Current perspectives on prevention of vascular cognitive impairment and promotion of vascular brain health

Figures & data

Figure 1. Classification of VCI according to level of impairment into mild VCI and major VCI (VaD). Major VCI (VaD or frank dementia of vascular origin) is classified into four main subtypes as depicted. The estimated 6-month temporal basis for cognitive decline after stroke differentiates PSD from other forms of major VCI (VaD). We propose that ICH-VCI is included since cerebral hemorrhages cause hemorrhagic dementia, which is more common in Asia and Africa than in Europe and the U.S.A. Abbreviations: AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; ICH, intracerebral hemorrhage; PSD, post stroke dementia. PSD-# denotes other possible combinations when comorbid neuropathology is present in mixed dementias. Figure adapted from [15] with permission of John Wiley & sons.

Table 1. Unmodifiable and modifiable risk factors for VCI*.

Factor	2020 Lancet Dementia Commission Risk Factors	Global versus US Population Attributable Fractions†	Definition or Status	Outcomes or features leading to VCI	Pathophysiology and Vascular Mechanisms
Age (SD)	-	-	>50 years	Accumulative non-symptomatic changes; CI doubles every 5 years particularly in women >90 years	Age-related atherosclerosis and arteriolosclerosis
Sex	-	-	Male or female	Risk in males > females up to 85 years	Unclear
Family history	-	-	Self- reported CVD or stroke	Heritability of stroke, greater risk for WMHs	Inheritance patterns in vasculature
Genetic Factors	-	-	APOE ε4 allele;NOTCH3 mutations	Greater progression to disability, dementia or death	Mutations/alleles cause loss of VSMC and increase in ECM
Education	Low education	19%; 6%	>7 years globally; >12 years in HICs	Low education is strong risk for all cause dementias globally	-
Brain Health	Traumatic brain injury	9%; 12%	Head injury with loss of consciousness	Increased risk of all cause dementia	Focal ICH, SAH, microbleeds
Cardiovascular Health	-	6%;7%	Ischemic/ICH; lacunar strokes	Disability, depression, CI, dementia	Cortical and lacunar infarcts, SVD pathology
Blood Pressure¶	Midlife hypertension	5%; 20%	≥140/90 mm Hg;	Risk for strokes	Hypertensive encephalopathy, ICH, arteriolosclerosis
Blood Sugar††	Diabetes	3%; 13%	fasting plasma glucose >5.6 mmol/L; HbA1c 6.5%;	Risk for SVD	SVD type changes
Blood Lipids	-	-	Total cholesterol ≥5.2 mmol/L; high triglycerides	Risk for atherosclerosis and stroke	Atheroma in small intracranial arteries
BloodHomocysteine	-	-	Homocysteine >14.0 mmol/L	Risk for stroke and VCI	SVD type of pathology
Cardiac Health	-		HD: Any cardiac problem including AF, CHD, IHD and MI‡	Atrial Fibrillation or flutter based on ECG data risk for embolism	Small and large infarcts related to thromboembolism
Peripheral Circulation	-	-	PAD described by decreased lower extremity arterial perfusion; systemic atherosclerosis	Risk of undiagnosed CI	Unclear
Obesity	Waist-to-Hip ratio	2%; 21%	BMI ≥30	Higher levels of leptin and resistin but not adiponectin associated with decreased risk of dementia	SVD type of pathology
Hearing	Hearing Loss	22%; 9%	Age-related hearing loss in tonal and non-tonal languages; >25 dB threshold	Association between hearing loss and cognitive impairment and dementia	-
Mental Health	Depression	11%; 6%	Late-life clinical depressive illness; PH! Score ≥ 10	Moderate-severe depression increases risk for all cause dementia	Diffuse WM changes
Physical Activity	Physical inactivity	10%; 20%	Low moderate to vigorous activity,<150 min per week	Increased risk for CVD and T2DM	PA increases microvasculature
Diet	-		Healthy diet (leafy vegetables, high fiber); Medi diet	Foods with high saturated fat content risk for CI	Antioxidants reduce inflammation in vessels
Tobacco use	Smoking	14%; 5%	Current or former smoker	Elevated risk of stroke	Arteriosclerotic changes in peripheral vessels
Alcohol intake	Excessive alcohol use	2%; .7%	>21 units per week; loss of consciousness	Risk for hypertension, HD and stroke, and all cause dementia	Alcohol encephalopathy; WM changes
Social Activity	Low social contact	4%; 7%	Loneliness; lack of networks	High social engagement and frequent social contact are significantly associated with a lower risk of dementia,	-
Air Quality	Air pollution	6%; 2%	Fine particulate matter of 2.5 (PM2.5) microns or less	PM2.5 is a risk for all cause dementia	Arteriosclerotic changes and damage to cerebral endothelium

