Introduction: The prevalence of mild and major neurocognitive disorders (NCDs), also referred to as mild cognitive impairment and dementia, is rising globally. The prevention of NCDs is a major global public health interest. We sought to synthesize the literature on potentially modifiable risk factors for NCDs. Methods: We conducted an umbrella review using a systematic search across multiple databases to identify relevant systematic reviews and meta-analyses. Eligible reviews examined potentially modifiable risk factors for mild or major NCDs. We used a random-effects multi-level meta-analytic approach to synthesize risk ratios for each risk factor while accounting for overlap in the reviews. We further examined risk factors for major NCD due to two common etiologies: Alzheimer’s disease and vascular dementia. Results: A total of 45 reviews with 212 meta-analyses were synthesized. We identified fourteen broadly defined modifiable risk factors that were significantly associated with these disorders: alcohol consumption, body weight, depression, diabetes mellitus, diet, hypertension, less education, physical inactivity, sensory loss, sleep disturbance, smoking, social isolation, traumatic brain injury, and vitamin D deficiency. All 14 factors were associated with the risk of major NCD, and five were associated with mild NCD. We found considerably less research for vascular dementia and mild NCD. Conclusion: Our review quantifies the risk associated with 14 potentially modifiable risk factors for mild and major NCDs, including several factors infrequently included in dementia action plans. Prevention strategies should consider approaches that reduce the incidence and severity of these risk factors through health promotion, identification, and early management.

Neurocognitive disorders (NCDs) are a leading cause of mortality and morbidity worldwide and a major subject of biomedical, clinical, and public health research [1]. NCDs were included in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which distinguished between mild and major forms [2]. It was hoped that the term “major NCD” would be viewed as less stigmatizing than “dementia” while the inclusion of criteria for a milder form of acquired cognitive decline would provide opportunities for earlier detection, advance care planning, and treatment before the condition progresses to a severe stage [3]. Major NCDs are marked by significant cognitive decline that results in impairments of activities of daily living, which are not better explained by delirium or another mental health disorder. Mild NCDs, also referred to as mild cognitive impairment in the neurology literature, are characterized by more modest cognitive decline that does not result in functional impairment with the same exclusionary criteria noted for major NCDs. While mild NCD is not necessarily progressive, between 30% and 50% of older adults with mild degrees of impaired cognition progress to a major NCD within 5 years [4‒6]. Both major and mild NCDs can be secondary to a variety of conditions including Alzheimer’s disease (AD) and vascular cognitive impairment (VCI).

Major NCD was estimated to affect 57.4 million individuals worldwide in 2019, a figure that is projected to increase to 152.8 million by 2050 (a 266% increase) [7]. This increase is due to the global growth of the older population offsetting declines in age-specific incidence rates in economically developed nations. While estimates of the prevalence of mild NCD vary widely from factors such as the population studied and definition used, a recent umbrella review found that, globally, approximately 15% of adults over the age of 50 were living with this condition [8]. The typical progressive nature of major NCDs, stage-dependent mortality and morbidity risk, and the limited treatment options has led governmental and public health organizations to emphasize the importance of its prevention [9, 10]. There is an extensive scientific literature on risk factors for major NCD that has been summarized in the Lancet Commission on Dementia Prevention, Intervention, and Care reports [11, 12]. Many of the risk factors identified for dementia are potentially modifiable, but whether this is also true for mild NCDs is less clear as the evidence on risk factors for this condition is less voluminous. Few reports to date have simultaneously examined the literature for risk factors of both major and mild NCDs.

Given that mild and major NCDs represent a continuum of severity with similar etiologies, many of their risk factors are likely shared. Evidence related to the overlap in risk factors, though, remains limited. As well, shared risk factors could still vary meaningfully in their relative importance to the development and/or progression of each condition. A synthesis of the modifiable risk factors for mild and major NCDs could inform prevention strategies that encompass the continuum. The objective of this systematic review of systematic reviews (i.e., umbrella review) and meta-analysis is to examine and synthesize the existing literature on modifiable risk factors for mild and major NCDs. We will compare the evidence on risk factors for both mild and major NCDs and for two of the more common etiologies of major NCDs.

This umbrella review and meta-analysis is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the JBI Manual for Evidence Synthesis [13, 14]. The protocol for this review was registered a priori in PROSPERO (CRD42021291607). We chose an umbrella review methodology given the large number of existing systematic reviews found in the literature.

Eligibility Criteria

Publications eligible for inclusion were systematic reviews with meta-analyses that examined risk factors for mild or major NCDs. No specific diagnostic criteria were enforced and we did not exclude any etiologies. Publications were excluded if they were in languages other than English, did not include longitudinal data, or primarily considered populations living in congregate living settings (e.g., nursing homes, etc.). Studies were ineligible if their outcome was cognitive decline apart from a new diagnosis of an NCD. Due to the large number of risk factors uncovered by the review, the present study considers only potentially modifiable risk factors. Non-modifiable risk factors, such as age, sex/gender, and family history, were not included. Potentially modifiable environmental and occupational (e.g., air pollution, pesticides, etc.) risk factors and early life adversity were also not considered in this review.

Study Selection

We searched MEDLINE (Ovid MEDLINE [R]), Web of Science (core collection), PsycINFO (Ovid interface), and Cochrane Library (Wiley online platform) for relevant articles from January 1984 until November 2021. An electronic search strategy (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000536643) was developed in consultation with academic librarians. The search string included terms related to systematic reviews and/or meta-analyses, identification of risk factors, and NCDs. After removal of duplicates, studies were first screened for relevance by title and abstract and then were assessed for eligibility by full-text review. Screening and eligibility assessment was performed by two independent reviewers; conflicts were resolved by a third reviewer. Risk factors were sorted by modifiable/non-modifiable after screening and eligibility, with only the potentially modifiable risk factors retained for this review. The scope of potentially modifiable risk factors was determined through consideration of previous literature [15], public health guidelines [16], and consensus within the research team.

Data Extraction and Quality Assessment

Quality assessment and data extraction were performed by a single reviewer and verified by a second reviewer. Quality was assessed using the AMSTAR-2 critical appraisal tool [17]. The AMSTAR-2 tool rates the evidence from a systematic review on 16 items across 10 domains. The tool is not intended to generate an overall score but rather a rating from very low to high based on the number of critical and non-critical weaknesses. Data extracted included year of publication, number of studies included, risk factors examined, outcomes examined, and number of participants. Study results extracted included the name and definition of each risk factor, name and definition of each outcome, and the meta-analyzed risk estimates with associated standard error, and/or 95% confidence interval. Outcomes were classified into major NCD (dementia) and mild NCD (mild cognitive impairment). Results for subgroups, including for dementia due to AD and dementia due to VCI (i.e., vascular dementia), were extracted where available.

Data Synthesis

We reported the characteristics of the included studies using descriptive statistics. For consistency in synthesizing results across reviews, we used relative risk (RR) to quantify the association between modifiable risk factors and the risk of NCDs. Hazard ratios were used as equivalent to risk ratios and odds ratios were converted to risk ratios from longitudinal/prospective studies using Cochrane recommended methods [18, 19]. For meta-analysis, we used a random-effects multi-level meta-analytic approach to account for dependency between effect estimates across reviews and to avoid possible unit of analysis error (i.e., a correlation between effect estimates due to overlap of studies across reviews or multiple measures/comparisons of the outcome within the same review with overlapping sub-sample sizes or population) [20, 21]. In such cases, possibly correlated effect estimates were nested at the within-review level first (reviews with overlapping studies or multiple measures from the same review). The variance in observed effect estimates was further decomposed into sampling variance, within-review variance, and between-review variance to account for intracluster (or intraclass) correlation in the true effects. The final pooled effect estimates were presented with 95% confidence intervals, which were used to judge statistical significance. When there was only a single systematic review available for a given association, we did not perform additional meta-analysis but reported the result of the underlying systematic review.

Overall heterogeneity for each summary effect estimate was estimated using the I2 statistic, which represents the heterogeneity not attributable to sample error and is the sum of within-cluster (i.e., across effect sizes or multiple arms from the same or overlapping reviews) and between-cluster heterogeneity (i.e., effect sizes across unique reviews) [22]. We considered I2 values of between 50% and 75% to represent moderate heterogeneity across studies and I2 values of >75% to represent substantial heterogeneity across studies. Cochran’s Q (α = 0.05) was also employed to detect statistical heterogeneity.

