Study selection and characteristics
Overall, 12015 articles were retrieved from systemic literature search and 611 articles were eligible for full-text screening (Fig 1). A total of 493 articles not meeting the inclusion criteria were excluded (S3 Table). Seventy systematic reviews and meta-analyses eligible for umbrella review (S4 Text) were comprised of 5 articles of RCTs, 64 articles of OPSs and 1 article of both RCTs and OPSs. Forty-eight MR studies containing 157 causal analyses were included.
Most of the eligible articles didn’t report a prior established protocol (item 2), a list of excluded studies (item 7) or the sources of funding for primary studies (item 10), which unfortunately downgraded the initial AMSTAR 2 rating. Therefore, we performed an adjusted analysis of the reporting quality by ruling out the above three domains. The adjusted reporting quality were high (39%) in 27 articles, moderate (24%) in 17 articles, low (31%) in 22 articles and critically low (6%) in 4 articles (S5 Table).
The included systematic reviews and meta-analyses published between 2010 and 2020 (median 2018, IQR 2016-2019) yielded 243 unique associations including 35 for ACD and CI/CD, 87 for ACD, 70 for AD, 21 for VD, 8 for Parkinson’s disease with dementia (PDD) and 22 for CI/CD. In 243 meta-analyses, study estimates number ranged from 3 to 31 (median 6, IQR 4-10), cases number ranged from 82 to 519247 (median 1138, IQR 486-2580) and participants sample size ranged from 266 to 12523553 (median 16067, IQR 6851-49134). Altogether 138 (57%) of 243 associations were significant (p<0.05) under the random effects model, of which 75 (31%) were p<1 × 10–3 and 29 (12%) were p<1 × 10–6.
Evidence from RCTs studies
Only 9 associations were available from RCTs (S6 Table). Two interventions (22%), antihypertensive medications in midlife to late life and nonpharmacological interventions in late life, were found significantly (p<0.05) protective of ACD and CI while the evidence was weak. Of 9 associations, none had a 95% PI excluding the null value, 4 (44%) showed large heterogeneity (I²>50%), 2 (22%) presented small-study effects (Egger’s p<0.10) and 3 (33%) were observed with excess significance bias.
Evidence from OPSs studies
We summarized 30 reported associations from OPSs for ACD and CI/CD (S7 Table). The association of one (3%) risk factor, overweight (body mass index [BMI] 23-30 Kg/m2) (RR 0.81, 95% CI 0.75-0.88) in late life, was graded as convincing evidence (Fig 2). The association of one (3%) risk factor, high BMI (BMI>23 Kg/m2) in late life, was graded as highly suggestive evidence. Six (20%) associations were graded as suggestive evidence covering the risk factors underweight (BMI<21 Kg/m2) in midlife, obesity (BMI>25.5 Kg/m2) and anemia in late life, insomnia, long nocturnal sleep duration, fruit and vegetables intake in midlife to late life. Eleven (37%) associations were graded as weak evidence. Of 30 associations, 3 (10%) had a 95% PI excluding the null value, 15 (50%) showed large heterogeneity, 4 (13%) presented small-study effects and 10 (33%) were observed with excess significance bias.
Eighty-five associations were examined in OPSs for ACD (S8 Table). Eight (9%) associations were graded as convincing evidence covering risk factors high education (RR 0.44, 95% CI 0.32-0.60) and low education (1.81, 1.59-2.06) in early life, depression (1.85, 1.67-2.04) and low gait speed (1.66, 1.43-1.92) in late life, severe hypoglycemia (1.69, 1.48-1.93), atrial fibrillation (1.34, 1.24-1.44) and benzodiazepine current (1.55, 1.31-1.83) or ever (1.49, 1.30-1.72) use in midlife to late life (Fig 3). Seven (8%) associations were graded as highly suggestive evidence covering risk factors diabetes mellitus, high homocysteine level, prevalent stroke, incident stroke, hearing impairment, respiratory illness and current smoking in midlife to late life. Eleven (13%) associations were graded as suggestive evidence covering risk factors high systolic blood pressure (SBP) in midlife, antihypertensive medications, orthostatic hypotension, cerebral small vessel disease (CSVD) - white matter hyperintensities (WMHs), apathy, living alone and feeling loneliness in late life, high fasting plasma glucose (FPG) level, physical activity, wine consumption and ever smoking in midlife to late life. Thirty (35%) associations were graded as weak evidence. Of 85 associations, 23 (27%) had a 95% PI excluding the null value, 25 (29%) showed large heterogeneity, 11 (13%) presented small-study effects and 12 (14%) were observed with excess significance bias.
