Rooney, Rachael F.E.a,b
Dementia is a worldwide public health priority, with increasing burden as populations age. The WHO [1▪] states: ‘Research identifying modifiable risk factors of dementia is in its infancy. In the meantime, primary prevention should focus on targets suggested by current evidence’. Identification of factors may also develop the understanding of pathogenesis and guide therapeutics. We will refer to Alzheimer's Disease, vascular dementia and dementia with Lewy bodies/dementia associated with Parkinson's Disease. There have been recent reviews of alcohol-associated dementia [2▪] and frontotemporal dementia ( – only genetic risks identified).
In 2010, the National Institutes of Health Conference concluded there were ‘no validated modifiable factors to reduce the incidence of Alzheimer's Disease’ and that current evidence was insufficient for any recommendations to be made . However, since review in 2009 , there is increasing evidence regarding vascular risk factors in overall dementia and Alzheimer's Disease, controversial factors and novel proposals.
These are myriad:
a. Dementia is not homogeneous – risks may be subtype specific, but presentation is often mixed, and it is argued that prevention ‘should be considered from this view and not a research perspective on “pure” Alzheimer's Disease’ [6▪]. When patients were compared, Mini-Mental State Examination only correlated with stenosis/plaques in vascular dementia. Hypertension, hyperlipidaemia and diabetes mellitus were significantly more prevalent in the vascular dementia than Alzheimer's Disease group, although they were fairly prevalent in Alzheimer's Disease too [7▪]. However, amongst patients with Parkinson's Disease, dementia has not been associated with vascular risk factors .
b. In many large studies, cognitive decline/dementia is not the primary outcome.
2. ‘Lifestyle Factors’
a. May be challenging to quantify, underestimated retrospectively, confounded and interact with genetics.
b. Some are known to have adverse effects on health, which may cause ‘survivorship bias’ and make randomized control trials (RCTs) unethical.
c. Cumulative approaches are important:
i. The Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) project produced a score for dementia risk from midlife profiles [9▪▪] using hypertension, hypercholesterolaemia, BMI, low physical activity and low educational level in addition to sex, age and, optionally, ApoE genotype. Two other recent European populations had comparable concordance statistics to the original of 0.78 ([10▪▪] and [11▪] – predictability not improved by addition of other factors), wherein a value of 0.5 indicates a model is no better than chance, and a perfect predictive model would have a value of 1.0.
ii. Amongst a cohort of young Swedish men conscripted for military service, those with at least two factors (including stroke, alcohol/drug intoxication, antipsychotic use, depression and hypertension) and in the lowest third of cognition at conscription had large association with increased rates of young-onset dementia [12▪].
iii. Japanese-American men were defined ‘low risk’ at midlife if nonsmokers, BMI less than 25.0 kg/m2, physically active and healthy diet – this 7.2% of cohort had the lowest dementia rates, although not significant for Alzheimer's Disease [13▪].
iv. Within the Whitehall II cohort, a cumulative association for cognitive decline was found for smoking with heavy alcohol consumption [14▪]. In their population, the Framingham general cardiovascular disease and stroke-risk scores had ‘slightly stronger associations with 10-year cognitive decline than the CAIDE’ [15▪▪].
3. Modifiable risk
a. Cannot be inferred from evidence of correlation – further work is required translating observational to interventional studies to see whether modification indeed alters outcomes. Associations could reflect:
i. Underlying genetic-risk overlap .
iii. Reverse causality – prodrome features of dementia manifest as perceived ‘risk factor’.
b. Recent longitudinal/trajectory studies have added to the evidence  considering ‘windows of opportunity’ or reverse causality, e.g., hypertension [18▪▪], vascular factors [19▪▪] and hormone replacement therapy (HRT) [20▪▪].
c. Friedland and Nandi [21▪] argue the ideal RCT is impossible but ‘absence of definitive evidence should not restrict physicians from making reasonable recommendations based on the evidence that is available.’
Factors which may cumulate in the metabolic syndrome include:
Recent studies [10▪▪,12▪] have replicated cross-sectional observations of the association of hypertension in midlife with increased rates of Alzheimer's Disease/dementia, but hypertension in later life with reduced rates [19▪▪]. Interestingly, midlife blood pressure was not found to be significantly associated with death from dementia [22▪]. A longitudinal study in women [18▪▪] examined the trajectories and considered potential modifications in observational studies by treatment. They found that, although women not taking antihypertensives in midlife had considerably lower blood pressures than those who did, the midlife baseline blood pressures were higher amongst those unmedicated women who subsequently developed dementia. However, for the women on antihypertensives, those who developed dementia actually had lower baseline blood pressures but steeper increases over midlife than those who did not develop dementia. Regardless of treatment or not, there was a steeper decline in blood pressure towards later life in those who developed dementia.