The primary grouping in the meta-analysis was based on risk factor, then by the type of NCD and further by the two of the more common causes of major NCD. To account for expected heterogeneity across life stages, analysis of body weight and hypertension was conducted by age-groups (mixed age-groups, mid-life [40–64], and late life [65+]). For body weight, body mass index (BMI) (kg/m2) categories were as follows: <18.5, ≥18.5 and <25, ≥25 and <30, and ≥30. The reference category was between 18.5 and 25 kg/m2. There were insufficient reported data across reviews to perform additional subgroup analyses (i.e., based on sex/gender, socio-economic status, length of follow-up, etc.). All analyses were performed using R v4.3.1 with packages metafor and dmetar packages [23, 24].

Literature Flow

After removing duplicates, 6,790 articles were screened via title and abstract, and 1,114 were assessed for eligibility at the full-text level (Fig. 1). Ultimately 45 [25‒69] articles were included with containing 212 meta-analyses with 89,671,556 participants examining 14 broadly defined risk factors.

Fig. 1.

Literature flow.

Study Characteristics

Eligible articles were published between 2006 and 2021 (Table 1). Of the 212 meta-analyses included, 86 examined the risk of major NCD, 83 examined dementia from AD, 29 examined dementia from VCI (i.e., vascular dementia), and 14 examined mild NCD. The broadly defined risk factors included alcohol consumption, body weight (BMI <18.5, BMI 25–29, BMI ≥30), depression, diabetes mellitus, diet (fish consumption, milk consumption, healthy dietary patterns), hypertension (combined, systolic, diastolic), less education, physical inactivity, sensory loss (hearing loss, visual impairment), sleep disturbances, smoking, social isolation, traumatic brain injury (TBI), vitamin D deficiency. Risk factor definitions varied within and between reviews (online suppl. Table S2) with the exception of body weight, which used standard BMI categories, and smoking, which consistently used current, former, and ever smoker categories. Health conditions were most commonly based on validated cut-offs of objective measures and/or scales but also included diagnoses noted in clinical records and self-report. Social isolation was primarily defined as living alone. Sleep disturbances included a variety of sleeping disorders as well as self-reported long and short sleep durations. Visual impairment included age-related macular degeneration as well as objective loss of visual acuity. Less education did not have a consistent definition but was related to fewer years of formal schooling.

Table 1.

Characteristics of included reviews (n = 45)

ReviewRisk factors examinedOutcomes examinedNumber of studies includedNumber of participants included across studies
Anstey [25] (2007) Smoking Major NCD; Alzheimer’s dementia, vascular dementia 22,441 
Anstey [26] (2009) Alcohol consumption Major NCD; Alzheimer’s dementia, vascular dementia 15 29,686 
Anstey [27] (2011) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 17 46,462 
Bakre [28] (2018) Diet Major NCD; Alzheimer’s dementia 11 33,964 
Beydoun [29] (2008) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 10 41,956 
Bubu [30] (2017) Sleep disturbance Alzheimer’s dementia 27 69,216 
Cherbuin [31] (2015) Depression Major NCD; Alzheimer’s dementia, vascular dementia 36 66,532 
Cooper [32] (2015) Diabetes; hypertension; depression Major NCD 62 15,223 
Danat [33] (2019) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 16 41,781 
Desai [34] (2020) Social isolation Major NCD 12 13,317 
Hamer [35] (2009) Physical inactivity Major NCD; Alzheimer’s dementia 16 163,797 
Hu [36] (2020) Depression Mild NCD 13 33,066 
Huang [37] (2013) TBI Major NCD; Alzheimer’s dementia 18 4,648,013 
Hudon [38] (2020) Sleep disturbance, depression Major NCD; mild NCD 18 72,287 
Kalra [39] (2020) Vitamin D deficiency Major NCD; Alzheimer’s dementia 19,259 
Kuring [40] (2020) Depression Major NCD; Alzheimer’s dementia, vascular dementia 36 828,767 
Lee [41] (2020) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 23 2,790,753 
Lennon [42] (2019) Hypertension Alzheimer’s dementia 877,321 
Li [43] (2019) Diabetes; hypertension; body weight; smoking Major NCD 24 159,594 
Liang [44] (2020) Alcohol consumption; sleep disturbance; diabetes; low education; hypertension; social isolation; body weight; physical inactivity; smoking Major NCD 43 277,294 
Liang [45] (2021) Sensory loss Major NCD; Alzheimer’s dementia 14 726,900 
Loef [46] (2013) Body weight Major NCD; Alzheimer’s dementia 13 59,978 
Loughrey [47] (2018) Sensory loss Major NCD; Alzheimer’s dementia, vascular dementia 40 34,471 
Mourao [48] (2016) Depression Major NCD 18 10,861 
Ou [49] (2020) Hypertension Major NCD; Alzheimer’s dementia, mild NCD 136 2,214,814 
Ownby [50] (2006) Depression Alzheimer’s dementia 20 102,172 
Pedditizi [51] (2016-A) Body weight Major NCD 21 62,425 
Perry [52] (2016) TBI Major NCD; mild NCD 30 8,232 
Power [53] (2011) Hypertension Alzheimer’s dementia 18 42,986 
Profenno [54] (2010) Diabetes; body weight Alzheimer’s dementia 15 41,480 
Qu [55] (2020) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 18 201,026 
Rong [56] (2019) Sensory loss Alzheimer’s dementia 21 7,876,499 
Sáiz-Vázquez [57] (2021) Depression Alzheimer’s dementia 28 50,051 
Snowden [58] (2020) TBI Major NCD 2,351,334 
Sommerlad [59] (2018) Social isolation Major NCD 15 812,047 
Tan [60] (2019) Depression Major NCD 35 14,158 
Vagelatos [61] (2013) Diabetes Alzheimer’s dementia 15 2,122,883 
Vu [62] (2021) Sensory loss Major NCD 40 47,913,570 
Wang [63] (2018) Hypertension Major NCD 21 830,631 
Wei [64] (2017) Sensory Loss Mild NCD 10 15,521 
Wu [65] (2016) Diet Major NCD; Alzheimer’s dementia 10,941 
Xu [66] (2015) Body weight, smoking, alcohol consumption, hypertension, diabetes, depression, low education, diet, physical inactivity, social isolation, TBI Alzheimer’s dementia 351 3,116,095 
Yates [67] (2013) Depression Major NCD; MCI 60 53,451 
Zhong [68] (2015) Smoking Major NCD; Alzheimer’s dementia, vascular dementia 37 960,280 
Zuin [69] (2021) Diabetes; hypertension Alzheimer’s dementia 9,788,021 
ReviewRisk factors examinedOutcomes examinedNumber of studies includedNumber of participants included across studies
Anstey [25] (2007) Smoking Major NCD; Alzheimer’s dementia, vascular dementia 22,441 
Anstey [26] (2009) Alcohol consumption Major NCD; Alzheimer’s dementia, vascular dementia 15 29,686 
Anstey [27] (2011) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 17 46,462 
Bakre [28] (2018) Diet Major NCD; Alzheimer’s dementia 11 33,964 
Beydoun [29] (2008) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 10 41,956 
Bubu [30] (2017) Sleep disturbance Alzheimer’s dementia 27 69,216 
Cherbuin [31] (2015) Depression Major NCD; Alzheimer’s dementia, vascular dementia 36 66,532 
Cooper [32] (2015) Diabetes; hypertension; depression Major NCD 62 15,223 
Danat [33] (2019) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 16 41,781 
Desai [34] (2020) Social isolation Major NCD 12 13,317 
Hamer [35] (2009) Physical inactivity Major NCD; Alzheimer’s dementia 16 163,797 
Hu [36] (2020) Depression Mild NCD 13 33,066 
Huang [37] (2013) TBI Major NCD; Alzheimer’s dementia 18 4,648,013 
Hudon [38] (2020) Sleep disturbance, depression Major NCD; mild NCD 18 72,287 
Kalra [39] (2020) Vitamin D deficiency Major NCD; Alzheimer’s dementia 19,259 
Kuring [40] (2020) Depression Major NCD; Alzheimer’s dementia, vascular dementia 36 828,767 
Lee [41] (2020) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 23 2,790,753 
Lennon [42] (2019) Hypertension Alzheimer’s dementia 877,321 
Li [43] (2019) Diabetes; hypertension; body weight; smoking Major NCD 24 159,594 
Liang [44] (2020) Alcohol consumption; sleep disturbance; diabetes; low education; hypertension; social isolation; body weight; physical inactivity; smoking Major NCD 43 277,294 
Liang [45] (2021) Sensory loss Major NCD; Alzheimer’s dementia 14 726,900 
Loef [46] (2013) Body weight Major NCD; Alzheimer’s dementia 13 59,978 
Loughrey [47] (2018) Sensory loss Major NCD; Alzheimer’s dementia, vascular dementia 40 34,471 
Mourao [48] (2016) Depression Major NCD 18 10,861 
Ou [49] (2020) Hypertension Major NCD; Alzheimer’s dementia, mild NCD 136 2,214,814 
Ownby [50] (2006) Depression Alzheimer’s dementia 20 102,172 
Pedditizi [51] (2016-A) Body weight Major NCD 21 62,425 
Perry [52] (2016) TBI Major NCD; mild NCD 30 8,232 
Power [53] (2011) Hypertension Alzheimer’s dementia 18 42,986 
Profenno [54] (2010) Diabetes; body weight Alzheimer’s dementia 15 41,480 
Qu [55] (2020) Body weight Major NCD; Alzheimer’s dementia, vascular dementia 18 201,026 
Rong [56] (2019) Sensory loss Alzheimer’s dementia 21 7,876,499 
Sáiz-Vázquez [57] (2021) Depression Alzheimer’s dementia 28 50,051 
Snowden [58] (2020) TBI Major NCD 2,351,334 
Sommerlad [59] (2018) Social isolation Major NCD 15 812,047 
Tan [60] (2019) Depression Major NCD 35 14,158 
Vagelatos [61] (2013) Diabetes Alzheimer’s dementia 15 2,122,883 
Vu [62] (2021) Sensory loss Major NCD 40 47,913,570 
Wang [63] (2018) Hypertension Major NCD 21 830,631 
Wei [64] (2017) Sensory Loss Mild NCD 10 15,521 
Wu [65] (2016) Diet Major NCD; Alzheimer’s dementia 10,941 
Xu [66] (2015) Body weight, smoking, alcohol consumption, hypertension, diabetes, depression, low education, diet, physical inactivity, social isolation, TBI Alzheimer’s dementia 351 3,116,095 
Yates [67] (2013) Depression Major NCD; MCI 60 53,451 
Zhong [68] (2015) Smoking Major NCD; Alzheimer’s dementia, vascular dementia 37 960,280 
Zuin [69] (2021) Diabetes; hypertension Alzheimer’s dementia 9,788,021 