Data were derived from several sources including the global burden of disease, INTERSTROKE and PURE studies assessing incidence estimates and risk factors in HIC and LMICs [19,39,184–200]. †Unweighted PAFs derived from the Relative Risks and references [41,190,201] ¶ Data from 186 countries indicated global PAF of hypertension for dementia was 15.8% [202].

Abbreviations: APOE, apolipoprotein E; BMI, body mass index; CI, cognitive impairment; CVD, cardiovascular disease; CHD, coronary heart disease; dB, deci Bells; ECG, electrocardiogram; ICH, intracerebral hemorrhage; INTERSTROKE, International case-control study in stroke; HD, heart disease; IHD, ischemic heart disease; Medi, Mediterranean; N/A, not available; OR, odds ratio; PA, physical activity; PAF, population attributable fraction; PM, particulate matter; PURE, Prospective Urban Rural Epidemiologic; SIREN, Stroke Investigative Research and Educational Network; SVD, small vessel disease; T2DM, Type 2 diabetes mellitus; VCI vascular cognitive impairment; WM, white matter.

Figure 2. Scheme illustrates how various risk factors may influence the cerebral as well as systemic vasculature at distinct levels to induce chronic brain or cerebral hypoperfusion and result in variable degrees of cognitive impairment over time. Several genetic and environmental factors may modify the intensity of vascular damage.

Table 2. Pharmacological approaches to control VRFs and prevent VCI progression.

Vascular Disease Risk Factor control	Class of Agents:	Specific used in Trials††	All-cause-dementia or VaD outcomes: meta-analyses*	Key References
Hypertension	Angiotensin-2 receptor blockers (ARBs):	Candesartan, Telmesartan, Irbesartan, Losartan, Valsartan, Olmesartan	Meta-analyses (90%) indicate antihypertensives generally reduce risk of incident dementia or improve certain cognitive domains Cognition or CBF not worsened but may even protect it. Single agents (e.g. candersartan, telmisartan, ramapril, atenolol) versus combination of two not shown consistent effects on BP lowering on cognition ARBs overall more effective compared to other classes Diuretics of benefit or reduced risk of incident dementia Certainty of overall evidence low due to sample sizes, design of trials, risk of bias in trials and statistical heterogeneity	[78,88–100]
	ACE Inhibitors: Inhibition of vasoconstrictor angiotensin II	Enalapril, Lisinopril, Perindopril, Ramipril
	Calcium Channel Blockers:	Amlodipine, Felodipine, Nifedipine, Diltiazem, Verapamil
	Beta Blockers	Atenolol, Bisoprolol
	Diuretics:	Indapamide, Bendroflumethiazide
Coagulation	Nonsteroidal anti-inflammatory drugs (NSAID)	Aspirin: 75 mg	No clear evidence to support the use of low-dose aspirin Risk of bleeds with aspiring but no evidence of harm of other NSAIDs, no need to trial low-dose aspirin for dementia prevention Other NSAIDs of any class (celecoxib, rofecoxib or naproxen) for the prevention of dementia	[101–103]
	Anti-coagulants: warfarin		While warfarin is useful in reducing stroke-like events and embolism subsequent to AF, oral anticoagulants are better in slowing cognitive decline. Patients at high risk of VCI may benefit from addition of long-term clopidogrel monotherapy Dual therapy more effective than monotherapy in reducing recurrent stroke or TIA risks of VCI	[104]
	Anti-platelet agents: clopidogrel			[104,105]
Diabetes/glucose-lowering drugs	Metformin		Metformin therapy likely reduces risk of cognitive decline in patients with 2TDM Majority (>60%) of studies reported reduced risk of CI and dementia (by 23–26%) but two (12%) suggested increased dementia risk with metformin use Studies addressing biases in general concluded lack of effect of metformin on dementia risk Dual therapy with metformin (Met) and (DPP-4i) but not sulfonylureas (SU) were associated with reduced incidence of all-cause dementia and VaD. Dual therapy with TZD lowered risk of all-cause dementia, VaD	[106–109]
	Glucagon-like peptide-1 (GLP-1) analogues and receptor agonists		Five studies suggest GLP-1 receptor agonists use was associated with reduction in risk of all-cause dementia by ~ 33% GLP-1 analogues exert no significant effects on general cognitive functioning but may be beneficial for patients <65 years with T2DM and those without history of cardio-cerebrovascular diseases	[110–112]
	DPP-4 inhibitors Dipeptidyl Peptidase IV (DPP 4) Inhibitors – gliptins: saxagliptin, vildagliptin, linagliptin, and sitagliptin		DPP-4 inhibitors use was associated with decreased risk of all-cause dementia and VaD (by ~ 40%). Previous studies found not enough irrefutable evidence to support positive effects of incretins (dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors/DPP-4I) and GLP-1receptor agonists on cognition	[111,113]
	Sodium glucose co-transporter-2 (SGLT2) inhibitors,		Findings from 3 studies suggest SGLT2 inhibitor users had a lower risk of all-cause dementia. SGLT2 inhibitors versus DPP-4 inhibitors were associated with lower risk of dementia over mean follow-up of 2.80 years. Dapagliflozin >empagliflozin but canagliflozin no association	[111,114]
Lipid-modifying agents†	Statins		Most recent meta-analyses showed CHD, PAD, and CAD were all associated with stroke and CI and dementia Several studies (one RCT and 55 cohorts) suggest post-stroke statin use decreased risk of CI Indication bias and design limitations may have been a factor in several studies where evidence showed no effects	[115,116]
Other ‘vascular’ agents	NO donors: isosorbide mononitrate	Increase NO signaling	LACI-2 trial in lacunar strokes suggested increased cerebrovascular reactivity	[117]
	PDE 5 Inhibitor: dipyridamole		Used in combination with aspirin short-term, effects on thrombosis but not CI	[104]
	PDE 3 inhibitor: cilostazol		Cilostazol use was associated with decreased risk of incident dementia Cilostazol use was also found to have a dose-dependent association with reduced rate of incident dementia LACI-2 trial showed reductions in recurrent stroke, dependence, and CI after lacunar stroke	[117,118]