A recent imaging study  adds weight to the proposed mechanism of subclinical cerebrovascular disease. There is mixed evidence as to whether lowering blood pressure/long-term antihypertensives reduces the incidence, with a recent vascular dementia review [24▪] concluding that generally meta-analyses have not found an association, although the number of dementia cases ‘reported in the placebo controlled trials is invariably lower in the actively treated group.’
Although not included in the CAIDE score, recent studies have replicated associations of midlife diabetes with cognition ([15▪▪,19▪▪] – wherein it was the strongest independent association), dementia or dementia deaths [22▪] even after adjusting for potential confounders. In addition, hyperglycaemia rather than diabetes diagnosis per se was associated with increased rates of cognitive decline [25▪▪], but even nonsevere hypoglycaemic episodes (a potential consequence of vigorous control) may also be detrimental .
An interpretation challenge is the frequent lack of distinction between type 1 and type 2 diabetes. A midlife study of childhood-onset type 1 patients showed increased frontal grey matter atrophy, independently of age/other vascular risks/diabetes complications [27▪]. Functional imaging studies in cognitively normal individuals demonstrated there was hyperglycaemia-associated cerebral hypometabolism in regions linked to Alzheimer's Disease [28▪]. However, there is still limited interventional evidence.
A 2011 meta-analysis  concluded that there was a significant increase in Alzheimer's Disease/vascular dementia/any dementia with being overweight in midlife (independently of comorbidities), but also that low BMI was associated with increased Alzheimer's Disease risk.
Overweight in midlife findings have been replicated in mixed sex studies [10▪▪,30▪], and amongst men [13▪] BMI [>25.0 vs. <22.6 kg/m(2)] was most strongly associated with increased rates. There are conflicting results as to whether being underweight in midlife is associated with increased dementia (or certain subtypes); paucity of underweight individuals may hamper a significant U-shaped relationship being detected. However, underweight midlife BMI was associated with dementia death [22▪].
A life-course approach has increasingly been taken, suggesting unstable weight is relevant, although there are discrepancies of the direction and potential reverse causation:
1. Two studies [30▪,31] (40–60 and 50–70 years) found decrease in BMI (not low BMI per se) to be associated with impairment/higher risk of dementia and Alzheimer's Disease specifically,
2. whereas others found weight gain in overweight individuals [10▪▪] or changes in either direction to associate with impairment ( – women,  – men).
More work is needed to clarify the discrepancies, untangle reverse causation, consider midlife underweight and sex differences, as previously highlighted , when the evidence was most discrepant between sexes for BMI. A recent study [35▪] directly measuring a proposed mediator, leptin, did not show an association.
Recent studies ([19▪▪] – impairment, [22▪] – deaths) have replicated previous associations, and a vascular dementia review  concluded: ‘elevated midlife serum cholesterol may increase risk’. However, in a twin study [10▪▪], self-reported hypercholesterolaemia did not increase rates. There are inconsistencies regarding dietary intake – amongst Japanese-American men [13▪] ‘healthy diet’ (including ratio of monounsaturated to saturated fat) was a midlife ‘low risk’ characteristic but individually not associated with vascular dementia/Alzheimer's Disease.
Hypercholesterolaemia may contribute via atherosclerosis, and it is also proposed that cellular cholesterol is involved in Alzheimer's Disease pathogenesis, with recent research highlighting metabolism pathway susceptibility genes [37▪]. Although some studies have shown treatment to reduce the risk, a 2012 meta-analysis [38▪] concluded: ‘the role of statins for the prevention of dementia is still highly debatable’.
Recent research ([13▪] – vascular dementia, [10▪▪] – impairment) is consistent with a 2011 meta-analysis  that high levels of midlife leisure physical activity are associated with reduced rates. Another study [40▪▪] found increased midlife treadmill-test fitness to be associated with lower rates of dementia, which retained significance when stratified by stroke history, so may be ‘independent of cerebrovascular disease.’ However, another prospective study [41▪] and meta-analysis were more cautious about the benefits, in part because of ‘small study bias’ suggesting an absence of null studies.
Research into this association includes gene–lifestyle interactions ( – later life) and insulin levels ( – midlife). Although there have been older-age short-term intervention trials, there is a lack in midlife.
Earlier studies suggested a protective effect of smoking, but this has since been attributed to ‘survivor bias’ or industry affiliations ( – Alzheimer's Disease). For vascular dementia, increased risk was also concluded at recent review [24▪]. Passive exposure to tobacco smoke in never-smokers increased the risk of all dementia and Alzheimer's Disease specifically [45▪▪]. In an Alzheimer's Disease mouse model, smoke exposure increased pathological correlates [46▪].
A recent review of alcohol-related dementia [2▪] concluded that it is unclear what level of drinking poses a risk, but there is ‘potential to at least partially recover - both structurally and functionally - if abstinence is maintained.’