The median number of studies per review was 18 (13–28), and the median number of participants per review across all reviews was 65,532 (33,066–830,631). Our quality appraisal of the literature using AMSTAR-2 found that 18 (40%) reviews were of high quality, 10 (22%) were of moderate quality, 8 (18%) were of low quality, and 9 (20%) were of very low quality (online suppl. Table S3).

Risk Factors for Major NCD

Major NCD was the most common outcome examined. We extracted results for 14 risk factors (Table 2) from 86 meta-analyses. There were statistically significant positive associations between major NCD and body weight (BMI ≥30, BMI 25–29, and BMI <18.5 at mid-life; BMI <18.5 in a mixed age-group), depression, diabetes mellitus, diet (low fish consumption), hypertension (combined hypertension at mid-life and in mixed age-groups; high systolic blood pressure at mid-life and in mixed age-groups; high diastolic blood pressure in mid-life), less education, physical inactivity, sensory loss (hearing loss, visual impairment), sleep disturbances, ever or current smoking, social isolation, TBI, vitamin D deficiency. The largest risk ratio was observed with sleep disturbances at 2.18 (95% CI, 1.44, 3.32). Heavy alcohol consumption was not a significant risk factor compared to no alcohol consumption but was a significant risk factor when compared to light/moderate alcohol consumption. Factors that were protective included BMI ≥30 and BMI 25–29 in late life, BMI 25–29 in the mixed age-group, and any or light/moderate alcohol intake versus no alcohol intake. Of the 25 associations for which the I2 statistic could be calculated, 1 study (4%) had a value between 50% and 75% and 4 (16%) had I2 ≥ 75%.

Table 2.

Results of meta-analysis of risk factors for major NCD

Risk factorNumber of reviewsRR (95% CI)Heterogeneity, I2
Alcohol consumption 
 Any versus none 0.66 (0.53, 0.82) 
 Light/moderate versus none 0.74 (0.61, 0.90) 
 Heavy versus none 1.19 (0.95, 1.50) 0% 
 Heavy versus light/moderate 1.41 (1.14, 1.73) 
Body weight (mid-life) 
 BMI ≥30 versus normal 1.57 (1.43, 1.72) 4% 
 BMI 25–29.9 versus normal 1.19 (1.12, 1.27) 4% 
 BMI <18.5 versus normal 1.42 (1.12, 1.80) 
Body weight (late life) 
 BMI ≥30 versus normal 0.80 (0.74, 0.87) 0% 
 BMI 25–29.9 versus normal 0.84 (0.89, 0.92) 0% 
 BMI <18.5 versus normal 1.11 (0.85, 1.46) 49% 
Body weight (mixed age-groups) 
 BMI ≥30 versus normal 1.23 (0.82, 1.85) 84% 
 BMI 25–29.9 versus normal 0.86 (0.81, 0.92) 0% 
 BMI <18.5 versus normal 1.26 (1.21, 1.32) 0% 
Depression 1.41 (1.16, 1.72) 87% 
Diabetes mellitus 1.67 (1.43, 1.95) 0% 
Diet 
 Low fish consumption versus high 1.25 (1.15, 1.35) 
 Low milk consumption versus high 1.37 (0.98, 1.96) 
Hypertension (mid-life) 
 Hypertension (combined) 1.51 (1.11, 2.04) 77% 
 High systolic pressure 1.51 (1.31, 1.74) 0% 
 High diastolic pressure 1.54 (1.16, 2.05) 0% 
Hypertension (late life) 
 Hypertension (combined) 1.03 (0.95, 1.11) 0% 
 High systolic pressure 1.09 (0.91, 1.30) 0% 
 High diastolic pressure 0.86 (0.64, 1.15) 32% 
Hypertension (mixed age-groups) 
 Hypertension (combined) 1.20 (1.04, 1.40) 0% 
 High systolic pressure 1.20 (1.02, 1.42) 
 High diastolic pressure 1.24 (0.85, 1.81) 
Less education 1.87 (1.40, 2.48) 
Physical inactivity 1.37 (1.17, 1.60) 0% 
Sensory loss 
 Hearing loss 1.59 (1.20, 2.11) 78% 
 Visual impairment 2.05 (1.36, 3.09) 
 Sleep disturbance 2.18 (1.44, 3.32) 
Smoking 
 Ever smokers 1.22 (1.04, 1.43) 57% 
 Current smokers 1.37 (1.20, 1.57) 49% 
 Former smokers 1.01 (0.97, 1.04) 0% 
Social isolation 1.22 (1.15, 1.29) 23% 
TBI 1.92 (1.70, 2.17) 0% 
Vitamin D deficiency 1.33 (1.15, 1.54) 
Risk factorNumber of reviewsRR (95% CI)Heterogeneity, I2
Alcohol consumption 
 Any versus none 0.66 (0.53, 0.82) 
 Light/moderate versus none 0.74 (0.61, 0.90) 
 Heavy versus none 1.19 (0.95, 1.50) 0% 
 Heavy versus light/moderate 1.41 (1.14, 1.73) 
Body weight (mid-life) 
 BMI ≥30 versus normal 1.57 (1.43, 1.72) 4% 
 BMI 25–29.9 versus normal 1.19 (1.12, 1.27) 4% 
 BMI <18.5 versus normal 1.42 (1.12, 1.80) 
Body weight (late life) 
 BMI ≥30 versus normal 0.80 (0.74, 0.87) 0% 
 BMI 25–29.9 versus normal 0.84 (0.89, 0.92) 0% 
 BMI <18.5 versus normal 1.11 (0.85, 1.46) 49% 
Body weight (mixed age-groups) 
 BMI ≥30 versus normal 1.23 (0.82, 1.85) 84% 
 BMI 25–29.9 versus normal 0.86 (0.81, 0.92) 0% 
 BMI <18.5 versus normal 1.26 (1.21, 1.32) 0% 
Depression 1.41 (1.16, 1.72) 87% 
Diabetes mellitus 1.67 (1.43, 1.95) 0% 
Diet 
 Low fish consumption versus high 1.25 (1.15, 1.35) 
 Low milk consumption versus high 1.37 (0.98, 1.96) 
Hypertension (mid-life) 
 Hypertension (combined) 1.51 (1.11, 2.04) 77% 
 High systolic pressure 1.51 (1.31, 1.74) 0% 
 High diastolic pressure 1.54 (1.16, 2.05) 0% 
Hypertension (late life) 
 Hypertension (combined) 1.03 (0.95, 1.11) 0% 
 High systolic pressure 1.09 (0.91, 1.30) 0% 
 High diastolic pressure 0.86 (0.64, 1.15) 32% 
Hypertension (mixed age-groups) 
 Hypertension (combined) 1.20 (1.04, 1.40) 0% 
 High systolic pressure 1.20 (1.02, 1.42) 
 High diastolic pressure 1.24 (0.85, 1.81) 
Less education 1.87 (1.40, 2.48) 
Physical inactivity 1.37 (1.17, 1.60) 0% 
Sensory loss 
 Hearing loss 1.59 (1.20, 2.11) 78% 
 Visual impairment 2.05 (1.36, 3.09) 
 Sleep disturbance 2.18 (1.44, 3.32) 
Smoking 
 Ever smokers 1.22 (1.04, 1.43) 57% 
 Current smokers 1.37 (1.20, 1.57) 49% 
 Former smokers 1.01 (0.97, 1.04) 0% 
Social isolation 1.22 (1.15, 1.29) 23% 
TBI 1.92 (1.70, 2.17) 0% 
Vitamin D deficiency 1.33 (1.15, 1.54) 