*Analyses specifically evaluating AD not included [162,203–205]. †Beneficial effects of fenofibrate are unclear. ††A network meta-analysis on cholinesterase inhibitors for VaD and VCI indicated moderate- to high-certainty evidence that donepezil 5 mg, donepezil 10 mg, and galantamine have a slight beneficial effect on cognition in people with VCI, although the size of the change is unlikely to be clinically important [206].

Abbreviations: ACE, angiotensin converting enzyme; CAD, carotid artery disease; CBF, cerebral blood flow; CHD, coronary heart disease; CI, cognitive impairment; GLP-1 glucagon-like peptide-1; LACI-2, Lacunar Intervention Trial-2; N/A, not available; NO, nitric oxide; PAD, peripheral arterial disease; PDE, phosphodiesterase; RCT, randomized control trials; VaD, vascular dementia; VCI, vascular cognitive impairment.

Table 3. Lifestyle and non-pharmacological approaches to prevent VCI.

Risk Control Factor	Specific features	Action(s); Treatment Indication	VCI outcome: Overall results	References
Diet	Mediterranean (Medi) diet	Antioxidants, anti-inflammatory properties	Adherence to Medi diet associated with better cognitive scores in 9 of 12 cross-sectional studies, 17 of 25 longitudinal studies, and 1 of 3 trials. Few other nutritional interventions were found to convincingly improve cognition of individuals with MCI Intake of ‘tropical fruits-oats’ dietary patterns protect against dementia incidence among older Malaysian Asians More quality trials in MCI and VCI populations required to assess reduction in progression to dementia Diet adherence advocated for both dementia and VCI	[145–147];
	MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay)		Greater adherence to MIND diet was associated with better cognitive scores in 1 cross-sectional study and 2 of 3 longitudinal studies In a meta-analysis of 11 cohort studies highest tertile of MIND diet score associated with lower risk of dementia Overall, MIND diet associated with lower risk of incident dementia in middle-aged and older adults, but more quality trials needed for VCI	[145; 148]
	DASH (Dietary Approaches to Stop Hypertension)		High adherence to DASH diet associated with better cognitive function in 1 cross-sectional study, 2 of 5 longitudinal studies, and 1 trial Collectively, adherence to Medi, DASH, or MIND diets slow cognitive decline and with strongest association for MIND diet	[145]
	Vitamins		B Complex vitamins, particularly folic acid, has positive effects on delaying risk of cognitive decline Ascorbic acid and high dose vitamin E, given separately, beneficial for cognitive performance Vitamin D supplementation trials inconclusive	[149]
	Berries		Berry-based supplements and foods show beneficial effects on resting brain perfusion Benefits also on cognitive domains involved in VCI including memory performance, executive functioning, processing speed and attention	[150]
	Citicoline	Food supplement (cytidine and choline)	Citicoline is safe and tolerated agent with evidenced neuroprotective properties Large clinical trials are needed to confirm its benefits	[151]
	Carotenoids		Carotenoid intervention associated with better cognitive outcomes (Hedge’s g = 0.14) No evidence of heterogeneity among the studies Further confirmatory studies are needed	[152]
