Prevention of dementia

INTRODUCTION — Dementia is an increasing problem as the global population ages. Alzheimer disease (AD) is the most common form of dementia in older adults, accounting for 60 to 80 percent of cases. Asymptomatic individuals often present with concerns about developing dementia, especially when they have a family history.

Two major reports released in 2017 review the literature on potentially modifiable risk factors for dementia and highlight strengths and weaknesses in the available data to support the impact of risk factor modification on dementia incidence [1,2]. While the overall evidence is generally of low quality and does not support any single intervention as effective in delaying or preventing dementia, there is optimism that intensive risk factor modification, especially during midlife (age 45 to 65 years), has the potential to delay or prevent a substantial number of dementia cases worldwide. In support of this, large population-based studies indicate that the incidence of dementia has declined in high-income countries over the last several decades [3-8].

Related material concerning risk factors for dementia is discussed separately. The risk factors, treatment, and prevention of vascular dementia are discussed separately. (See "Risk factors for cognitive decline and dementia" and "Epidemiology, pathology, and pathogenesis of Alzheimer disease" and "Etiology, clinical manifestations, and diagnosis of vascular dementia" and "Treatment of vascular cognitive impairment and dementia".)

LIFESTYLE AND ACTIVITY — Based on epidemiologic evidence and biologic plausibility regarding the relationship between a healthy lifestyle and dementia risk (as well as other health benefits), we encourage patients to maintain or increase physical activity, exercise, cognitive leisure activities, and social interaction.

Observational evidence supports an inverse association between various components of a healthy lifestyle (eg, social interaction, education and mental activities, physical exercise) and the incidence of dementia, even after adjusting for relevant confounders [9-31]. However, it is not known whether these interventions effectively reduce dementia risk, and most trials have looked at relatively short-term interventions and outcomes.

Physical exercise — Although numerous observational studies have found an inverse association between physical exercise and risk of dementia, the protective effects of exercise remain unproven [2,32-35]. It remains possible that physical exercise has synergistic benefits as part of a more comprehensive risk factor reduction strategy. (See 'Vascular risk factor modification' below.)

In a meta-analysis of 12 randomized trials, aerobic exercise in healthy older adults did not improve cognitive outcomes in any domain, even in trials in which cardiorespiratory fitness improved in the exercise group [32]. The duration of the trials ranged from two to six months. Two trials of more prolonged and intensive lifestyle interventions in sedentary older adults and adults with type 2 diabetes also found no improvement in cognitive function or rates of cognitive decline and dementia [36,37].

Some have posited that exercise in early and middle adulthood may have greater chance of influencing dementia risk than exercise in late adulthood. In particular, midlife levels of cardiorespiratory fitness may predict risk of dementia later in life, independent of cerebrovascular disease [38]. However, a prospective cohort study that began following exercise levels in healthy adults between 35 and 55 years of age failed to find a protective effect of exercise over nearly 30 years of follow up [39]. In patients diagnosed with dementia, exercise levels began to decline up to nine years before diagnosis, suggesting that reverse causation may partially explain previous observations that exercise is associated with a lower risk of dementia.

Cognitive training — Various cognitive interventions including memory training, the use of external memory cues, and organizational aids have shown positive short-term effects on cognition in healthy older adults, but the long-term impacts are less clear [2,40-44]. Examples of the largest individual trials include the following:

●The ACTIVE trial randomly assigned 2832 older adults to one of three cognitive interventions or a control group, and found that a 10-week training program in inductive reasoning (but not in verbal memory or speed of processing) resulted in improved performance on the Instrumental Activities of Daily Living that was sustained at five years [42]. The rate of incident dementia at five years was unaffected [45], and longer-term follow up of the cohort is still in progress.

●The FINGER trial tested a multidomain intervention that included diet, exercise, cognitive training, and vascular risk monitoring in 1260 at-risk elderly adults [43]. Compared with controls who were given general health advice, individuals who were randomly assigned to the intervention showed greater improvements in neuropsychological test battery scores at two years. The magnitude of benefit was relatively small, however, and longer follow up is needed to determine whether the intervention has any impact on rates of cognitive decline or dementia.