Risk Factors for Mild NCD

We extracted results from 14 meta-analyses concerning mild NCD for 5 risk factors (Table 3). We found statistically significant positive associations between risk of mild NCD and depression, hearing loss, hypertension (combined hypertension at mid- and late life, high systolic pressure at mid-life, high diastolic pressure at mid-life), sleep disturbances, and TBI. The highest risk ratio was observed with TBI at 2.51 (1.50, 4.18). No protective factors were found. The I2 statistic could be calculated for 2 associations, one of which (50%) was greater than 50% but less than 75%.

Table 3.

Results of meta-analysis of risk factors for mild NCD

Risk factorNumber of reviewsRR (95% CI)Heterogeneity, I2
Depression 1.80 (1.40, 2.31) 69% 
Hypertension (mid-life) 
 Hypertension (combined) 1.55 (1.19, 2.02) 
 High systolic pressure 2.17 (1.44, 3.27) 
 High diastolic pressure 1.09 (1.02, 1.17) 
Hypertension (late life) 
 Hypertension (combined) 1.26 (1.04, 1.53) 
 High systolic pressure 1.34 (0.93, 1.93) 
 High diastolic pressure 0.97 (0.89, 1.06) 
Sensory loss 
 Hearing loss 1.30 (1.12, 1.51) 
Sleep disturbance 1.27 (1.12, 1.43) 0% 
TBI 2.51 (1.50, 4.18) 
Risk factorNumber of reviewsRR (95% CI)Heterogeneity, I2
Depression 1.80 (1.40, 2.31) 69% 
Hypertension (mid-life) 
 Hypertension (combined) 1.55 (1.19, 2.02) 
 High systolic pressure 2.17 (1.44, 3.27) 
 High diastolic pressure 1.09 (1.02, 1.17) 
Hypertension (late life) 
 Hypertension (combined) 1.26 (1.04, 1.53) 
 High systolic pressure 1.34 (0.93, 1.93) 
 High diastolic pressure 0.97 (0.89, 1.06) 
Sensory loss 
 Hearing loss 1.30 (1.12, 1.51) 
Sleep disturbance 1.27 (1.12, 1.43) 0% 
TBI 2.51 (1.50, 4.18) 

Risk Factors for AD Dementia

We extracted results from the 83 meta-analyses related to AD dementia for 14 risk factors (Table 4). We found statistically significant positive associations between risk of AD dementia and body weight (BMI ≥30 and BMI 25–29 at mid-life; BMI <18.5 in a mixed age-group), depression, diabetes mellitus, diet (low fish consumption, low milk consumption), hypertension (combined hypertension at mid-life and in mixed age-groups; high systolic pressure in mixed age-group; high diastolic pressure at mid-life), less education, physical inactivity, sensory loss (hearing loss), sleep disturbances, ever or current smoking, and vitamin D deficiency. The largest risk ratio was observed with BMI ≥30 at mid-life at 2.13 (1.75, 2.59). Heavy alcohol consumption was not a significant risk factor compared to no alcohol consumption but was a significant risk factor when compared to light/moderate alcohol consumption. Factors that were found to be protective included BMI ≥30 and BMI 25–29 at late life and BMI 25–29 in mixed age-groups, any and light/moderate alcohol intake versus no alcohol intake, and healthy dietary patterns. Of the 26 associations for which the I2 statistics could be calculated, 3 (12%) had I2 between 50% and 75% and 4 (15%) had I2 ≥ 75%.

Table 4.

Results of meta-analysis of risk factors for AD dementia

Risk factorNumber of reviewsRR (95% CI)Heterogeneity, I2
Alcohol consumption 
 Any versus none 0.60 (0.42, 0.85) 13% 
 Light/moderate versus none 0.65 (0.56, 0.77) 60% 
 Heavy versus none 1.36 (0.68, 2.72) 
 Heavy versus light/moderate 1.89 (1.12, 3.18) 
Body weight (mid-life) 
 BMI ≥30 versus normal 2.13 (1.75, 2.59) 52% 
 BMI 25–29.9 versus normal 1.40 (1.25, 1.57) 0% 
 BMI <18.5 versus normal 1.43 (0.95, 2.17) 57% 
Body weight (late life) 
 BMI ≥30 versus normal 0.75 (0.67, 0.93) 4% 
 BMI 25–29.9 versus normal 0.71 (0.59, 0.84) 0% 
 BMI <18.5 versus normal 1.17 (0.70, 1.94) 
Body weight (mixed age-groups) 
 BMI ≥30 versus normal 1.30 (0.80, 2.11) 79% 
 BMI 25–29.9 versus normal 0.89 (0.81, 0.98) 
 BMI <18.5 versus normal 1.37 (1.20, 1.57) 6% 
Depression 1.64 (1.20, 2.23) 92% 
Diabetes mellitus 1.39 (1.18, 1.65) 92% 
Diet 
 Low fish consumption versus high 1.39 (1.23, 1.54) 0% 
 Low milk consumption versus high 1.54 (1.10, 2.17) 
 Healthy dietary patterns 0.46 (0.27, 0.79) 
Hypertension (mid-life) 
 Hypertension (combined) 1.19 (1.08, 1.32) 0% 
 High systolic pressure 1.37 (0.97, 1.92) 0% 
 High diastolic pressure 1.53 (1.12, 2.10) 0% 
Hypertension (late life) 
 Hypertension (combined) 0.91 (0.82, 1.02) 0% 
 High systolic pressure 0.97 (0.81, 1.16) 0% 
 High diastolic pressure 0.79 (0.54, 1.14) 0% 
Hypertension (mixed age-groups) 
 Hypertension 1.05 (1.04, 1.06) 0% 
 High systolic pressure 1.04 (1.01, 1.06) 75% 
 High diastolic pressure 1.33 (0.62, 2.86) 
Less education 1.35 (1.14, 1.60) 
Physical inactivity 1.56 (1.28, 1.90) 0% 
Sensory loss 
 Hearing loss 2.03 (1.31, 3.14) 0% 
 Visual impairment 1.27 (0.53, 3.04) 
Sleep disturbance 1.55 (1.25, 1.93) 
Smoking 
 Ever smokers 1.12 (1.00, 1.26) 0% 
 Current smokers 1.53 (1.35, 1.74) 30% 
 Former smokers 1.00 (0.92, 1.08) 0% 
Social isolation 1.47 (0.80, 2.70) 
TBI 1.19 (0.95, 1.50) 0% 
Vitamin D deficiency 1.87 (1.03, 3.40) 
Risk factorNumber of reviewsRR (95% CI)Heterogeneity, I2
Alcohol consumption 
 Any versus none 0.60 (0.42, 0.85) 13% 
 Light/moderate versus none 0.65 (0.56, 0.77) 60% 
 Heavy versus none 1.36 (0.68, 2.72) 
 Heavy versus light/moderate 1.89 (1.12, 3.18) 
Body weight (mid-life) 
 BMI ≥30 versus normal 2.13 (1.75, 2.59) 52% 
 BMI 25–29.9 versus normal 1.40 (1.25, 1.57) 0% 
 BMI <18.5 versus normal 1.43 (0.95, 2.17) 57% 
Body weight (late life) 
 BMI ≥30 versus normal 0.75 (0.67, 0.93) 4% 
 BMI 25–29.9 versus normal 0.71 (0.59, 0.84) 0% 
 BMI <18.5 versus normal 1.17 (0.70, 1.94) 
Body weight (mixed age-groups) 
 BMI ≥30 versus normal 1.30 (0.80, 2.11) 79% 
 BMI 25–29.9 versus normal 0.89 (0.81, 0.98) 
 BMI <18.5 versus normal 1.37 (1.20, 1.57) 6% 
Depression 1.64 (1.20, 2.23) 92% 
Diabetes mellitus 1.39 (1.18, 1.65) 92% 
Diet 
 Low fish consumption versus high 1.39 (1.23, 1.54) 0% 
 Low milk consumption versus high 1.54 (1.10, 2.17) 
 Healthy dietary patterns 0.46 (0.27, 0.79) 
Hypertension (mid-life) 
 Hypertension (combined) 1.19 (1.08, 1.32) 0% 
 High systolic pressure 1.37 (0.97, 1.92) 0% 
 High diastolic pressure 1.53 (1.12, 2.10) 0% 
Hypertension (late life) 
 Hypertension (combined) 0.91 (0.82, 1.02) 0% 
 High systolic pressure 0.97 (0.81, 1.16) 0% 
 High diastolic pressure 0.79 (0.54, 1.14) 0% 
Hypertension (mixed age-groups) 
 Hypertension 1.05 (1.04, 1.06) 0% 
 High systolic pressure 1.04 (1.01, 1.06) 75% 
 High diastolic pressure 1.33 (0.62, 2.86) 
Less education 1.35 (1.14, 1.60) 
Physical inactivity 1.56 (1.28, 1.90) 0% 
Sensory loss 
 Hearing loss 2.03 (1.31, 3.14) 0% 
 Visual impairment 1.27 (0.53, 3.04) 
Sleep disturbance 1.55 (1.25, 1.93) 
Smoking 
 Ever smokers 1.12 (1.00, 1.26) 0% 
 Current smokers 1.53 (1.35, 1.74) 30% 
 Former smokers 1.00 (0.92, 1.08) 0% 
Social isolation 1.47 (0.80, 2.70) 
TBI 1.19 (0.95, 1.50) 0% 
Vitamin D deficiency 1.87 (1.03, 3.40) 

