Prevention of Alzheimer’s Disease: Lessons Learned and Applied

 2017 Aug 2. doi: 10.1111/jgs.14997. [Epub ahead of print]

Prevention of Alzheimer’s Disease: Lessons Learned and Applied.

Galvin JE


Alzheimer’s disease (AD) affects more than 5 million Americans, with substantial consequences for individuals with AD, families, and society in terms of morbidity, mortality, and healthcare costs. With disease-modifying treatment trials unsuccessful at the present time and only medications to treat symptoms available, an emerging approach is prevention.

Advances in diagnostic criteria, biomarker development, and greater understanding of the biophysiological basis of AD make these initiatives feasible. Ongoing pharmacological trials using anti-amyloid therapies are underway in sporadic and genetic forms of AD, although a large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau.

This suggests that prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits. Rather than relying solely on large-sample, long-duration, randomized clinical trial designs, a precision medicine approach using N-of-1 trials may provide more-rapid information on whether personalized prevention plans can improve person-centered outcomes.

Because there appear to be multiple pathways to developing AD, there may also be multiple ways to prevent or delay the onset of AD. Even if these precision approaches alone are not successful in preventing AD, they may greatly improve the likelihood of amyloid- or tau-specific therapies to reach their endpoints by reducing comorbidities. Keeping this in mind, dementia may be a disorder that develops over a lifetime, with individualized ways to build a better brain as we age.

Alzheimer’s disease (AD) affects more than 5 million Americans, with substantial costs to individuals with AD, families, and society.[1] Projections by the Alzheimer Association are that, if nothing is done, by 2050, there will be more than 16 million people with AD in the United States and more than 60 million worldwide. Over the past 25 years, only five symptomatic medications have met their primary clinical trial endpoints in Phase III clinical trials and successfully come to market; of these, four are still available. Since 2003, every symptom- and disease-modifying agent has failed in Phase II or III trials because of challenges with safety or efficacy. This led to a bold initiative put forth in the National Alzheimer Plan Act to develop a disease-modifying treatment (DMT) by 2025.[2]

Two important concepts are associated with success to reach this target date. First, only medications that have already entered Phase II testing can make it to market by 2025.[2] Second, if a DMT were available by 2025, then the 2050 projection of 16 million Americans with AD would be reduced by 5.7 million cases, with societal savings of $367 billion.[1] To complement efforts to develop a DMT for individuals with symptomatic AD, a concerted effort is underway to initiate preventive measures in asymptomatic individuals. Such efforts are also consistent with the 2025 target goal.An important question, is whether AD can be prevented. A large number of modifiable (e.g., exposures, lifestyle and social habits) and nonmodifiable (e.g., age, sex, genetics) risk factors have been identified (Table 1).

Recent revisions to the clinical criteria for AD[3] and mild cognitive impairment (MCI)[4] helped clarify the role of biomarkers in defining the pathological cascade, and the addition of research criteria for presymptomatic disease[5] sets the stage for better modeling of the preclinical and prodromal stages of disease.[6] Efforts developing and validating fluid (blood and cerebrospinal fluid) and imaging biomarkers make it possible to explore underlying pathological changes in amyloid, tau, dopamine transport, inflammation, signaling pathways, and in the future, alpha-synuclein and TDP-43 in symptomatic, prodromal, and presymptomatic individuals. Advances in genetic, epigenetic, and “omic” (e.g., proteomic, lipidomic, metabolomic) approaches will permit the modeling of transcriptional, translational, and posttranslational changes. Furthermore, precision medicine approaches with demonstrable benefits in oncology are being applied to neurodegenerative disorders. Thus, the platform is in place to begin prevention initiatives.

Table 1. Alzheimer’s Disease Risk and Protective Factors
  1. Apolipoprotein E is the major risk gene; a number of other minor risk genes have been identified.
Risk Factors (Nonmodifiable)
Family history
Apolipoprotein E ε4 allele*
Risk Factors (Modifiable)
Diabetes mellitus and insulin resistance
Metabolic syndrome
Cerebrovascular disease
Psychological and physiological stress
Traumatic brain injury
Sleep disordered breathing
Alcohol abuse
Protective Factors (Modifiable)
Cognitive reserve and mental activity
Educational attainment and lifelong learning
Cognitive leisure activities
Physical activity and exercise
Social engagement
Mindfulness and wellness activities
Optimism and purpose in life
Omega-3 intake


These efforts have a great potential for pharmaceutical and nonpharmacological approaches, with earlier identification of at-risk individuals, expanding opportunities for faster and earlier diagnoses, better stratification of at-risk individuals, higher enrollment into randomized clinical trials (RCTs) by reducing screen failure rates, and eventually more-effective treatments. Although the focus of this article is on AD, the principles discussed are relevant to related neurodegenerative disorders (e.g., Parkinson’s disease, Lewy body dementia, vascular dementia). Assuming that curing AD remains a substantial unsolved challenge, preventing or simply delaying the onset of dementia could significantly change the face of disease.

Pharmacological Approaches to Prevention

A number of prevention studies are ongoing in sporadic and autosomal-dominant forms of AD. Results are still pending, but a review of[7] provides important details about these studies. One such study is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study, which is recruiting individuals aged 65 to 86 with normal cognitive function but positive AD biomarkers (amyloid deposition according to positron emission tomography). These individuals are followed for 3 years of treatment with an anti-amyloid monoclonal antibody.