●The Multidomain Alzheimer Preventive Trial (MAPT) tested a multidomain intervention of physical activity, cognitive training, and nutritional advice with or without omega-3 fatty acid supplementation versus placebo in 1525 older adults with subjective memory complaints [46]. At three years, there were no differences in cognitive test scores among the groups.

At present, there is no evidence to support the notion that computerized "brain training" programs marketed commercially, most of which are not as intensive as the intervention in the ACTIVE trial, have benefits beyond short-term gains in the specific cognitive tasks that are being rehearsed [1,2].

Role of education and cognitive reserve — Higher levels of education have been associated with a reduced risk of dementia, or at least a later onset of symptoms relative to neuropathologic disease burden [47-51]. Advanced education is believed to represent a higher cognitive reserve that decreases the impact of degenerative pathology on cognitive function, rather than providing a protective effect against the accumulation of amyloid or other pathologic changes [49,52-55].

Once clinical dementia develops, however, patients with higher education or occupational levels appear to experience a somewhat more rapid cognitive decline, at least in part because they are assumed to have accumulated a greater degree of Alzheimer pathology by the time dementia is apparent, compared with those with less education [56-58].

VASCULAR RISK FACTOR MODIFICATION — An analysis based upon the observed prevalence of potentially modifiable risk factors (hypertension, diabetes, inactivity) combined with their associated relative risk for dementia suggests that risk factor reductions of 10 to 25 percent may prevent up to half of Alzheimer disease (AD) cases [59].

Although population-based data are not entirely consistent, it does appear that the incidence of all-cause dementia, and especially vascular dementia, is declining in high-income countries over the past several decades [3-8]. This trend has occurred as the prevalence of many vascular risk factors has also decreased over time [3]. While evidence is still lacking to support the routine use of any of these measures for the specific indication of preventing AD or dementia [60,61], epidemiologic studies offer optimism that multimodality risk factor reduction is worthwhile, not just for cardiovascular outcomes but also for cognitive health.

Vascular risk factor management as it relates to dementia prevention is discussed in more detail separately. (See "Treatment of vascular cognitive impairment and dementia", section on 'Vascular risk modification'.)

Antihypertensive therapy — Hypertension appears to be associated with an increased risk of both vascular dementia and AD, but the effect of antihypertensive treatment on reducing risk is uncertain and may be most important in midlife [62]. One analysis estimated that based upon the prevalence of hypertension and the relative risk for dementia, lowering the prevalence of hypertension by 25 percent could reduce the incidence of AD by nearly 100,000 cases [59]. (See "Risk factors for cognitive decline and dementia", section on 'Hypertension'.)

Until more data are available, firm conclusions regarding antihypertensive treatment for prevention of dementia or cognitive impairment cannot be made [2,63,64]. However, there are enough other reasons to treat patients with hypertension that the prevention of dementia alone is unlikely to influence therapeutic decisions. A consensus-based scientific review by the American Heart Association/American Stroke Association (AHA/ASA) concluded that blood pressure lowering to lower the risk of post-stroke dementia is effective and that it is reasonable to lower blood pressure in mid-life to lower the risk of late-life dementia [62]. The review cautions that less is known about the effects of blood pressure lowering among those older than 80 years of age. (See "Overview of hypertension in adults", section on 'Treatment'.)

Although observational studies suggest that antihypertensive therapy is associated with a decreased risk of cognitive decline and dementia [65], randomized trials have yielded mixed results [63,66-75]. Some of this discrepancy may be explained by the length of follow-up in these trials (ranging from two to five years) and/or the type of antihypertensive therapy used. Also, some trials had significant loss to follow-up and/or had a number of patients allocated to placebo who were on active treatment [63].