Risk Factors for Vascular Dementia

We extracted results from 29 meta-analyses concerning vascular dementia for 6 risk factors (Table 5). We found statistically significant positive associations between vascular dementia and body weight (BMI ≥30 and BMI 25–29 at mid-life; BMI <18.5 in late life; BMI ≥30 and BMI ≤18.5 in a mixed age-group), depression, hypertension (combined hypertension at mid-life and late life; high systolic pressure at mid-life and late life; high diastolic pressure at late life), and ever or current smoking. The largest risk ratio was observed with combined hypertension at mid-life at 7.68 (3.50, 16.85). Heavy alcohol consumption was not a significant risk factor compared to no alcohol consumption but was a significant risk factor when compared to light/moderate alcohol consumption. Factors that were protective included BMI ≥30 at late life and light/moderate alcohol intake versus none. The I2 statistic could be calculated for 8 associations, all of which were <50%.

Table 5.

Results of meta-analysis of risk factors for vascular dementia

Risk factorNumber of reviewsRR (95% CI)Heterogeneity, I2
Alcohol consumption 
 Light/moderate versus none 0.75 (0.57, 0.98) 
 Heavy versus none 0.92 (0.59, 1.44) 
 Heavy versus light/moderate 1.23 (1.03, 1.47) 
Body weight (mid-life) 
 BMI ≥30 versus normal 4.04 (2.59, 6.31) 26% 
 BMI 25–29.9 versus normal 1.39 (1.12, 1.72) 0% 
 BMI <18.5 versus normal 1.47 (0.50, 4.33) 
Body weight (late life) 
 BMI ≥30 versus normal 0.73 (0.61, 0.86) 0% 
 BMI 25–29.9 versus normal 1.00 (0.74, 1.35) 
 BMI <18.5 versus normal 2.18 (1.18, 4.02) 
Body weight (mixed age-groups) 
 BMI ≥30 versus normal 1.49 (1.11, 2.00) 0% 
 BMI 25–29.9 versus normal 1.03 (0.84, 1.26) 
 BMI <18.5 versus normal 1.76 (1.20, 2.58) 
Depression 2.57 (2.16, 3.07) 0% 
Hypertension (mid-life) 
 Hypertension (combined) 7.68 (3.50, 16.85) 
 High systolic pressure 1.30 (1.08, 1.57) 
Hypertension (late life) 
 Hypertension (combined) 3.69 (1.58, 8.70) 
 High systolic pressure 1.40 (1.17, 1.67) 
 High diastolic pressure 4.60 (1.79, 11.83) 
Sensory loss 
 Hearing loss 2.26 (0.99, 5.18) 
Smoking 
 Ever smokers 1.25 (1.06, 1.48) 0% 
 Current smokers 1.51 (1.19, 1.91) 43% 
 Former smokers 0.98 (0.84, 1.13) 0% 
Risk factorNumber of reviewsRR (95% CI)Heterogeneity, I2
Alcohol consumption 
 Light/moderate versus none 0.75 (0.57, 0.98) 
 Heavy versus none 0.92 (0.59, 1.44) 
 Heavy versus light/moderate 1.23 (1.03, 1.47) 
Body weight (mid-life) 
 BMI ≥30 versus normal 4.04 (2.59, 6.31) 26% 
 BMI 25–29.9 versus normal 1.39 (1.12, 1.72) 0% 
 BMI <18.5 versus normal 1.47 (0.50, 4.33) 
Body weight (late life) 
 BMI ≥30 versus normal 0.73 (0.61, 0.86) 0% 
 BMI 25–29.9 versus normal 1.00 (0.74, 1.35) 
 BMI <18.5 versus normal 2.18 (1.18, 4.02) 
Body weight (mixed age-groups) 
 BMI ≥30 versus normal 1.49 (1.11, 2.00) 0% 
 BMI 25–29.9 versus normal 1.03 (0.84, 1.26) 
 BMI <18.5 versus normal 1.76 (1.20, 2.58) 
Depression 2.57 (2.16, 3.07) 0% 
Hypertension (mid-life) 
 Hypertension (combined) 7.68 (3.50, 16.85) 
 High systolic pressure 1.30 (1.08, 1.57) 
Hypertension (late life) 
 Hypertension (combined) 3.69 (1.58, 8.70) 
 High systolic pressure 1.40 (1.17, 1.67) 
 High diastolic pressure 4.60 (1.79, 11.83) 
Sensory loss 
 Hearing loss 2.26 (0.99, 5.18) 
Smoking 
 Ever smokers 1.25 (1.06, 1.48) 0% 
 Current smokers 1.51 (1.19, 1.91) 43% 
 Former smokers 0.98 (0.84, 1.13) 0% 

Data Availability by Type and Etiology of NCD

Table 6 contains a summary of findings across all risk factors and outcomes. It shows risk factors for which at least one statistically significant association was noted for each type and etiology of NCD and risk factors for which no data were available. Notably, we extracted no data on 9 of 14 risk factors for mild NCD and no data on 8 of 14 risk factors for vascular dementia.

Table 6.

Summary of results and evidence availability

Table 6.

Summary of results and evidence availability

Close modal

We conducted a systematic review and meta-analysis of systematic reviews for modifiable risk factors for mild and major NCDs, including an examination across two of the more common etiologies of major NCD. We synthesized findings on 14 broadly defined risk factors, all of which were found to be significantly associated with major NCD. Five of these risk factors were definitely associated with mild NCD based on the available data. In general, the risk estimates were consistent across types and etiologies of NCDs, though some notable differences in magnitude were observed. Far less research has been reported on vascular dementia and mild NCD compared to major NCD and AD dementia.