Earlier studies focused on excessive drinking increasing risk of dementia (replicated [12▪]). For vascular dementia especially, research has suggested a dose-dependent/U-shaped relationship [24▪]. When cognition was assessed over 5 years, important sex differences were noted (only in women was total consumption of alcoholic beverages inversely associated with decline) and drink-specific protective effects (only red wine consumption and maximally at ∼1.5 glasses per day) [47▪▪]. A protective effect for red wine has been proposed due to antioxidant flavinoid content.
A systematic review  concluded that there was ‘no consensus regarding alcohol's impact on Alzheimer's Disease’.
As with smoking, RCTs may be unethical, but future studies should consider clear stratification into alcohol-related dementias, sex effects and potential confound with other health/lifestyle behaviours. Although it is advisable to recommend reduction in heavy drinking, very strong levels of evidence would be required to promote moderate red wine to nondrinkers.
Recent review [49▪▪] concluded that early-onset (<65 years) and recurrent depression may constitute long-term risk factors but later life symptoms may be prodromal. Other potential confounds are comorbidity (awareness of deterioration in cognition may also contribute) and ‘pseudo-dementia’.
There has been one recent study considering subtype of dementia: individuals with dementia with Lewy bodies were more likely than those with Alzheimer's Disease/controls to have a history of a depression [50▪▪].
Review [49▪▪] concluded: ‘Recent studies suggest that long-term treatment with antidepressants may decrease the risk of developing some types of dementia…’
Individuals with dementia with Lewy bodies were more likely than controls to have a history of anxiety [50▪▪] and individuals with young-onset dementia were more likely to have taken antipsychotics and been intoxicated by drugs other than alcohol [12▪].
This is a controversial risk factor, with additional debate as to whether it is modifiable. Studies have strengthened the evidence for a role: ‘greater Neuroticism is associated with decline, and greater Conscientiousness is associated with improvement’ in 10-year Mini-Mental State Examination at midlife , and this pattern was replicated with longer-term Alzheimer's Disease outcome and meta-analysis [52▪▪].
Neuroimaging correlates of midlife self-reports of female psychological distress have been reported as moderate-to-severe white matter lesions and temporal lobe/central brain atrophy .
A retrospective cohort study [54▪] of all Taiwanese patients above 50 years old with a first diagnosis of ‘long-term insomnia’ tracked for 3 years found, after adjusting for vascular factors, that those aged 50–65 had significantly higher rates of dementia, and that this was more marked than above 65 years, suggesting this is not reverse causation.
Recent studies have found that regular use of benzodiazepines, especially at a younger age (but no dose–response effect seen), was associated with marked increased incidence of dementia, which persisted despite adjustments, including psychological distress [55▪]. A significant association in past users only was also found ( – later life) and in the insomnia study ‘hypnotics with a longer half-life and at a higher prescribed dose predicted a greater increased risk of dementia’ [54▪].
Recent studies have added weight to previous proposals that risk is reduced by higher levels of:
a. For young-onset dementia, low cognitive function at conscription increased risk [12▪].
2. Educational attainment/levels
a. Patients with dementia with Lewy bodies were found likely to ‘be more educated’ than with Alzheimer's Disease [50▪▪].
3. Occupational cognitive demand
a. In the Israel Ischaemic Heart Disease study, it was found that midlife satisfaction with work status and lack of motivation to change was associated with increased risk [57▪].
4. Cognitively stimulating leisure activities
a. At older age, past exposure to multilingualism (compared with bilingualism) was associated with reduced cognitive impairment [58▪▪].
Two recent studies have considered an association with church attendance/prayer, with varied results:
1. In the later life Cache County population [59▪], participants were clustered into subpopulations with distinct lifestyle behaviour patterns. Compared with ‘unhealthy-religious’, individuals in all other groups (unhealthy-nonreligious, healthy-moderately-religious and healthy-very-religious) had significantly lower dementia rates with similar trends for Alzheimer's Disease. They attribute this to behaviours of not smoking, healthy diet, exercise and social activity.
2. Higher reported midlife monthly praying amongst Arabic women significantly associated with reduced cognitive impairment but not Alzheimer's Disease. They suggest prayer may function as a repetitive cognitive activity that may protect against cognitive decline but not specific Alzheimer's Disease pathology .
A recent study [61▪] found educational level to be highly associated with cognitive performance at both baseline and 15-year follow-up, but not with rate of change. Therefore, when considering diagnostic thresholds, this supports a ‘brain reserve’ protective effect, and inclusion in CAIDE scores may be an advantage over general Framingham scoring for the detection of dementia as opposed to decline [15▪▪]. There have been numerous RCTs of cognitive stimulation in later life but a lack in midlife – it would also be important to control for confounds such as intelligence, socioeconomic status and other health/lifestyle behaviours.