A meta-analysis that included nine randomized trials and 55,325 participants with hypertension found that blood pressure lowering therapy did not reduce the risk of dementia (pooled odds ratio [OR] 0.95, p = 0.24; absolute risk 4.0 versus 4.2 percent) [76]. A subsequent randomized trial in 1439 patients with type 2 diabetes mellitus found no benefit of intensive blood pressure control (goal systolic blood pressure 120 mmHg) versus standard blood pressure control (goal 140 mmHg) on cognitive outcomes at 40 months [77]. In a subset of patients who underwent baseline and follow up brain MRIs, intensive control was associated with an increased decline in total brain volume compared with standard control, raising some concern about aggressive lowering at least in this subset of patients with increased cardiovascular risk.

Low quality data do not support an advantage of one antihypertensive agent over another, and some of the evidence is conflicting [72,78,79]. A network meta-analysis of randomized and observational studies in patients without prior cerebrovascular disorders found that angiotensin receptor blockers had greater positive effects on cognition than did other classes [65]. The effect size was small, however, and no benefit was seen with longer treatment duration (ie, greater than six months). In contrast, when trials of diuretics and/or calcium channel blockers (DIU/CCB) were considered separately from ace inhibitors and angiotensin receptor blocking drugs (ACE/ARB) in a 2011 meta-analysis, there was a small but statistically significant reduction in dementia risk for DIU/CCB versus placebo (OR 0.88, p = 0.02; absolute risk difference 0.4 percent) but not ACE/ARB (OR 1.01) [76].

INTERVENTIONS WITH UNPROVEN BENEFIT

Dietary modifications — While many aspects of a healthy diet have been observed to correlate with positive health outcomes, including cognitive health and freedom from dementia, the evidence is insufficient to conclude that specific diets or dietary supplements reduce the risk of dementia [1,2,60,80]. Omega-3 fatty acids (via fish consumption or dietary supplementation) and a Mediterranean style diet are among the most studied.

Omega-3 fatty acids — Fish oil consumption through dietary intake of fish or omega-3 fatty acid supplementation influences several cardiovascular risk factors. This is discussed separately. (See "Fish oil: Physiologic effects and administration".)

The potential benefits of fish oil consumption on the risk of dementia have also been studied fairly extensively in observational studies, but the findings have been mixed [81,82]. Many longitudinal cohort studies have shown an association between higher fish oil consumption and reduced risk of dementia, cognitive decline, and/or accumulation of white matter abnormalities on brain MRI [83-88], with some exceptions [89,90]. Other studies have suggested that the benefit may vary according to apolipoprotein E (APOE) genotype, with epsilon 4 carriers deriving more benefit from fish consumption than non-carriers [91-93].

However, randomized trials to date have not shown a benefit to cognitive function and have lacked power and duration to test whether consumption reduces incident dementia. A meta-analysis of three trials that studied the impact of omega-3 supplementation on cognitive performance found no effect of treatment after 6 to 40 months of supplementation [94]. Subsequent to this review, other trials have also found no benefit [46,95], including a trial in 4203 older adults at risk for macular degeneration that found no effect of fish oil supplementation and/or lutein on composite cognitive function scores over a five-year period [95].

Mediterranean diet — There is no single Mediterranean diet, but such diets are typically high in fruits, vegetables, whole grains, beans, nuts, and seeds and include olive oil as an important source of fat. There are typically low to moderate amounts of fish, poultry, and dairy products, and there is little red meat. (See "Healthy diet in adults".)

Observational studies using dietary questionnaires to assess and quantify adherence to the diet in different population cohorts have found that patients who were most adherent to the diet had a lower incidence of mild cognitive impairment and AD and slower rates of cognitive decline compared with those who did not follow this diet [9,96-101].

Similar benefits have been reported for those who are adherent to a modified Mediterranean diet that places particular emphasis on natural plant-based foods, berries, and leafy green vegetables [102]. These studies are subject to the same limitations discussed above regarding confounding from economic and educational factors. In addition, the use of questionnaires to assess diet may be problematic given that individuals at risk for AD may have baseline mild cognitive impairment.

Nonetheless, multiple cohort studies and one large randomized trial (PREDIMED) have suggested that adherence to a Mediterranean diet improves cardiovascular outcomes, including stroke, and these effects may directly or indirectly promote lower dementia risk [103,104]. In addition, a post-hoc subset analysis of the PREDIMED trial found that cognitive test scores were improved in patients assigned to the Mediterranean diet compared with controls among those who completed both baseline and end-of-study testing [105]. (See "Healthy diet in adults" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.)

