg’s test, p > 0.05) (Table 3).

Mind-body therapy

One study investigated the effect of mind-body therapy (i.e., mindfulness) on subjective memory performance. However, there was no significant benefit compared with an active control group (Hedges’ g = –0.16, 95% CI –1.18 to 0.85). In addition, Smart et al. also found that mindfulness intervention resulted in a selective increase in the P3 event-related component and percent volume brain change in structural MRI [16].

Lifestyle

In the present study, five studies investigating the effect of lifestyle modification on subjective memory and objective memory performance were analyzed.

Physical exercise. Only one study reported the impact of physical exercise on objective memory-total memory score. Boa Sorte Silva et al. found that the exercise intervention group showed greater improvements in the Paired Associates tasks compared with the control group at 24 weeks [34]. However, the overall effect of the exercise intervention on global memory score was not significant (Hedges’ g = 0.16, 95% CI –0.18 to 0.51).

Functional foods and nutrients supplementation. We explored the effect of functional foods and nutrients supplementation on objective memory [35 –38]. As is shown in Table 3, the result revealed that functional foods and nutrients supplementation had a nonsignificant effect on objective memory-total memory score (Hedges’ g = 0.12, 95% CI –0.11 to 0.36, Z = 1.02, p = 0.31). Moreover, three studies found that the nutrients supplementation did not significantly improve objective memory-recognition function (Hedges’ g = 0.05, 95% CI –0.20 to 0.29, Z = 0.38, p = 0.71) [35 , 38].

Cognitive training

The analysis results are shown in Table 3. A total of 8 articles involving subjective memory outcome were included in the analysis. There were two types of subjective memory assessment tools used in these studies. For several assessment tools, such as Subjective Memory Complaints Questionnaire (SMCQ), Cognitive Failure Questionnaire (CFQ) total score, and the self-report of memory difficulties, higher score means worse subjective memory performance. In contrast, other assessment tools, such as Memory self-efficacy (MSE), Memory Inventory for the Chinese (MIC), and Multifactorial Memory Questionnaire (MMQ)-total score, represent great subjective memory performance when the score is high. Five studies adopted former assessment tools [30 , 43], while three used the latter [32 , 44]. In five studies, the overall effect of the cognitive training intervention on subjective memory outcome was not significant (Hedges’ g = –0.11, 95% CI –0.32 to 0.10, Z = 1.01, p = 0.31). Nevertheless, cognitive training had a small-to-medium effect on subjective memory for the rest of three studies (Hedges’ g = 0.49, 95% CI 0.22 to 0.76, Z = 3.61, p = 0.0003) (Supplementary Figure 4).

We further evaluated the benefits of the cognitive training on objective memory, including total memory score [30 , 41–43], immediate recall [39 , 43], delayed recall [39 , 43], and recognition [39]. The results showed that cognitive training had an approximate small effect on total memory score (Hedges’ g = 0.19, 95% CI 0 to 0.37, Z = 1.98, p = 0.05), a nonsignificant effect on immediate recall (Hedges’ g = 0.04, 95% CI –0.21 to 0.28, Z = 0.28, p = 0.78), and delayed recall (Hedges’ g = 0.18, 95% CI –0.16 to 0.52, Z = 1.04, p = 0.30). Only one study involved recognition outcome, with a large effect (Hedges’ g = 0.96, 95% CI 0.23 to 1.70) [39]. The forest plot of objective memory-total memory score is shown in Supplementary Figure 5.

In four studies, the effect of cognitive training on global cognitive function was also analyzed [30 , 41]. However, the results revealed a nonsignificant effect (Hedges’ g = –0.01, 95% CI –0.23 to 0.20, Z = 0.11, p = 0.91). Three studies investigated the impact of the cognitive training on psychological well-being [30 , 44]. There was a small positive effect on this outcome (Hedges’ g = 0.27, 95% CI 0.03 to 0.52, Z = 2.16, p = 0.03) (Supplementary Figure 6). Finally, we reported the effect of the cognitive training on mood (depression and anxiety). In three studies [32 , 42], the cognitive training intervention did not significantly influence the mood (Hedges’ g = –0.20, 95% CI –0.54 to 0.14, Z = 1.16, p = 0.25). For all outcome measures, no publication bias was observed (Begg’s test, p > 0.05) (Table 3). The funnel plots of cognitive training on subjective memory and objective memory-total memory score are also shown in Supplementary Figures 7 and 8.