The epidemiology of modifiable risk factors for dementia is a topic of considerable interest as a globally aging population is increasing the burden of mortality and morbidity related to NCDs. Notably, the Lancet Commission produced several reports on risk factors for dementia, which were widely cited by public health agencies, associations, and patient groups [11, 12]. Our umbrella review examined several potentially modifiable risk factors not included in the latest Lancet Commission report (i.e., sleep disturbances, diet, visual impairment, vitamin D deficiency). We found they were significantly associated with a heightened risk of major NCD. These additional factors are important to consider as dementia prevention strategies evolve. Conversely, we do not report on air pollution, which was designated by the Lancet Commission as an important risk factor [70]. While the Lancet Commission only considered major NCD, we also examined two common dementia etiologies and mild NCD. Nevertheless, the results from our review are largely concordant with the Lancet Commission, although we found lower RR estimates for social isolation and a higher for less education. Methodological differences likely underlie these disparities. The Lancet Commission did not utilize an umbrella review methodology, but rather relied on a mix of previous reports and systematic and non-systematic reviews to produce the RRs used in their report. Variation in the definition of risk factors may also play a role in the heterogeneity seen between and within reviews.

We synthesized risk factors estimates on two of the most common etiologies of dementia: AD and vascular disease. While evidence suggests that the majority of individuals with major neurological disorders have co-occurrence of multiple pathologies [71], we were not able to include mixed dementia as a separate subcategory. There was considerably more research on the risk factors for AD dementia than vascular dementia, where we were only able to find reviews of six risk factors. The limited evidence available for vascular dementia is likely a result of the lower incidence of dementia that is felt to be solely due to vascular disease. Even when evidence was available for extraction, there were fewer studies per risk factor and fewer participants per study than with the major NCD reports, reducing the precision of our estimates. Nevertheless, we found that the risk associated with mid-life obesity and hypertension in our study was notably higher for vascular dementia than for AD dementia. We also found that TBIs had a strong association with major NCD, but not with AD dementia, despite the fact that TBIs are considered by many as a risk factor for AD. It is possible post-TBI dementia cases are being categorized as due to TBI, chronic traumatic encephalopathy, or another cause rather than AD.

Our inclusion of mild NCD was a novel element of this study. Mild NCD had the least evidence available for synthesis but was significantly associated with each of the five risk factors where data could be extracted. The magnitude of the risk factors estimates for mild NCD were not consistently different than major NCD with the exception of sleep disturbances where the risk ratio for major NCD was notably higher than mild NCD. Our research question and search strategy were designed to allow us to find risk factors for mild NCD that were not risk factors for major NCD. While we did not find any such factors, we cannot conclude they do not exist. More research is needed on mild NCD given its place on the continuum of neurodegenerative diseases. There is a trend toward developing novel therapeutics for patients with this stage of cognitive loss because it is hoped those treated earlier may be more responsive to disease-modifying interventions for NCDs [72].

Finally, we found imbalances in the extent of research done on specific risk factors. Body weight and depression had by far the most research available to synthesize. While clearly important risk factors, the relative volume of the literature on them may well not be congruent with their overall impact on NCD occurrence. For example, the Lancet Commission report identified that among the risk factors included, less education and hearing loss had the highest population attributable fractions for worldwide dementia cases [11]. These factors and others with more limited evidence such as diet and social isolation should be the focus of further research. Additionally, more research should focus on the implications that the high prevalence of mixed pathologies has for dementia prevention.

Limitations

Our study is limited to English language articles. Furthermore, while there were sufficient data to report body weight and hypertension by life stage, this could not be done for other variables, likely contributing to heterogeneity across reviews. We were unable to explore other sources of heterogeneity, for example, varying definitions of outcomes and risk factors. A limitation of an umbrella review is that it may not include recent primary studies that have not yet been incorporated into a systematic review. As noted previously, we did not examine air pollution, other environmental and occupational risk, or early life adversity. Additionally, as there is not full agreement among researchers on which risk factors are modifiable, there is an element of subjectivity in our determination of which risk factors to include. Finally, we were not able to separately analyze risk factors for other common causes of dementia such as Lewy body, frontotemporal, and mixed dementias.

We conducted an umbrella review and synthesized evidence on 14 modifiable risk factors for major and mild NCDs: alcohol consumption, body weight, depression, diabetes mellitus, diet, hypertension, less formal education, physical inactivity, sensory loss, sleep disturbance, smoking, social isolation, TBI, and vitamin D deficiency. We found evidence that all of these factors are related to the risk of major NCD. Prevention strategies should consider approaches that reduce the incidence and severity of these risk factors through health promotion, identification, and management, using individual and organizational-focused implementation strategies [73]. More research is needed specific to mild NCD and non-Alzheimer’s dementia.

We would like to thank Denise Smith for assistance in developing our electronic search strategy.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

This study received funding from the Public Health Agency of Canada (2021-HQ-000076). PR holds the Raymond and Margaret Labarge Chair in Optimal Aging and Knowledge Application for Optimal Aging, is the director of the McMaster Institute for Research on Aging and the Labarge Centre for Mobility in Aging, and holds a Tier 1 Canada Research Chair in GeroScience. LG is supported by the McLaughlin Foundation Professorship in Population and Public Health. DD is funded with a doctoral scholarship through the Canadian Institutes of Health Research (CIHR) (funding reference number #FBD-181577). TLA holds a Tier 1 Canada Research Chair in Healthy Aging.

A.J., M.U.A., M.K., A.M., M.O., T.L.-A., V.T., J.M.M., D.B.H., S.K., A.P.C., C.W., P.R., and L.G. contributed to the conception/design of the work. A.J., M.U.A., M.K., A.M.,V.M.,H.H.,S.L.,E.Y.,K.P.,D.S.,R.D.,K.A.,R.H.C.,D.D., and D.R.M. contributed to data acquisition. M.U.A. conducted data analysis. A.J. drafted the initial manuscript. All authors reviewed the work critically for important intellectual content and approved the final version.

All data used in this study were taken from the published literature. Further inquiries can be directed to the corresponding author.