Further support for a beneficial effect of the Mediterranean diet on the course of AD comes from a community-based study of 192 patients with AD [106]. Incremental reductions in AD-related mortality were noted in higher diet adherence groups suggesting a possible dose-response effect.

Alcohol — While there is some evidence that light to moderate alcohol use may be protective, this is largely based on observational studies and the findings have been inconsistent. These data are presented in detail separately. (See "Overview of the risks and benefits of alcohol consumption", section on 'Dementia'.)

Vitamin supplementation

Antioxidant vitamins — Preclinical and autopsy studies suggest that oxidative stress may be important in the pathogenesis of Alzheimer disease (AD) and other forms of dementia, and some observational studies have found an association between higher dietary intake of antioxidants and lower risk of AD, independent of measured confounders [107-116]. These findings led to interest in assessing the role of supplemental antioxidants (eg, vitamin E, beta-carotene, flavonoids, vitamin C) for the prevention of AD.

Randomized trials to date have failed to confirm a benefit, however. In multiple large randomized clinical trials in older individuals with normal cognition or mild cognitive impairment, supplementation with a variety of antioxidant vitamins, including vitamin E, vitamin C, beta-carotene, and selenium, has shown no impact on cognitive change or incident dementia over follow-up times that have ranged from 7 to 10 years [117-121].

Supplementation with beta-carotene was studied in a subset of 4052 patients enrolled in the Physicians' Health Study who agreed to re-enroll in a follow-up study [122]. While the investigators reported a benefit in cognitive scores for individuals receiving long-term supplementation (18 years) compared with those on placebo, methodological issues with this study cast doubt on the validity of these findings [123].

Since there are potential risks of vitamin E supplementation, we do not recommend supplementation with vitamin E or other antioxidants for the prevention of AD or other types of dementia. (See "Vitamin intake and disease prevention".)

Data from randomized trials suggest that the antioxidant vitamin E may be beneficial in slowing the progression of disease in patients with established AD [124,125]. These data and the role of vitamin E in patients with dementia are reviewed separately. (See "Treatment of Alzheimer disease", section on 'Antioxidants'.)

Vitamins B6, B12, and folate — While there is some evidence that elevated serum homocysteine and/or low serum levels of folate, vitamin B6, and vitamin B12 may be associated with impaired cognition and risk of dementia, there is no convincing evidence from clinical trials that vitamin supplementation prevents dementia. (See "Risk factors for cognitive decline and dementia", section on 'Homocysteine'.)

This was illustrated by a meta-analysis of 11 randomized trials including 22,000 participants [126]. Four trials in 1340 individuals assessed the impact of B vitamin treatment on specific cognitive domains over a mean of 2.3 years, and seven trials in over 20,000 individuals measured global cognitive function scores (typically by Mini-Mental State Examination [MMSE]) over a mean of five years. Although B vitamin treatment lowered homocysteine concentrations by 26 to 28 percent, allocation to B vitamins versus placebo had no impact on cognitive domain scores (z score difference: 0.0, 95% CI -0.05-0.06) or MMSE-type scores (z score difference: -0.01, 95% CI -0.03-0.02) from baseline to the end of treatment.

Vitamin D — There is some evidence that vitamin D deficiency is associated with cognitive impairment in older adults [127]. The effect appears to be small and of uncertain clinical significance. (See "Risk factors for cognitive decline and dementia".)

Whether vitamin D supplementation in healthy adults or those with vitamin D deficiency reduces risk of cognitive decline or dementia is not clear, and there is low quality evidence that it is not beneficial for these outcomes [1,2]. Pending the results of a controlled intervention study, there is no compelling reason to prescribe vitamin D supplementation for the purpose of preventing cognitive decline or dementia.

Multivitamins — Randomized trials of both short-term and long-term multivitamin supplementation have shown no benefit in the prevention of cognitive decline in healthy adults [128,129].