Multidomain interventions

One study found that there was no significant effect of the physical plus mental activity intervention on global cognitive function compared with an active control group (Hedges’ g = 0.20, 95% CI –0.31 to 0.72) [45]. Another explored the effect of the simultaneous exercise and memory training on objective memory-total memory score. The results revealed that a 4-week simultaneous memory training and aerobic exercise program was potential to improve memory (Hedges’ g = 0.51, 95% CI –0.02 to 1.05) [46].

DISCUSSION

In the present study, we performed a meta-analysis to assess the effect sizes of NPIs on various indicators for individuals with SCD. The results revealed that psychological and health-related interventions exhibited a medium effect on objective memory function, while cognitive training showed a small effect on objective memory, which was marginal in statistical significance. In addition, cognitive training also significantly improved subjective memory performance and psychological well-being. It demonstrates that cognitive enhancement is possible even in cognitively normal persons. NPIs have the potential to serve as an alternative therapeutic strategy for persons with SCD. Furthermore, we will provide the future perspectives for clinical trials of NPIs in adults with SCD.

Single-domain interventions for SCD

We first summarized the efficacy of psychoeducation and health-related education interventions on subjective memory and objective memory function. We found a positive effect on subjective memory but this was not statistically significant. In a prior review, Metternich et al. reported that the expectancy change intervention, including psychoeducation, appeared to be most efficient in influencing subjective memory complaints [25]. The most recent meta-analysis also revealed that psychoeducation had a positive effect on subjective memory, although not reaching statistical significance [28]. Thus, psychological and health-related education interventions may be a helpful intervention strategy in improving subjective memory performance. However, the statistically nonsignificant effect may be due to the limited number of eligible studies. In addition, there was a significant improvement in objective memory, indicating its benefits in ameliorating objective cognitive function.

There was a significant diversity of SCD intervention studies, with cognitive training dominating the field. Cognitive training refers to a series of repeated and standardized tasks targeting specific cognitive domains (e.g., memory, attention, and executive function), which has been implemented in patients with MCI and AD [48 –50]. It is now recognized that cognitive training may also hold promise for preventing cognitive decline in SCD [31]. For instance, after an 8-week memory training, fifty-three elderly adults with SCD showed improvements in their working memory [51]. Youn et al. reported significant improvements in the word list delayed recall, visuospatial recognition and categorical fluency test after the memory training, suggesting raised abilities both in memory and other cognitive domains that are not trained [39]. In this study, we found that cognitive training exhibited a small effect but was marginal statistically on objective memory-total memory score (Hedges’ g = 0.19, p = 0.05). Nevertheless, there was no significant pooled effect on immediate recall, and delayed recall. Metternich et al. once reported that memory training was the only effective intervention for improving objective memory [25]. Canevelli et al. found that most cognitive interventions could objectively improve cognitive performance [26]. In Bhome’s review, a small but significant pooled effect sizes on objective cognitive performance were also found [28]. However, most of previous systematic reviews investigated the efficacy of cognitive interventions on objective cognitive function without focusing on the memory domain. Our study suggested a positive impact of cognitive training on objective memory function.

The efficacy of cognitive training on subjective memory complaints seems to be controversial in different studies. A pilot study found that cognitive training contributed to memory complaints in SCD persons [30]. However, two previous reviews reported no effect of cognitive training on subjective memory [25, 28]. In our study, cognitive training led to different effects on subjective memory performance when adopting different types of assessment tools, indicating the potential discrepancy of measurement instruments in evaluating the response to interventions.