TRAUMATIC BRAIN INJURY
Numerous previous studies have demonstrated strong evidence of increased risk of dementia, including Alzheimer's Disease, following head trauma, modulated by the nature of the injury (e.g. loss of consciousness duration) and personal factors (e.g. genetics or sex). Recent pathology research [62▪] in patients with an earlier single injury has better characterized persisting white matter changes as a more active/evolving process.
OTHER DIETARY ASPECTS
There have been a number of recent reviews regarding associations:
1. Vascular dementia – most convincing evidence for reduction with antioxidants such as Vitamins E and C, whereas lower levels of folate and vitamin B12 and higher homocysteine increased rates .
2. Alzheimer's Disease – lower rates with higher fruit, vegetable and fish consumption, and adherence to healthy/Japanese/Mediterranean diets [63▪▪].
Other substances proposed to reduce risk include polyphenols, flavinoids (red wine, tea, fruit and vegetables) and caffeine (coffee associated with reduced Alzheimer's Disease [63▪▪], and individuals with dementia with Lewy bodies less likely to use caffeine [50▪▪]). A recent animal model has been demonstrated in which chronic caffeine consumption was associated with increased hippocampal dendritic changes .
However, many dietary RCTs thus far contradict observational studies.
FEMALE REPRODUCTIVE HEALTH
Numerous large-scale HRT studies included cognitive outcomes, and reproductive health is now considered more widely, although there may be ‘windows of opportunity’ accounting for seemingly contrasting ovarian hormone effects.
Hormone replacement therapy
Within the Cache County population [20▪▪] ‘women who used any type of HRT within 5 years of menopause had 30% less risk of Alzheimer's Disease… especially if use was for 10 or more years’, but there was no reduction if initiated 5+ years after. There was a trend towards increased Alzheimer's Disease rates among those who began ‘opposed’ estrogen-progestin compounds within the 3 years preceding study baseline, which was consistent with cognitive scores in the Women's Health Initiative Memory Study  and previous RCTs.
When two cohort studies were combined, a complex hormonal relationship was suggested: compared with women with no surgery, the risks of impairment/dementia escalated with hysterectomy alone, further with hysterectomy with unilateral oopherectomy and again with hysterectomy with bilateral oopherectomy . Individuals with dementia with Lewy bodies were much more likely than those with Alzheimer's Disease to have had an oophorectomy below 45 years old [50▪▪].
A recent retrospective cohort study [67▪▪] found breastfeeding and for longer duration (which can be considered a proxy for postpregnancy oestrogen/progesterone deficiency or restoration of insulin sensitivity) associated with reduced Alzheimer's Disease rates, although recorded occupation, but not education, in part confounded this.
A recent review [68▪▪] discusses the epidemiologic evidence for this association and potential mechanisms (with rat/mouse models) such as systemic inflammation. There have been a number of recent studies also supportive of an association [69,70], although often not restricted to midlife, and potential confounds include age itself, dietary and other health/mood/personality behaviours and reverse causation.
It was recently proposed that ‘especially chronic noise exposure, can cause Alzheimer's Disease-like neuropathological changes, and that persistence of these changes have an etiological association with the development of Alzheimer's Disease’. They suggest epidemiological studies should be completed, although they feel the other harmful effects ‘warrant that actions should be taken to protect the public health from noise hazards without waiting for the results’ [71▪].
The ‘hygiene hypothesis’ has been modelled in relation to Alzheimer's Disease [72▪▪] with the findings that countries with higher pathogen prevalence and infant mortality were associated with lower Alzheimer's Disease rates but those with higher levels of hygiene, economic measures and people living in urban settings had higher rates. Importantly, the analyses suggested that greater exposure to microbes across the lifespan, rather than only in earlier years, was relevant.
Although there is increasing evidence of associations between numerous modifiable factors and specific subtypes or overall dementia, there remains a lack of evidence from interventional studies from midlife. However, it has been argued that the ideal studies are impossible and, especially in view of other known effects on morbidity and mortality (especially cardio/cerebrovascular), that public health strategies should be promoted in the interim. As many of these factors are current public health priorities in high-income countries, it may be that ongoing epidemiological study and a worldwide perspective as other countries emerge into a dementia epidemic provide further evidence.
With thanks to Dr C. Cooper for her encouragement and editing.
With thanks to Elizabeth for her patience.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
1▪. World Health Organization and Alzheimer's Disease InternationalDementia: a public health priority. Geneva:WHO, 2012; . 112. ISBN: 9789241564458.
This report takes a global approach to comprehensively consider the epidemiology, policy/planning/legislation/ethics, health and social care systems, caregiving/carers, public understanding and future strategies.
2▪. Ridley NJ, Draper B, Withall A. Alcohol-related dementia: an update of the evidence. Alzheimers Res Ther 2013; 5:3.