Others — In the Nurses’ Health Study, dietary intake of berries high in flavonoids (eg, blueberries, strawberries) was associated with slower rates of cognitive decline [130]. Flavonoids are believed to have antioxidant and anti-inflammatory actions that may contribute to a protective effect.

Isoflavone-rich soy protein supplementation did not improve cognitive outcomes after 2.5 years in a randomized trial in 350 healthy postmenopausal women [131].

Statins — There has been some interest in, but no established role for, the use of HMG CoA reductase inhibitors (statins) in the prevention of dementia [132]. Statins also have no currently defined role in the treatment of dementia or AD. (See "Treatment of Alzheimer disease".)

In several large retrospective studies, statin use has been associated with a reduced risk of dementia, with relative risk reductions ranging from 15 to 40 percent [133-138]. In one study, the benefit was similar in lipophilic and hydrophilic statins and was not observed in patients taking non-statin cholesterol lowering drugs [136]. In another study, the association varied by gender and specific drug and was not present in black American males [138].

A preventive effect of statins has been hypothesized based upon one or more of the following mechanisms:

●A direct association between amyloid processing and cholesterol in the brain [139-141]. In preclinical models, statins reduce amyloid burden by promoting the nonamyloidogenic alpha-secretase pathway of amyloid precursor protein metabolism and decreasing inflammation [142-145].

●An indirect effect via decreasing the risk of stroke, since even small cerebral infarcts worsen the severity of AD [146]. (See "Overview of secondary prevention of ischemic stroke".)

On the other hand, the observed association could be confounded by indication bias; physicians might be less likely to prescribe a statin to a patient with early, as yet undiagnosed, AD, or to discontinue its use in a patient with more severe dementia. It is also possible that statin use is a marker of more general health-promoting behaviors that reduce dementia risk, rather than an independent factor.

Prospective observational studies using variable methods, patient populations, and outcome measures have yielded somewhat mixed results regarding the efficacy of current or past statin use in reducing the incidence of dementia, the degree of age-related cognitive decline, or the neuropathologic burden of Alzheimer pathology [147-156]. In some studies, but not in others, the observed efficacy was linked to lipid-lowering [149,151].

Data from two large randomized controlled clinical trials of more than 25,000 patients with cardiovascular disease did not show any protective effect of statins for cognition [132,157,158], but these studies were not designed to identify dementia or AD, and treatment was started relatively late in life, possibly after the pathogenic process was already in progress. Randomized controlled clinical trials with incident dementia or cognitive decline as a primary endpoint are needed to determine the effect of statins on the risk of dementia [159].

In contrast to the above observations suggesting that statins may have a role in the prevention of dementia, other studies have suggested that statins may cause cognitive dysfunction in selected patients. (See "Statins: Actions, side effects, and administration", section on 'Behavioral and cognitive'.)

INEFFECTIVE THERAPIES

Cholinesterase inhibitors — Low quality evidence suggests that cholinesterase inhibitors, which have modest symptomatic benefits in some patients with established dementia, do not delay the development of dementia in patients with mild cognitive impairment, and these drugs are not recommended for this purpose. This topic is discussed separately. (See "Mild cognitive impairment: Prognosis and treatment", section on 'Acetylcholinesterase inhibitors'.)

Hormone therapy — Hormone therapy is not recommended for the prevention of dementia [1,2]. Although epidemiologic studies suggested that estrogen replacement might prevent dementia [160-163], data from the Women's Health Initiative (WHI) and the WHI Memory Study (WHIMS) do not support these observations, and suggest that estrogen replacement does not protect against dementia and may increase the risk [164-167]. This topic is discussed separately. (See "Estrogen and cognitive function".)

The hormone dehydroepiandrosterone (DHEA) is produced by the adrenal gland; peak production and serum concentrations occur in young adulthood and decline progressively thereafter. DHEA has been proposed to have many potential benefits in retarding diseases associated with aging, including cognitive impairment and dementia. A systematic review of three small clinical trials of DHEA concluded that the data did not support a benefit for DHEA on cognitive function [168].