1.
Li
X
,
Feng
X
,
Sun
X
,
Hou
N
,
Han
F
,
Liu
Y
.
Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2019
.
Front Aging Neurosci
.
2022
;
14
:
937486
. .
2.
Sachs-Ericsson
N
,
Blazer
DG
.
The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment
.
Aging Ment Health
.
2015
;
19
(
1
):
2
12
. .
3.
Petretto
DR
,
Carrogu
GP
,
Gaviano
L
,
Pili
L
,
Pili
R
.
Dementia and major neurocognitive disorders: some lessons learned one century after the first Alois Alzheimer’s clinical notes
.
Geriatrics
.
2021
;
6
(
1
):
5
. .
4.
Lopez
OL
,
Kuller
LH
,
Becker
JT
,
Dulberg
C
,
Sweet
RA
,
Gach
HM
, et al
.
Incidence of dementia in mild cognitive impairment in the cardiovascular health study cognition study
.
Arch Neurol
.
2007
;
64
(
3
):
416
20
. .
5.
Ward
A
,
Tardiff
S
,
Dye
C
,
Arrighi
HM
.
Rate of conversion from prodromal Alzheimer’s disease to Alzheimer’s dementia: a systematic review of the literature
.
Dement Geriatr Cogn Dis Extra
.
2013
;
3
(
1
):
320
32
. .
6.
Mitchell
AJ
,
Shiri-Feshki
M
.
Rate of progression of mild cognitive impairment to dementia: meta-analysis of 41 robust inception cohort studies
.
Acta Psychiatr Scand
.
2009
;
119
(
4
):
252
65
. .
7.
GBD 2019 Dementia Forecasting Collaborators
;
Steinmetz
JD
,
Vollset
SE
,
Fukutaki
K
,
Chalek
J
,
Abd-Allah
F
.
Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019
.
Lancet Public Health
.
2022
;
7
(
2
):
e105
25
. .
8.
Bai
W
,
Chen
P
,
Cai
H
,
Zhang
Q
,
Su
Z
,
Cheung
T
, et al
.
Worldwide prevalence of mild cognitive impairment among community dwellers aged 50 years and older: a meta-analysis and systematic review of epidemiology studies
.
Age Ageing
.
2022
;
51
(
8
):
afac173
. .
9.
Public Health Agency of
.
A Dementia Strategy for Canada: Together We Aspire
.
Ottawa, Canada
;
2019
. [cited 2022 Nov 30].Available from: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/dementia-strategy.html.
10.
World Health, World Health Organization
.
Global action plan on the public health response to dementia (2017-2025)
.
Geneva
;
2017
. Available from: https://www.who.int/publications/i/item/global-action-plan-on-the-public-health-response-to-dementia-2017---2025.
11.
Livingston
G
,
Huntley
J
,
Sommerlad
A
,
Ames
D
,
Ballard
C
,
Banerjee
S
, et al
.
Dementia prevention, intervention, and care: 2020 report of the Lancet Commission
.
Lancet
.
2020
;
396
(
10248
):
413
46
. .
12.
Livingston
G
,
Sommerlad
A
,
Orgeta
V
,
Costafreda
SG
,
Huntley
J
,
Ames
D
, et al
.
Dementia prevention, intervention, and care
.
Lancet
.
2017
;
390
(
10113
):
2673
734
. .
13.
JBI. Chapter 10
.
Umbrella reviews. JBI Manual for Evidence Synthesis
;
2020
. .
14.
Page
MJ
,
McKenzie
JE
,
Bossuyt
PM
,
Boutron
I
,
Hoffmann
TC
,
Mulrow
CD
, et al
.
The PRISMA 2020 statement: an updated guideline for reporting systematic reviews
.
BMJ
.
2021
;
372
:
n71
. .
15.
Baumgart
M
,
Snyder
HM
,
Carrillo
MC
,
Fazio
S
,
Kim
H
,
Johns
H
.
Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective
.
Alzheimers Dement
.
2015
;
11
(
6
):
718
26
. .
16.
Canada PHA of
. Dementia: Risk factors and prevention [Internet]. 2021 Dec [cited 2023 Jun 15]. Available from: https://www.canada.ca/en/public-health/services/diseases/dementia/risk-factors-prevention.html.
17.
Shea
BJ
,
Reeves
BC
,
Wells
G
,
Thuku
M
,
Hamel
C
,
Moran
J
, et al
.
Amstar 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both
.
BMJ
.
2017
;
358
:
j4008
. .
18.
[Chapter 15]: Interpreting results and drawing conclusions [Internet]. [cited 2023 Jun 12]. Available from: https://training.cochrane.org/handbook/current/chapter-15.
19.
Zhang
J
,
Yu
KF
.
What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes
.
JAMA
.
1998
;
280
(
19
):
1690
1
. .
20.
Berkey
CS
,
Hoaglin
DC
,
Antczak-Bouckoms
A
,
Mosteller
F
,
Colditz
GA
.
Meta-analysis of multiple outcomes by regression with random effects
.
Stat Med
.
1998
;
17
(
22
):
2537
50
. .
21.
Van den Noortgate
W
,
López-López
JA
,
Marín-Martínez
F
,
Sánchez-Meca
J
.
Three-level meta-analysis of dependent effect sizes
.
Behav Res
.
2013
;
45
(
2
):
576
94
. .
22.
Konstantopoulos
S
.
Fixed effects and variance components estimation in three-level meta-analysis
.
Res Synth Methods
.
2011
;
2
(
1
):
61
76
. .
23.
Harrer
M
,
Furukawa
T
. dmetar: Companion R Package For The Guide ’Doing Meta-Analysis in R. 2023 Feb [cited 2023 Jun 13]. Available from: https://github.com/MathiasHarrer/dmetar.
24.
Viechtbauer
W
.
metafor: meta-analysis package for R
;
2023
. [cited 2023 Jun 13]. Available from: https://cran.r-project.org/web/packages/metafor/index.html.
25.
Anstey
KJ
,
von Sanden
C
,
Salim
A
,
O’Kearney
R
.
Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies
.
Am J Epidemiol
.
2007
;
166
(
4
):
367
78
. .
26.
Anstey
KJ
,
Mack
HA
,
Cherbuin
N
.
Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies
.
Am J Geriatr Psychiatry
.
2009
;
17
(
7
):
542
55
. .
27.
Anstey
KJ
,
Cherbuin
N
,
Budge
M
,
Young
J
.
Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies
.
Obes Rev
.
2011
;
12
(
5
):
e426
37
. .
28.
Bakre
AT
,
Chen
R
,
Khutan
R
,
Wei
L
,
Smith
T
,
Qin
G
, et al
.
Association between fish consumption and risk of dementia: a new study from China and a systematic literature review and meta-analysis
.
Public Health Nutr
.
2018
;
21
(
10
):
1921
32
. .
29.
Beydoun
MA
,
Beydoun
HA
,
Wang
Y
.
Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis
.
Obes Rev
.
2008
;
9
(
3
):
204
18
. .
30.
Bubu
OM
,
Brannick
M
,
Mortimer
J
,
Umasabor-Bubu
O
,
Sebastião
YV
,
Wen
Y
, et al
.
Sleep, cognitive impairment, and Alzheimer’s disease: a systematic review and meta-analysis
.
Sleep
.
2017
;
40
(
1
):
zsw032
. .
31.
Cherbuin
N
,
Kim
S
,
Anstey
KJ
.
Dementia risk estimates associated with measures of depression: a systematic review and meta-analysis
.
BMJ open
.
2015
;
5
(
12
):
e008853
. .
32.
Cooper
C
,
Sommerlad
A
,
Lyketsos
CG
,
Livingston
G
.
Modifiable predictors of dementia in mild cognitive impairment: a systematic review and meta-analysis
.
Aust J Pharm
.
2015
;
172
(
4
):
323
34
. .
33.
Danat
IM
,
Clifford
A
,
Partridge
M
,
Zhou
W
,
Bakre
AT
,
Chen
A
, et al
.
Impacts of overweight and obesity in older age on the risk of dementia: a systematic literature review and a meta-analysis
.
J Alzheimers Dis
.
2019
;
70
(
s1
):
S87
99
. .
34.
Desai
R
,
John
A
,
Stott
J
,
Charlesworth
G
.
Living alone and risk of dementia: a systematic review and meta-analysis
.
Ageing Res Rev
.
2020
;
62
:
101122
. .
35.
Hamer
M
,
Chida
Y
.
Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence
.
Psychol Med
.
2009
;
39
(
1
):
3
11
. .
36.
Hu
M
,
Shu
X
,
Wu
X
,
Chen
F
,
Hu
H
,
Zhang
J
, et al
.
Neuropsychiatric symptoms as prognostic makers for the elderly with mild cognitive impairment: a meta-analysis
.
J Affect Disord
.
2020
;
271
:
185
92
. .
37.
Huang
C-H
,
Lin
C-W
,
Lee
Y-C
,
Huang
C-Y
,
Huang
R-Y
,
Tai
Y-C
, et al
.
Is traumatic brain injury a risk factor for neurodegeneration? A meta-analysis of population-based studies
.
BMC Neurol
.
2018
;
18
(
1
):
184
8
. .
38.
Hudon
C
,
Escudier
F
,
De Roy
J
,
Croteau
J
,
Cross
N
,
Dang-Vu
TT
, et al
.
Behavioral and psychological symptoms that predict cognitive decline or impairment in cognitively normal middle-aged or older adults: a meta-analysis
.
Neuropsychol Rev
.
2020
;
30
(
4
):
558
79
. .
39.
Kalra
A
,
Teixeira