This is a comprehensive recent review of alcohol-related dementia, which may be highly modifiable by midlife interventions.
3. Onyike CU, Diehl-Schmid J. The epidemiology of frontotemporal dementia. Int Rev Psychiatry 2013; 25:130–137.
4. Williams JW, Plassman BL, Burke J, et al. Preventing Alzheimer's Disease and Cognitive Decline. Evidence Report/Technology Assessment No. 193. (Prepared by the Duke Evidence-based Practice Center under Contract No. HHSA 290-2007-10066-I). Rockville, MD:Agency for Healthcare Research and Quality: AHRQ Publication No. 10-E005; 2010. National Institutes of Health: Consensus Development Conference Statement on Preventing Alzheimer's Disease and Cognitive Decline. Bethesda, MD: National Institutes of Health; 2010.
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6▪. Román GC, Nash DT, Fillit H. Translating current knowledge into dementia prevention. Alzheimer Dis Assoc Disord 2012; 26:295–299.
This review provides a helpful emphasis on clinical practice, considering common forms of dementia in the community and advice to patients.
7▪. Stefanova E, Pavlovic A, Jovanovic Z, et al. Vascular risk factors in Alzheimer's disease: preliminary report. J Neurol Sci 2012; 322:166–169.
This study explicitly considers vascular factors in Alzheimer's Disease patients and emphasizes the prevalence of these factors, as compared with patients with a diagnosis of vascular dementia, and how they correlate with clinical findings of severity in both, which may lead to further consideration of whether they represent incidental comorbidities in Alzheimer's Disease or may also be causal.
8. Schelp AO, Mendes-Chiloff CL, Bazan R, et al. Metabolic syndrome and dementia associated with Parkinson's disease: impact of age and hypertension. Arq Neuropsiquiatr 2012; 70:114–118.
9▪▪. Solomon A, Kivipelto M, Soininen H. Prevention of Alzheimer's disease: moving backward through the lifespan. J Alzheimers Dis 2013; 33 (Suppl 1):S465–S469.
This article helpfully summarizes the Finnish research related to Alzheimer's Disease from the 1970s onwards, including the significant large-scale CAIDE study wherein cognition is one of the primary outcomes and the only specific scoring system for dementia risk factors has been developed. It also mentions their current ongoing multicentre multidomain RCT in early later life, which may lead to midlife intervention studies.
10▪▪. Virta JJ, Heikkilä K, Perola M, et al. Midlife cardiovascular risk factors and late cognitive impairment. Eur J Epidemiol 2013; 28:405–416.
This is a Finnish twin study (which importantly allows co-twin control analysis of 54–67 pairs with discordant cognition to consider later nongenetic effects) with a 23-year follow-up period assessing cognitive function, and was another population comparison for the utility of the CAIDE score factors.
11▪. Exalto LG, Quesenberry CP, Barnes D, et al. Midlife risk score for the prediction of dementia four decades later. Alzheimers Dement 2013; . [Epub ahead of print].
This study was important as external validation of the CAIDE score in another country, with different race strata and average follow-up time of 36.1 years. It also considered whether other midlife risk factors (central obesity, depression, diabetes mellitus, head trauma and smoking) could improve the predictability.
12▪. Nordström P, Nordström A, Eriksson M, et al. Risk factors in late adolescence for young-onset dementia in men: a Nationwide Cohort Study. JAMA Intern Med 2013; 173:1612–1618.
This study unusually considers young-onset dementia, which may be a specific subtype with distinct risk factors, or a helpful model with shorter latency time and modifiable factors interacting with genetic predisposition. They had a large sample of all Swedish men conscripted for military service within a 10-year period, with baseline mean age of 18 years and median follow-up 37 years, that considered population attributable and cumulative risks.
13▪. Gelber RP, Petrovitch H, Masaki KH, et al. Lifestyle and the risk of dementia in Japanese-American men. J Am Geriatr Soc 2012; 60:118–123.
This case–control prospective study from the Honolulu-Asia Ageing Study with 25 years’ follow-up considered the most modifiable of vascular factors (smoking, BMI, physical activity and diet) and, importantly, a cumulative effect.
14▪. Hagger-Johnson G, Sabia S, Brunner EJ, et al. Combined impact of smoking and heavy alcohol use on cognitive decline in early old age: Whitehall II prospective cohort study. Br J Psychiatry 2013; 203:120–125.
This British study considered the multiplicative/cumulative effect of two very modifiable lifestyle factors within a large prospective cohort study from early later life for 10 years.
15▪▪. Kaffashian S, Dugravot A, Elbaz A, et al. Predicting cognitive decline: a dementia risk score vs. the Framingham vascular risk scores. Neurology 2013; 80:1300–1306.