NSAID therapy — There is moderate quality evidence that nonsteroidal antiinflammatory drugs (NSAIDs) do not prevent dementia, and given potential harms, they should not be used for the treatment or prevention of dementia or cognitive impairment.

A large randomized trial studied the efficacy of naproxen, celecoxib, and placebo in the prevention of AD in 2528 individuals >70 years with a history of at least one family member with AD-like dementia [169]. Imperfect screening had led to the enrollment of 53 persons with premorbid dementia or mild cognitive impairment. Analysis of the study population with these individuals excluded, after two years of follow-up, demonstrated that AD risk was actually increased in both active treatment groups (HR = 4.1, 3.6). Other measures of cognition were not improved and were possibly worse in the treated groups [170]. The trial was stopped early because of an increased risk of myocardial infarction in patients treated with naproxen [169]. Long-term use of certain COX-2 inhibitor inhibitors has also been associated with an increased risk of cardiovascular events. (See "NSAIDs: Adverse cardiovascular effects".)

Another large, randomized study of 6377 participants found that older women randomly assigned to low dose aspirin had similar rates of cognitive decline compared to the placebo-treated group after more than 5 years of follow-up [171]. Similarly, a 5-year study of low dose aspirin in 3350 individuals over 50 years found no effective of treatment on cognitive test scores [172].

Ginkgo biloba — A multi-center, randomized, double-blind placebo-controlled study of Ginkgo biloba in 3069 older adults (75 years or older) found that after a median six years of follow-up, treatment was not effective in reducing the incidence of AD or all-cause dementia and did not slow cognitive decline in individuals with either normal cognition or mild cognitive impairment at baseline [173,174]. Similarly, in another clinical trial of 2854 patients aged 70 years and older with memory complaints, treatment with gingko biloba was not associated with a reduced incidence of dementia after five years of treatment [175]. (See "Clinical use of ginkgo biloba".)

CLINICAL TRIALS — Several large clinical trials are ongoing or in development for individuals at risk for Alzheimer disease (AD) and other dementias. Preventive pharmacologic strategies range from anti-amyloid antibodies to immunotherapy. As an example, the A4 Study aims to test whether solanezumab, an anti-amyloid antibody, delays time to cognitive decline in older adults who have evidence of brain amyloid by positron emission tomography (PET) but do not yet show symptoms of AD cognitive impairment or dementia [176]. Additional information and instructions for referring an individual to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●We encourage all patients, especially those with early dementia and those with risk factors for dementia, to maintain or increase physical activity and exercise as long as there are no contraindications. Similarly, we encourage cognitive leisure activities and social interaction for as long as these are feasible. However, we recognize that these lifestyle factors remain unproven as a means of preventing dementia. (See 'Lifestyle and activity' above.)

●Epidemiologic studies offer optimism that multimodality risk factor reduction in midlife is worthwhile, not just for cardiovascular outcomes but also for cognitive health. Hypertension is associated with an increased risk of both vascular dementia and Alzheimer disease (AD), and treatment of hypertension is recommended to reduce the risk of cerebrovascular disease, among other benefits. (See 'Vascular risk factor modification' above.)

●Mediterranean-style diets that are high in fruits, vegetables, whole grains, beans, nuts, and seeds and include olive oil as an important source of fat have been associated with a variety of health benefits, including reduced cardiovascular risk, which may directly or indirectly reduce dementia risk. High-quality evidence of a preventive effect of dietary interventions on cognitive impairment and dementia remains lacking, however. (See 'Dietary modifications' above.)

●Prospective studies and randomized controlled trials have not shown an overall benefit from vitamins, statins, cholinesterase inhibitors, estrogen replacement, or nonsteroidal antiinflammatory drugs (NSAIDs) for the prevention of dementia. (See 'Vitamin supplementation' above and 'Statins' above and 'Ineffective therapies' above.)

●While vitamin E is not recommended in healthy adults for the purposes of preventing dementia, it may have a modest benefit in slowing disease progression in patients with established mild to moderate Alzheimer disease. (See "Treatment of Alzheimer disease", section on 'Antioxidants'.)