Physical Activity (PA)/Exercise	Single and multiple regimes		Decreased risk of all-cause dementia (20%), and VaD (30%), even in longer follow-ups (≥20 years) for all-cause dementia Neither baseline age, follow-up length nor study quality moderated associations PA as a modifiable protective lifestyle factor for VCI even after reducing the effects of reverse causation Multicomponent exercise beneficial effects on global cognition, especially executive function, flexibility, agility, mobility, muscle strength, gait speed and ADLs. Some evidence for HIFT benefits on general cognition in older adults with CI Two articles showed improvement in cognitive function but there is heterogeneity of intervention protocols, measurement time points, and control group activities, mixed results Cognitive function improved in 2 studies, deteriorated in 3 studies, and remained stable in 11 studies. In another review 9 out 16 studies showed greater improvement in cognition	[153; 154] [155] [156] [157]
	Multidomain exercise training		Dose response study suggests every 500 kcal or 10 MET-h increase/week, ~10% in risk of any dementia Analyses of 8 studies suggested multicomponent PA affects global cognition on MCI or dementia only when aerobic exercise is included	[158; 159]
Multidomain strategy			After 2-year follow, FINGER trial showed effects on overall cognition including executive function and processing speed, and body mass index, dietary habits, and physical activity Other multidomain non-pharmacological interventions seem to have small to medium improvements on global cognition in older MCI subjects, but it is not clear which specific cognitive domains are affected It is expected that the J-MINT PRIME Tamba will support results from the FINGER trial	[160; 161]; [162; 163]

Other strategies in prevention of VCI such as cognitive therapy and rehabilitation have been used but it is too early to convey if there are definite beneficial effects. Abbreviations: ADLs, activities of daily living; FINGER, Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability; HIFT, high intensity fitness training; J-MINT PRIME, Study to Prevent Cognitive Impairment and Disability Japan-Multimodal Intervention Trial for Prevention of Dementia PRIME Tamba; MCI, mild cognitive impairment; Medi, Mediterranean; MET, metabolic equivalent of task; VCI, vascular cognitive impairment.

Skrobot OA, O’Brien J, Black S, et al. The vascular impairment of cognition classification consensus study. Alzheimer’s Dementia. 2017;13(6):624–633. doi: 10.1016/j.jalz.2016.10.007

 PubMed Web of Science ®Google Scholar

Akinyemi RO, Owolabi MO, Ihara M, et al. Stroke, cerebrovascular diseases and vascular cognitive impairment in Africa. Brain Res Bull. 2019;145:97–108. doi: 10.1016/j.brainresbull.2018.05.018

 PubMed Web of Science ®Google Scholar

Collaborators GBDS, Stark BA, Johnson CO. Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the global burden of disease study 2019. Lancet Neurol. 2021;20(10):795–820. doi: 10.1016/S1474-4422(21)00252-0

 PubMed Web of Science ®Google Scholar

Collaborators GBDD. The burden of dementia due to down syndrome, Parkinson’s disease, stroke, and traumatic brain injury: a systematic analysis for the global burden of disease study 2019. Neuroepidemiology. 2021;55(4):286–296

 PubMed Web of Science ®Google Scholar

Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–446. doi: 10.1016/S0140-6736(20)30367-6

 PubMed Web of Science ®Google Scholar

Mukadam N, Sommerlad A, Huntley J, et al. Population attributable fractions for risk factors for dementia in low-income and middle-income countries: an analysis using cross-sectional survey data. Lancet Glob Health. 2019;7(5):e596–e603. doi:10.1016/S2214-109X(19)30074-9