In addition to the objective memory and subjective memory performance, cognitive training appears to decrease loneliness [30], reduce feelings of anxiety and stress [52], and improve psychological well-being [42]. In this study, cognitive training had a small but significant effectiveness on psychological well-being (Hedges’ g = 0.27). However, cognitive training showed no significant effect on global cognitive function, which was consistent with the findings of the Bhome et al. review [28].

Modifiable lifestyle risk factors, such as obesity, physical inactivity, innutrition, and smoking, have a close association with the incidence of cognitive decline and dementia [20 , 53]. Thus, lifestyle-based interventions may be a potential approach to prevent or delay cognitive decline in people at risk for AD. In previous studies, physical exercise has been suggested to have a protective effect on global cognition with ageing [54]. Older adults who are physically active seem less likely to experience cognitive decline than sedentary persons in later life [55, 56]. Functional foods, generally defined as foods containing one or more functional ingredients that affect specific functions in the body, are considered to be beneficial for improving physical or mental health [57]. Numerous nutrient components, such as polyamines, flavonoids, fish oil, etc., may play an important role in anti-Aβ aggregation, anti-oxidative stress, and anti-inflammation processes [58, 59]. In our study, we also explored the effect of physical exercise and nutrients supplementation on objective memory. However, the evidence for their efficacy is not encouraging.

There is limited evidence available with regards to the mindfulness intervention for SCD. Mindfulness is considered as a promising and rapidly developing field of research in the AD management [60]. It emphasizes focused, nonjudgemental awareness of present moment experiences [61]. Smart et al. found that SCD subjects had decreased cognitive complaints after mindfulness training, with an increase in the error-related negativity but without an increase in the error positivity based on electroencephalogram, suggesting that mindfulness may ameliorate subjective memory by modifying physiological function [16]. However, it is essential for more related studies to confirm the results.

Multidomain interventions for SCD

Accumulating evidences supports the designation of AD as a multifactorial neurodegenerative disorder. Concurrent multidomain interventions against a series of risk factors and disease mechanisms may have more preventive effects than single-domain intervention strategies [62]. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study, which involved a two-year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring for at-risk elderly people, has validated an improvement or maintenance of cognitive function compared with the general population [63]. Cohen-Mansfield et al. also suggested that multiple interventions should be offered to older adults with SCD due to the heterogeneous features of this population [30]. In our study, combined memory training and aerobic exercise for 4 weeks was potential to improve memory function in older adults with SCD. Combined physical exercise and mental activity was associated with significant improvements in global cognitive function but did not differ between intervention and active control groups. Currently, an ongoing multidomain dementia prevention trial, called BBl-Cd (Body, Brain, life for Cognitive decline), aims to provide a cost-effective method for minimizing any further damage or delaying the progression of dementia for individuals with SCD and MCI [64]. Taken together, multidomain interventions appear to be an effective prevention strategy for individuals with SCD. Future studies with larger sample sizes are needed.

Limitations

The main limitations of this study are as follows. First, there is a high diversity in measurement instruments of outcomes across studies. It is common for NPIs to use neuropsychological measures as the main outcomes. The sensitivity of various neuropsychological tests in response to interventions is likely to be different. Thus, the selection of standardized and sensitive measurement tools is necessary to capture subtle changes in cognitive, behavioral, or psychological outcomes [65]. Second, the characteristics of intervention strategies were heterogenous to some extent across studies, even in the same categories. There are differences in terms of the intervention duration, sessions, key components, and frequency. For instance, most of cognitive training interventions focus on the memory domain, while several involve integrated attention or other cognitive domains. The nutrients also include numerous components, such as spermidine, fish oil, ginkgo biloba extract, probiotics, multivitamins, etc., which may lead to discrepancies in evaluating the effectiveness of interventions. Third, the included studies in this meta-analysis contained active control groups and non-active control groups, which may create potentially different effectiveness in the control group, and further confuse the true impact of the intervention. Moreover, although there was no publication bias in this meta-analysis, it is difficult to infer the true publication bias condition due to the small sample sizes. Finally, the lack of high-quality researches on SCD interventions and small sample sizes in most of studies limit the rigor of conclusions. In addition, there is a relatively low number of included studies in most comparisons. However, except for the psychological and health-related education on subjective memory, most analyses yielded results without considerable heterogeneity. In the future, researchers should calculate necessary sample sizes in advance based on available effect sizes for interventions. Furthermore, larger, multicenter RCTs of NPIs for adults with SCD are needed.