A total of 69 associations were extracted from OPSs for AD (S9 Table). Three (4%) associations were graded as convincing evidence covering risk factors low education (RR 1.78, 95% CI 1.43-2.22) in early life, depression (1.65, 1.42-1.92) in late life, high FPG level (1.13, 1.09-1.17) in midlife to late life (Fig 4). The association of one (1%) risk factor, diabetes mellitus in midlife to late life, was graded as highly suggestive evidence. Seven (10%) associations were graded as suggestive evidence covering risk factors hypertension, obesity, overweight and high BMI in midlife, antihypertensive medications in late life, statins and hearing impairment in midlife to late life. Twenty-three (33%) associations were graded as weak evidence. Of 69 associations, 4 (6%) had a 95% PI excluding the null value, 20 (29%) showed large heterogeneity, 7 (10%) presented small-study effects and 17 (25%) were observed with excess significance bias.
For VD, 21 associations were evaluated in OPSs (S10 Table). No association was graded as convincing evidence. The association of one (5%) risk factor, diabetes mellitus in midlife to late life, was graded as highly suggestive evidence. The association of one (5%) risk factor, current smoking in midlife to late life, was graded as suggestive evidence. Ten (48%) associations were graded as weak evidence. Of 21 associations, 3 (14%) had a 95% PI excluding the null value, 9 (43%) showed large heterogeneity, 5 (24%) presented small-study effects and 5 (24%) were observed with excess significance bias.
Eight associations for PDD were explored in only one OPS (S11 Table). No association was graded as convincing, highly suggestive or suggestive evidence. Four (50%) associations were graded as weak evidence. none association had a 95% PI excluding the null value, 5 (63%) showed large heterogeneity, 1 (13%) presented small-study effects and 5 (63%) were observed with excess significance bias.
Finally, 21 associations were assessed in OPSs for CI/CD (S12 Table). No association was graded as convincing evidence. The associations of two (10%) risk factors, low gait speed in late life and physical activity in midlife to late life, were graded as highly suggestive evidence. The associations of two (10%) risk factors, diabetes mellitus and hearing impairment in midlife to late life, were graded as suggestive evidence. Seven (33%) associations were graded as weak evidence. Of 21 associations, 3 (14%) had a 95% PI excluding the null value, 5 (24%) showed large heterogeneity, 3 (14%) presented small-study effects and 2 (10%) were observed with excess significance bias.
On the whole, the evidence gradation was convincing for 12 associations, highly suggestive for 12 associations and suggestive for 27 associations throughout the life course (Fig 5). In early life, education is the only, but determining, protective factor for dementia. While in midlife, blood pressure and BMI critically influence the risk of dementia and cognitive impairment. When it moves into late life, blood pressure and BMI still matter and antihypertensive medications will benefit for prevention of dementia. Late-life depression, apathy, social isolation, low gait speed, WMHs and anemia would affect the risk of dementia and cognitive impairment as well. Additionally, the incidence of dementia and cognitive impairment are related to benzodiazepine use, plasma glucose, homocysteine, atrial fibrillation, stroke, statins, hearing impairment, respiratory illness, smoking, alcohol consumption, sleep, healthy diet and physical activity in midlife to late life.
Evidence from MR studies
As for MR studies (S13 Table), genetically predicted increment of intelligence, education especially college/university completion, height, DBP (diastolic blood pressure), lipoprotein-a, cancer, rheumatoid arthritis, gut blautia and downstream product γ-aminobutyric acid (GABA), Vitamin D and Vitamin D binding protein play protective roles in AD. In contrast, elevated fasting glucose, white matter hyperintensities, periodontitis, alcohol consumption, branched-chain amino acids (isoleucine), decreased β cell function and complement C3 may increase the risk of AD.