 PubMed Web of Science ®Google Scholar

Mulligan MD, Murphy R, Reddin C, et al. Population attributable fraction of hypertension for dementia: global, regional, and national estimates for 186 countries. EClinicalMedicine. 2023;60:102012. doi: 10.1016/j.eclinm.2023.102012

 PubMedGoogle Scholar

Mahinrad S, Sorond FA, Gorelick PB. Hypertension and cognitive dysfunction: a review of mechanisms, life-course observational studies and clinical trial results. Rev Cardiovasc Med. 2021;22(4):1429–1449. doi:10.31083/j.rcm2204148

 PubMed Web of Science ®Google Scholar

Alexander P, Visagan S, Jawhar S, et al. Antiplatelets and vascular dementia: a systematic review. J Aging Res. 2022;2022:9780067. doi: 10.1155/2022/9780067

 PubMedGoogle Scholar

Wong KS, Wang Y, Leng X, et al. Early dual versus mono antiplatelet therapy for acute non-cardioembolic ischemic stroke or transient ischemic attack: an updated systematic review and meta-analysis. Circulation. 2013;128(15):1656–1666. doi: 10.1161/CIRCULATIONAHA.113.003187

 PubMed Web of Science ®Google Scholar

Tang H, Shao H, Shaaban CE, et al. Newer glucose-lowering drugs and risk of dementia: a systematic review and meta-analysis of observational studies. J American Geriatrics Society. 2023;71(7):2096–2106. doi: 10.1111/jgs.18306

 PubMed Web of Science ®Google Scholar

Jin Y, Zhao H, Hou Y, et al. The effects of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists on cognitive functions in adults with type 2 diabetes mellitus: a systematic review and meta-analysis. Acta Diabetol. 2020;57(10):1129–1144. doi:10.1007/s00592-020-01529-1

 PubMed Web of Science ®Google Scholar

Wu CY, Iskander C, Wang C, et al. Association of Sodium–glucose cotransporter 2 inhibitors with time to dementia: a population-based cohort study. Diabetes Care. 2023;46(2):297–304. doi: 10.2337/dc22-1705

 PubMed Web of Science ®Google Scholar

Yang Z, Wang H, Edwards D, et al. Association of blood lipids, atherosclerosis and statin use with dementia and cognitive impairment after stroke: a systematic review and meta-analysis. Ageing Res Rev. 2020;57:100962. doi: 10.1016/j.arr.2019.100962

 PubMed Web of Science ®Google Scholar

McGuinness B, Craig D, Bullock R, et al. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016;2016(1):CD003160. doi:10.1002/14651858.CD003160.pub3

 PubMedGoogle Scholar

Wardlaw JM, Woodhouse LJ, Mhlanga II, et al. Isosorbide mononitrate and Cilostazol treatment in patients with symptomatic cerebral small vessel disease: the lacunar intervention trial-2 (LACI-2) randomized clinical trial. JAMA Neurol. 2023;80(7):682. doi: 10.1001/jamaneurol.2023.1526

 PubMed Web of Science ®Google Scholar

Tai SY, Chien CY, Chang YH, et al. Cilostazol use is associated with reduced risk of dementia: a nationwide cohort study. Neurotherapeutics. 2017;14(3):784–791. doi:10.1007/s13311-017-0512-4

 PubMed Web of Science ®Google Scholar

Kumagai R, Osaki T, Oki Y, et al. The Japan-multimodal intervention trial for prevention of dementia PRIME Tamba (J-MINT PRIME Tamba): study protocol of a randomised controlled multi-domain intervention trial. Arch Gerontol Geriatr. 2023;104:104803. doi: 10.1016/j.archger.2022.104803

 PubMed Web of Science ®Google Scholar

Battle CE, Abdul-Rahim AH, Shenkin SD, et al. Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis. Cochrane Database Syst Rev. 2021;2(2):CD013306. doi:10.1002/14651858.CD013306.pub2

 PubMedGoogle Scholar

van den Brink AC, Brouwer-Brolsma EM, Berendsen AAM, et al. The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH intervention for neurodegenerative delay (MIND) diets are associated with less cognitive decline and a lower risk of Alzheimer’s disease—a review. Adv Nutr. 2019;10(6):1040–1065. doi:10.1093/advances/nmz054