Future directions

Other prospective NPI strategies for SCD

A healthy dietary pattern may prevent cognitive decline. Currently, the Mediterranean diet (MeDi) has been the spotlight of dietary research [66] A prospective cohort study that enrolled 51,529 US males showed that participants with long-term adherence to a MeDi pattern had a decreased risk of poor subjective memory [67]. The possible mechanism may be that: 1) MeDi can indirectly prevent cognitive decline by reducing cardiovascular risk factors [68]. 2) MeDi adherence may contribute to less brain atrophy and glucose hypermetabolism [66, 69]. 3) MeDi can affect the composition, activity, and diversity of the intestinal microorganisms that are associated with AD [70]. Thus, we propose a hypothesis that the adherence to a MeDi pattern may also be beneficial for SCD.

Recent studies emphasize that light stimulation emerges as a cognitive modulator. Light exposure could modulate brain responses to cognitive tasks through visual and non-visual pathways, which initially involve the subcortical and limbic structures, followed by modulations of activity in cortical areas [71]. The intensity of light could affect hippocampal structural plasticity [72]. Additionally, exposure to a non-invasive 40Hz light-flickering regime could attenuate the amyloid load [73]. The investigators also noted that auditory stimulation is beneficial for Aβ clearance. Hampton et al. further proposed that the combination of visual and auditory stimulation may hold promise [74]. Therefore, in the future, it may be of great value to consider the utilization of light and sound as a therapeutic NPI to slow disease progression for individuals with SCD.

Standardized participant selection and longitudinal trials

In prior RCTs, the subjects in the placebo group had variable trajectories of cognitive change, underscoring the importance of subject selection and monitoring. Veitch et al. suggested that “selection criteria based on Aβ positivity, hippocampal volume, baseline cognitive/functional measures and apolipoprotein ɛ4 status were projected to decrease clinical trial duration and cost” [62]. Standardized subject selection is key for identifying ideal candidates to participate in secondary prevention trials.

Recently, most studies have focused on evaluating the short-term effects of NPIs on cognition, behavior, and neuropsychology, while neglecting the follow-up assessments. Moreover, AD is a consecutively pathophysiological process, and a specific treatment targeting individuals in the preclinical, MCI or dementia stages may result in different effects. In this review, we have also summarized all the RCTs of NPIs in patients with MCI [75, 76] and AD [77] in Supplementary Tables 1 and Table 2. Therefore, in the future, more longitudinal intervention trials are needed to prove the long-term efficacy of NPIs in maintaining cognition, and to compare the differences in the therapeutic effects for individuals with SCD and MCI and AD patients.

Conclusion

In summary, the current systematic review and meta-analysis indicates that NPIs exhibit a small-to-medium effect on objective memory function, and can improve subjective memory performance and psychological well-being in older adults with SCD. The current findings are encouraging and the implementation of NPIs in SCD is promising. Due to the inevitable progression of AD-related pathologies, interventions at the earliest stage of AD have been emphasized as a crucial element to counteract the onset of dementia. Targeting SCD is beneficial to facilitate early intervention of AD. A great challenge for AD is the failure to develop effective pharmacological agents. Hence noninvasive, cost-effective non-pharmacological therapies may be feasibly implemented in clinical practice. In the future, the combination of multiple therapeutic interventions has the potential to provide opportunities for promoting healthy aging in individuals with SCD.

Footnotes

ACKNOWLEDGMENTS

This article was supported by the National Key Research and Development Program of China (2016YFC1306300, 2018YFC1312001), National Natural Science Foundation of China (61633018, 81801052), Beijing Nature Science Foundation (7161009), Beijing Municipal Commission of Health and Family Planning (PXM2019_026283_000002).

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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