From the Whitehall II Cohort, this longitudinal study was the first comparison of potential risk scores – with Framingham cardiovascular disease score (age, sex, SBP, treatment for hypertension, high-density lipoprotein cholesterol, total cholesterol, smoking and diabetes) and stroke-risk score [age, SBP, treatment for hypertension, diabetes, smoking, prior cardiovascular disease (myocardial infarction, angina pectoris, coronary insufficiency, intermittent claudication or congestive heart failure, atrial fibrillation and left-ventricular hypertrophy)] compared with the specific CAIDE for cognitive decline over 10 years in midlife. They argue for potential advantages of a more general score in clinical practice but limitations of a measurement of cognition vs. diagnosis of dementia.
16. Kotze MJ, van Rensburg SJ. Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease. Metab Brain Dis 2012; 27:255–266.
17. Treves TA, Korczyn AD. Modeling the dementia epidemic. CNS Neurosci Ther 2012; 18:175–181.
18▪▪. Joas E, Bäckman K, Gustafson D, et al. Blood pressure trajectories from midlife to late life in relation to dementia in women followed for 37 years. Hypertension 2012; 59:796–801.
In this study, blood pressure was observed as a trajectory with multiple measurements from midlife to late life, and so takes a life-course approach to demonstrate a complex interaction. Also they crucially stratify into those treated with antihypertensives and those not, which helps to consider the impact of treatment in observational studies.
19▪▪. Reijmer YD, van den Berg E, Dekker JM, et al. Development of vascular risk factors over 15 years in relation to cognition: the Hoorn Study. J Am Geriatr Soc 2012; 60:1426–1433.
This longitudinal population-based study from late midlife with 15 years’ follow-up measured multiple cognitive functions and a number of vascular factors at four medical examinations. This life-course approach adds to evidence regarding a potential ‘window of opportunity’.
20▪▪. Shao H, Breitner JC, Whitmer RA, et al. Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. Neurology 2012; 79:1846–1852.
This study may account for discrepancies between previous cross-sectional/short follow-up observational studies and interventional studies by taking a life-course approach to HRT in relation to menopause timing. They also considered type of HRT.
21▪. Friedland RP, Nandi S. A modest proposal for a longitudinal study of dementia prevention (with apologies to Jonathan Swift, 1729). J Alzheimers Dis 2013; 33:313–315.
This editorial satirically highlights some of the challenges in this area of research.
22▪. Strand BH, Langballe EM, Hjellvik V, et al. Midlife vascular risk factors and their association with dementia deaths: results from a Norwegian prospective study followed up for 35 years. J Neurol Sci 2013; 324:124–130.
This large longitudinal study from the Norwegians used an alternative endpoint of dementia-related deaths (as per Cause of Death Registry) as a proxy endpoint.
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24▪. Peters R. Blood pressure, smoking and alcohol use, association with vascular dementia. Exp Gerontol 2012; 47:865–872.
This review traces some of the trends in research regarding these factors and systematic review and meta-analysis.
25▪▪. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med 2013; 369:540–548.
This study was important in demonstrating a continuum effect of hyperglycaemia (albeit in an older population with relatively short follow-up) on cognition rather than diagnosis of diabetes per se, and so may have significant clinical implications for large numbers of patients in midlife.
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27▪. Hughes TM, Ryan CM, Aizenstein HJ, et al. Frontal gray matter atrophy in middle aged adults with type 1 diabetes is independent of cardiovascular risk factors and diabetes complications. J Diabetes Complications 2013; 27:558–564.
This study demonstrates potential structural correlates of changes in type 1 diabetes specifically (fewer research studies are explicit about subtypes of diabetes) with comparison to other cardiovascular risk factors and complications of diabetes. As life-expectancy of type 1 diabetes extends, there may be increased cases of clinically significant cognitive decline, and it may be a model, over a shorter time frame, for common pathways with type 2.
28▪. Burns CM, Chen K, Kaszniak AW, et al. Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions. Neurology 2013; 80:1557–1564.
This study is suggestive of a potential mechanism of association between diabetes/hyperglycaemia and specifically Alzheimer's Disease. Importantly, the study was in cognitive normal and nondiabetic individuals, although they did have a first-degree family history of Alzheimer's Disease, and so this may suggest a causal pathway prior to clinical manifestations.
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30▪. Tolppanen AM, Ngandu T, Kåreholt I, et al. Midlife and late-life body mass index and late-life dementia: results from a prospective population-based cohort. J Alzheimers Dis 2014; 38:201–209.
This study used the CAIDE participants with a life-course perspective over 28 years’ follow-up. Importantly, they included both sexes and stratified by type of dementia.
31. Dahl AK, Hassing LB, Fransson EI, et al. Body mass index across midlife and cognitive change in late life. Int J Obes (Lond) 2013; 37:296–302.
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This study is important for making direct measurement of a factor hypothesized to underlie the association between midlife overweight and increased risk of dementia.