 PubMed Web of Science ®Google Scholar

Chen H, Dhana K, Huang Y, et al. Association of the mediterranean dietary approaches to stop hypertension intervention for neurodegenerative delay (MIND) diet with the risk of dementia. JAMA Psychiatry. 2023;80(6):630–638. doi: 10.1001/jamapsychiatry.2023.0800

 PubMed Web of Science ®Google Scholar

Gil Martinez V, Avedillo Salas A, Santander Ballestin S. Vitamin supplementation and dementia: a systematic review. Nutrients. 2022;14(5):1033. doi: 10.3390/nu14051033

 PubMed Web of Science ®Google Scholar

Bonyadi N, Dolatkhah N, Salekzamani Y, et al. Effect of berry-based supplements and foods on cognitive function: a systematic review. Sci Rep. 2022;12(1):3239. doi:10.1038/s41598-022-07302-4

 PubMed Web of Science ®Google Scholar

Bermejo PE, Dorado R, Zea-Sevilla MA. Role of Citicoline in patients with mild cognitive impairment. J Exp Neurosci. 2023;18:26331055231152496. doi:10.1177/26331055231152496

 Google Scholar

Davinelli S, Ali S, Solfrizzi V, et al. Carotenoids and cognitive outcomes: a meta-analysis of randomized intervention trials. Antioxidants. 2021;10(2):223. doi: 10.3390/antiox10020223

 Web of Science ®Google Scholar

Iso-Markku P, Kujala UM, Knittle K, et al. Physical activity as a protective factor for dementia and Alzheimer’s disease: systematic review, meta-analysis and quality assessment of cohort and case–control studies. Br J Sports Med. 2022;56(12):701–709. doi:10.1136/bjsports-2021-104981

 PubMed Web of Science ®Google Scholar

Balbim GM, Falck RS, Barha CK, et al. Effects of exercise training on the cognitive function of older adults with different types of dementia: a systematic review and meta-analysis. Br J Sports Med. 2022;56(16):933–940. doi: 10.1136/bjsports-2021-104955

 Web of Science ®Google Scholar

Yan J, Li X, Guo X, et al. Effect of multicomponent exercise on cognition, physical function and activities of daily life in older adults with dementia or mild cognitive impairment: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2023. doi:10.1016/j.apmr.2023.04.011.

 Web of Science ®Google Scholar

Rivas-Campo Y, Garcia-Garro PA, Aibar-Almazan A, et al. The effects of high-intensity functional training on cognition in older adults with cognitive impairment: a systematic review. Healthcare. 2022;10(4):670. doi: 10.3390/healthcare10040670

 Web of Science ®Google Scholar

Liu L, Dong H, Jin X, et al. Tackling dementia: a systematic review of interventions based on physical activity. J Geriatr Phys Ther. 2022;45(4):E169–E180. doi:10.1519/JPT.0000000000000332

 PubMed Web of Science ®Google Scholar

Xu W, Wang HF, Wan Y, et al. Leisure time physical activity and dementia risk: a dose-response meta-analysis of prospective studies. BMJ Open. 2017;7(10):e014706. doi:10.1136/bmjopen-2016-014706

 PubMed Web of Science ®Google Scholar

Venegas-Sanabria LC, Cavero-Redondo I, Martinez-Vizcaino V, et al. Effect of multicomponent exercise in cognitive impairment: a systematic review and meta-analysis. BMC Geriatr. 2022;22(1):617. doi:10.1186/s12877-022-03302-1

 PubMed Web of Science ®Google Scholar

Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol. 2018;14(11):653–666. doi:10.1038/s41582-018-0070-3

 PubMed Web of Science ®Google Scholar

Gomez-Soria I, Marin-Puyalto J, Peralta-Marrupe P, et al. Effects of multi-component non-pharmacological interventions on cognition in participants with mild cognitive impairment: a systematic review and meta-analysis. Arch Gerontol Geriatr. 2022;103:104751. doi:10.1016/j.archger.2022.104751

 PubMed Web of Science ®Google Scholar

Solomon A, Stephen R, Altomare D, et al. Multidomain interventions: state-of-the-art and future directions for protocols to implement precision dementia risk reduction. A user manual for brain health services—part 4 of 6. Alzheimer’s Res Ther. 2021;13(1):171. doi: 10.1186/s13195-021-00875-8

 PubMed Web of Science ®Google Scholar