AL
,
Diniz
BS
.
Association of vitamin D levels with incident all-cause dementia in longitudinal observational studies: a systematic review and meta-analysis
.
J Prev Alzheimers Dis
.
2020
;
7
(
1
):
14
20
. .
40.
Kuring
JK
,
Mathias
JL
,
Ward
L
.
Risk of dementia in persons who have previously experienced clinically-significant depression, anxiety, or PTSD: a systematic review and meta-analysis
.
J Affect Disord
.
2020
;
274
:
247
61
. .
41.
Lee
CM
,
Woodward
M
,
Batty
GD
,
Beiser
AS
,
Bell
S
,
Berr
C
, et al
.
Association of anthropometry and weight change with risk of dementia and its major subtypes: a meta-analysis consisting 2.8 million adults with 57 294 cases of dementia
.
Obes Rev
.
2020
;
21
(
4
):
e12989
. .
42.
Lennon
MJ
,
Makkar
SR
,
Crawford
JD
,
Sachdev
PS
.
Midlife hypertension and Alzheimer’s disease: a systematic review and meta-analysis
.
J Alzheimers Dis
.
2019
;
71
(
1
):
307
16
. .
43.
Li
X-Y
,
Zhang
M
,
Xu
W
,
Li
J-Q
,
Cao
X-P
,
Yu
J-T
, et al
.
Midlife modifiable risk factors for dementia: a systematic review and meta-analysis of 34 prospective cohort studies
.
Curr Alzheimer Res
.
2019
;
16
(
14
):
1254
68
. .
44.
Liang
J
,
Lu
L
,
Li
J
,
Qu
X
,
Li
J
,
Qian
S
, et al
.
Contributions of modifiable risk factors to dementia incidence: a bayesian network analysis
.
J Am Med Dir Assoc
.
2020
;
21
(
11
):
1592
9.e13
. .
45.
Liang
Z
,
Li
A
,
Xu
Y
,
Qian
X
,
Gao
X
.
Hearing loss and dementia: a Meta-Analysis of Prospective Cohort Studies
.
Front Aging Neurosci
.
2021
;
13
:
695117
. .
46.
Loef
M
,
Walach
H
.
Midlife obesity and dementia: meta-analysis and adjusted forecast of dementia prevalence in the United States and China
.
Obesity
.
2013
;
21
(
1
):
E51
5
. .
47.
Loughrey
DG
,
Kelly
ME
,
Kelley
GA
,
Brennan
S
,
Lawlor
BA
.
Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: a systematic review and meta-analysis
.
JAMA Otolaryngol Head Neck Surg
.
2018
;
144
(
2
):
115
26
. .
48.
Mourao
RJ
,
Mansur
G
,
Malloy-Diniz
LF
,
Castro Costa
E
,
Diniz
BS
.
Depressive symptoms increase the risk of progression to dementia in subjects with mild cognitive impairment: systematic review and meta-analysis
.
Int J Geriatr Psychiatry
.
2016
;
31
(
8
):
905
11
. .
49.
Ou
Y-N
,
Tan
C-C
,
Shen
X-N
,
Xu
W
,
Hou
X-H
,
Dong
Q
, et al
.
Blood pressure and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 209 prospective studies
.
Hypertension
.
2020
;
76
(
1
):
217
25
. .
50.
Ownby
RL
,
Crocco
E
,
Acevedo
A
,
John
V
,
Loewenstein
D
.
Depression and risk for alzheimer disease: systematic review, meta-analysis, and metaregression analysis
.
Arch Gen Psychiatry
.
2006
;
63
(
5
):
530
8
. .
51.
Pedditzi
E
,
Peters
R
,
Beckett
N
.
The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies
.
Age Ageing
.
2016
;
45
(
1
):
14
21
. .
52.
Perry
DC
,
Sturm
VE
,
Peterson
MJ
,
Pieper
CF
,
Bullock
T
,
Boeve
BF
, et al
.
Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis
.
J Neurosurg
.
2016
;
124
(
2
):
511
26
. .
53.
Power
MC
,
Weuve
J
,
Gagne
JJ
,
McQueen
MB
,
Viswanathan
A
,
Blacker
D
.
The association between blood pressure and incident Alzheimer disease: a systematic review and meta-analysis
.
Epidemiology
.
2011
;
22
(
5
):
646
59
. .
54.
Profenno
LA
,
Porsteinsson
AP
,
Faraone
SV
.
Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders
.
Biol Psychiatry
.
2010
;
67
(
6
):
505
12
. .
55.
Qu
Y
,
Hu
H-Y
,
Ou
Y-N
,
Shen
X-N
,
Xu
W
,
Wang
Z-T
, et al
.
Association of body mass index with risk of cognitive impairment and dementia: a systematic review and meta-analysis of prospective studies
.
Neurosci Biobehav Rev
.
2020
;
115
:
189
98
. .
56.
Rong
SS
,
Lee
BY
,
Kuk
AK
,
Yu
XT
,
Li
SS
,
Li
J
, et al
.
Comorbidity of dementia and age-related macular degeneration calls for clinical awareness: a meta-analysis
.
Br J Ophthalmol
.
2019
;
103
(
12
):
1777
83
. .
57.
Sáiz-Vázquez
O
,
Gracia-García
P
,
Ubillos-Landa
S
,
Puente-Martínez
A
,
Casado-Yusta
S
,
Olaya
B
, et al
.
Depression as a risk factor for Alzheimer’s disease: a systematic review of longitudinal meta-analyses
.
J Clin Med
.
2021
;
10
(
9
):
1809
. .
58.
Snowden
TM
,
Hinde
AK
,
Reid
HM
,
Christie
BR
.
Does mild traumatic brain injury increase the risk for dementia? A systematic review and meta-analysis
.
J Alzheimers Dis
.
2020
;
78
(
2
):
757
75
. .
59.
Sommerlad
A
,
Ruegger
J
,
Singh-Manoux
A
,
Lewis
G
,
Livingston
G
.
Marriage and risk of dementia: systematic review and meta-analysis of observational studies
.
J Neurol Neurosurg Psychiatry
.
2018
;
89
(
3
):
231
8
. .
60.
Tan
EY
,
Köhler
S
,
Hamel
RE
,
Muñoz-Sánchez
JL
,
Verhey
FR
,
Ramakers
IH
.
Depressive symptoms in mild cognitive impairment and the risk of dementia: a systematic review and comparative meta-analysis of clinical and community-based studies
.
J Alzheimers Dis
.
2019
;
67
(
4
):
1319
29
. .
61.
Vagelatos
NT
,
Eslick
GD
.
Type 2 diabetes as a risk factor for Alzheimer’s disease: the confounders, interactions, and neuropathology associated with this relationship
.
Epidemiol Rev
.
2013
;
35
(
1
):
152
60
. .
62.
Vu
TA
,
Fenwick
EK
,
Gan
ATL
,
Man
REK
,
Tan
BKJ
,
Gupta
P
, et al
.
The bidirectional relationship between vision and cognition: a systematic review and meta-analysis
.
Ophthalmology
.
2021
;
128
(
7
):
981
92
. .
63.
Wang
Z-T
,
Xu
W
,
Wang
H-F
,
Tan
L
,
Tan
C-C
,
Li
J-Q
, et al
.
Blood pressure and the risk of dementia: a dose-response meta-analysis of prospective studies
.
Curr Neurovasc Res
.
2018
;
15
(
4
):
345
58
. .
64.
Wei
J
,
Hu
Y
,
Zhang
L
,
Hao
Q
,
Yang
R
,
Lu
H
, et al
.
Hearing impairment, mild cognitive impairment, and dementia: a meta-analysis of cohort studies
.
Dement Geriatr Cogn Dis Extra
.
2017
;
7
(
3
):
440
52
. .
65.
Wu
L
,
Sun
D
.
Meta-analysis of milk consumption and the risk of cognitive disorders
.
Nutrients
.
2016
;
8
(
12
):
824
. .
66.
Xu
W
,
Tan
L
,
Wang
H-F
,
Jiang
T
,
Tan
M-S
,
Tan
L
, et al
.
Meta-analysis of modifiable risk factors for Alzheimer’s disease
.
J Neurol Neurosurg Psychiatry
.
2015
;
86
(
12
):
1299
306
. .
67.
Yates
JA
,
Clare
L
,
Woods
RT
.
Mild cognitive impairment and mood: a systematic review
.
Rev Clin Gerontol
.
2013
;
23
(
4
):
317
56
. .
68.
Zhong
G
,
Wang
Y
,
Zhang
Y
,
Guo
JJ
,
Zhao
Y
.
Smoking is associated with an increased risk of dementia: a meta-analysis of prospective cohort studies with investigation of potential effect modifiers
.
PLoS One
.
2015
;
10
(
3
):
e0118333
. .
69.
Zuin
M
,
Roncon
L
,
Passaro
A
,
Cervellati
C
,
Zuliani
G
.
Metabolic syndrome and the risk of late onset alzheimer’s disease: an updated review and meta-analysis
.
Nutr Metab Cardiovasc Dis
.
2021
;
31
(
8
):
2244
52
. .
70.
Wilker
EH
,
Osman
M
,
Weisskopf
MG
.
Ambient air pollution and clinical dementia: systematic review and meta-analysis
.
BMJ
.
2023
;
381
:
e071620
. .
71.
Nichols
E
,
Merrick
R
,
Hay
SI
,
Himali
D
,
Himali
JJ
,
Hunter
S
, et al
.
The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia
.
Lancet Healthy Longev
.
2023
;
4
(
3
):
e115
25
. .
72.
Cummings
J
,
Lee
G
,
Ritter
A
,
Zhong
K
.
Alzheimer’s disease drug development pipeline: 2018
.
Alzheimers Dement
.
2018
;
4
:
195
214
. .
73.
Teper
MH
,
Godard-Sebillotte
C
,
Vedel
I
.
Achieving the goals of dementia plans: a review of evidence-informed implementation strategies
.
Healthc Pol
.
2019
;
14
(
4
):
10
20
. .