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37▪. Engelman CD, Koscik RL, Jonaitis EM, et al. Interaction between two cholesterol metabolism genes influences memory: findings from the Wisconsin Registry for Alzheimer's prevention. J Alzheimers Dis 2013; 36:749–757.
This examined interactions between the known ApoE genotype risk factor with other proposed susceptibility genes with cognitive assessment in middle-aged adults who were enriched with a first-degree relative history of Alzheimer's Disease.
38▪. Menezes AR, Lavie CJ, Milani RV, O’Keefe J. The effects of statins on prevention of stroke and dementia: a review. J Cardiopulm Rehabil Prev 2012; 32:240–249.
This review assess the evidence regarding an intervention to lower cholesterol, which is helpful in view of discrepant study findings for a protective or no effect or case reports/anecdotes of decline associated with statin use. However, many of these studies have been in later life or as secondary prevention.
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This study was a prospective observational community cohort with median follow-up of 25 years. It was helpful to objectively measure actual fitness rather than proxies of time spent and, by also stratifying into a history of previous stroke or not, gave suggestions as to potential mechanisms.
41▪. Morgan GS, Gallacher J, Bayer A, et al. Physical activity in middle-age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-analysis. J Alzheimers Dis 2012; 31:569–580.
This meta-analysis is helpful because of considerations as to length of follow-up and confounders.
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44. Cataldo JK, Prochaska JJ, Glantz SA. Cigarette smoking is a risk factor for Alzheimer's Disease: an analysis controlling for tobacco industry affiliation. J Alzheimers Dis 2010; 19:465–480.
45▪▪. Chen R. Association of environmental tobacco smoke with dementia and Alzheimer's disease among never smokers. Alzheimers Dement 2012; 8:590–595.
This extension of another potential risk factor to passive exposure may have significant public health implications if replicable.
46▪. Moreno-Gonzalez I, Estrada LD, Sanchez-Mejias E, Soto C. Smoking exacerbates amyloid pathology in a mouse model of Alzheimer's disease. Nat Commun 2013; 4:1495.
This provides an animal model for potential mechanism of an association with smoking.
47▪▪. Nooyens AC, Bueno-de-Mesquita HB, van Gelder BM, et al. Consumption of alcoholic beverages and cognitive decline at middle age: the Doetinchem Cohort Study. Br J Nutr 2013; . [Epub ahead of print].
This study included both sexes and considered the differences in the association with alcohol. It also quantified the amounts and characterized types of drink with which there were associations.
48. Piazza-Gardner AK, Gaffud TJ, Barry AE. The impact of alcohol on Alzheimer's disease: a systematic review. Aging Ment Health 2013; 17:133–146.
49▪▪. Kessing LV. Depression and the risk for dementia. Curr Opin Psychiatry 2012; 25:457–461.
This review considers the life-course association with depression and unanswered questions.
50▪▪. Boot BP, Orr CF, Ahlskog JE, et al. Risk factors for dementia with Lewy bodies: a case-control study. Neurology 2013; 81:833–840.
This study is important as it considered differences between subtypes of dementia, including dementia with Lewy bodies, which is less frequently considered amongst a wide range of candidate risk factors.
51. Hock RS, Lee HB, Bienvenu OJ, et al. Personality and cognitive decline in the Baltimore Epidemiologic Catchment Area Follow-up Study. Am J Geriatr Psychiatry 2013; . [Epub ahead of print].
52▪▪. Terracciano A, Sutin AR, An Y, et al. Personality and risk of Alzheimer's disease: new data and meta-analysis. Alzheimers Dement 2013; . [Epub ahead of print].
This study involved a longitudinal study (up to 22 years’ follow-up) and meta- analysis from five prospective studies to give pooled hazard ratios comparable to associations with well-established clinical factors.
53. Johansson L, Skoog I, Gustafson DR, et al. Midlife psychological distress associated with late-life brain atrophy and white matter lesions: a 32-year population study of women. Psychosom Med 2012; 74:120–125.
54▪. Chen PL, Lee WJ, Sun WZ, et al. Risk of dementia in patients with insomnia and long-term use of hypnotics: a population-based retrospective cohort study. PLoS ONE 2012; 7:e49113.
This study was a comprehensive retrospective cohort study amongst Taiwanese patients; although the follow-up was a short 3 years, adjustments were made for vascular factors and stratifications by age and type of hypnotic.
55▪. Gallacher J, Elwood P, Pickering J, et al. Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS). J Epidemiol Community Health 2012; 66:869–873.
This prospective study assessed on five occasions over 22 years and considered the life-course of exposures.
56. Billioti de Gage S, Bégaud B, Bazin F, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012; 345:e6231.
57▪. Ravona-Springer R, Beeri MS, Goldbourt U. Satisfaction with current status at work and lack of motivation to improve it during midlife is associated with increased risk for dementia in subjects who survived thirty-seven years later. J Alzheimers Dis 2013; 36:769–780.
This study had a 3-decade follow-up and controlled for age, but also checked to see whether attenuated by midlife diabetes, blood pressure values, serum-cholesterol levels and coronary heart disease, which were controlled for in the analysis. This association was partially attenuated by socioeconomic status.
58▪▪. Perquin M, Vaillant M, Schuller AM, et al. Lifelong exposure to multilingualism: new evidence to support cognitive reserve hypothesis. PLoS ONE 2013; 8:e62030.
This retrospective nested case–control study carefully assessed the number of languages practised, age of acquisition and duration of practice, so may add to the ‘cognitive reserve’ hypothesis.
59▪. Norton MC, Dew J, Smith H, et al. Lifestyle behavior pattern is associated with different levels of risk for incident dementia and Alzheimer's disease: the Cache County study. J Am Geriatr Soc 2012; 60:405–412.
This study grouped participants into four distinct lifestyle groups using latent class analysis of six domains of behaviour, and argues for taking an approach in which patterns of behaviour are examined. Although based on current behaviours and with short follow-up, this approach may be applicable to complex midlife patterns.
60. Inzelberg R, Afgin AE, Massarwa M, et al. Prayer at midlife is associated with reduced risk of cognitive decline in Arabic women. Curr Alzheimer Res 2013; 10:340–346.
61▪. Schneider AL, Sharrett AR, Patel MD, et al. Education and cognitive change over 15 years: the atherosclerosis risk in communities study. J Am Geriatr Soc 2012; 60:1847–1853.
This was a prospective cohort study with cognitive evaluation over a 15-year period that used a threshold of high school education or beyond in both white and black ethnicities. It adds to the ‘cognitive reserve’ hypothesis and highlights the importance of educational level.
62▪. Johnson VE, Stewart JE, Begbie FD, et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 2013; 136 (Pt 1):28–42.
This study used cases of traumatic brain injury with survivals ranging from 10 h to 47 years postinjury and compared pathological changes seen in brain sections to demonstrate the ongoing changes that may be involved in a link with dementia.
63▪▪. Hu N, Yu JT, Tan L, et al. Nutrition and the risk of Alzheimer's disease. Biomed Res Int 2013; 2013: . [Epub ahead of print].
This review tackles the complex associations between nutrition and Alzheimer's Disease.
64. Vila-Luna S, Cabrera-Isidoro S, Vila-Luna L, et al. Chronic caffeine consumption prevents cognitive decline from young to middle age in rats, and is associated with increased length, branching, and spine density of basal dendrites in CA1 hippocampal neurons. Neuroscience 2012; 202:384–395.
65. Maki PM, Henderson VW. Hormone therapy, dementia, and cognition: the Women's Health Initiative 10 years on. Climacteric 2012; 15:256–262.
66. Rocca WA, Grossardt BR, Shuster LT, Stewart EA. Hysterectomy, oophorectomy, estrogen, and the risk of dementia. Neurodegener Dis 2012; 10:175–178.
67▪▪. Fox M, Berzuini C, Knapp LA. Maternal breastfeeding history and Alzheimer's Disease risk. J Alzheimers Dis 2013; 37:809–821.
This article reviews previous evidence regarding reproductive factors and associations with dementia and reports a retrospective study of breastfeeding with proposed mechanisms for the effects observed.
68▪▪. Noble JM, Scarmeas N, Papapanou PN. Poor oral health as a chronic, potentially modifiable dementia risk factor: review of the literature. Curr Neurol Neurosci Rep 2013; 13:384.
This review summarizes the associations of aspects of poor oral health with dementia and potential mechanisms including animal models.
69. Batty GD, Li Q, Huxley R, et al. Oral disease in relation to future risk of dementia and cognitive decline: prospective cohort study based on the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial. Eur Psychiatry 2013; 28:49–52.
70. Paganini-Hill A, White SC, Atchison KA. Dentition, dental health habits, and dementia: the Leisure World Cohort Study. J Am Geriatr Soc 2012; 60:1556–1563.
71▪. Cui B, Li K. Chronic noise exposure and Alzheimer disease: is there an etiological association? Med Hypotheses 2013; 81:623–626.
A proposal for a role of chronic noise exposure as a risk factor based upon Alzheimer's Disease-like pathology seen in animal models. This could have worldwide health implications as nations urbanize or levels of occupational noise increase.
72▪▪. Fox M, Fincher CL, Andrews P, Knapp L. Hygiene and the world distribution of Alzheimer's Disease. EMPH 2013; 1:173–186.
This study used 2004 data from the WHO Global Burden of Disease report for ‘Alzheimer's and other dementias’ and various sources for their proxy measures of ‘hygiene’. This may have significant implications for global patterns of dementia as countries develop.