The Alzheimer Prevention Initiative will study individuals aged 60 to 75 with normal cognition who have two copies of the apolipoprotein E e4 allele, putting them at high risk of AD. These individuals are followed for 2 years of treatment with a different anti-amyloid monoclonal antibody. The TOMMORROW Study will enroll individuals aged 65 to 83 with normal cognition who have a polymorphism of the TOMM40 gene that is associated with greater risk of AD. Individuals are followed for 5 years of treatment with pioglitazone, an anti-diabetes drug. In parallel to these trials in sporadic cases with enhanced risk, trials are ongoing in individuals with autosomal-dominant forms of AD, including the Alzheimer Prevention Initiative and Dominantly Inherited Alzheimer Network—Treatment Unit using monoclonal antibodies. A particular advantage of the trials in familial AD is that age of onset is predictable so that, if a DMT effect exists, it is more likely to be detected. A potential disadvantage of these trials is that the results may not be generalizable to the much more common sporadic forms in which risk factors other than genetics may predominate.

Similar to prevention trials, there are number of prodromal studies with a major focus on individuals with MCI. Results are pending for many of these trials, but at least one Phase II study had promising results. Aducanumab immunotherapy[8] against the amyloid protein not only demonstrated changes in cerebrospinal fluid amyloid over 54 weeks in a dose-dependent manner, but also demonstrated significant changes in cognitive and functional measures. These findings support the concept that there may be a critical window for these agents to be administered to increase the likelihood of success.

Lifestyle Modification Interventions

Modifiable Lifestyle Factors

A number of modifiable risk and preventive factors for AD have been described in observational studies (Table 1). Risk factors that have been found in several studies include diabetes mellitus, hypertension, renal dysfunction, alcohol and smoking patterns, high cholesterol, coronary heart disease, depression, sedentary life style, low cognitive activity, and diet. These factors combined account for more than half of the attributable risk for AD.[9] The most difficult of these factors to address is diet because it is highly dependent on income and access to fresh foods.[10] In a 16-year observational study of 949 individuals using the Lifestyle for Brain Health (LIBRA) measure of modifiable risk factors, a 1-point increase in LIBRA score was associated with a 19% greater risk of dementia.[11]

In a meta-analyses of 19 studies, cognitive leisure activities,[12] including crossword puzzles, card games, computer use, arts and crafts, life-long learning, group discussions, and music, had a protective effect (odds ratio (OR) = 0.58). In addition, physical activities may lead to a 20% to 65% risk reduction depending on the type and intensity of activity through mechanisms involving lower vascular disease risk, better respiratory function, stimulation of trophic factors, and lower oxidative stress and inflammation.[13] Objective measurement of midlife vascular risk factors demonstrated greater risk of dementia in late life.[14] In a study of 2,000 individuals aged 71 to 78, work-related stress increased the risk of MCI (OR = 1.38), dementia (OR = 1.53), and AD (OR = 1.55).[15]

Despite the differences between countries of origin, culture, language, educational attainment, and ages studied, the aforementioned studies and many others are convergent for a short list of risk factors that seem to play a critical role in the development or prevention of AD and related disorders. This consistency has led to the implementation of a number of dementia prevention initiatives to modify these risk factors, most of which cannot be directly linked to amyloid or tau deposition.

Ongoing Prevention Initiatives

The European Prevention of AD[16] initiative is recruiting participants to examine whether alteration of risk factors for AD that occur in early and mid-life potentiate pathophysiological changes decades before dementia onset. The Innovative Midlife Intervention for Dementia Deterrence trial[9] is examining 11 identified risk factors (e.g., diabetes, hypertension, renal) that account for half of the attributable risk and has enrolled 600 individuals to participate in an on-line education intervention. The largest initiative to date is the FINGER study,[17] enrolling 1,260 individuals in an educational intervention that includes modules in diet, exercise, cognitive training, and vascular risk reduction. Overall between-group differences were statistically significant for global cognition, executive function, and processing speed but not episodic memory.[17] These results suggest that lifestyle modification may offer some benefit in cognitive function, albeit with a small effect size.

Precision Medicine Approaches to Prevention

Although age is the single greatest risk factor for AD, AD is not inevitable. The best estimates suggest that, at age 85, there is 42% risk of developing AD,[1] which means that 58% of older adults do not develop dementia, even if amyloid can be detected in the brain. The reasons are unknown, but may be explained in part by a host of modifiable and nonmodifiable risk factors (Table 1). Up to 30% of AD cases may be preventable through modification of risk factors and behavioral changes to mitigate the effect of those risk factors that are not modifiable.[18]

There is an ongoing debate as to whether the current evidence base is sufficient to initiate prevention programs because it is difficult to prove causation from observational studies, and it is difficult to pool multiple RCTs because of differences in study design, measurements used, and anticipated outcomes.[18] Although a well-balanced, healthy lifestyle may be the cornerstone of disease prevention and brain health, each risk factor (vascular, lifestyle choices, psychosocial) may both act independently and potentiate the effects of each other.[19, 20] Therefore, a prevention initiative needs to be multimodal and tailored to address individual risks.

These requirements lead to a number of design and analytical challenges. Many prevention RCTs use time-to-event analytical strategies to demonstrate a DMT effect. Such designs are optimal when anticipated treatment effects remain constant over time, but in the case of dementia prevention, this is unknown. Thus, time-to-event analyses such hazard ratios may not be the best way to model effects, particularly if the detectable signal is a late effect of the intervention.[21] Because AD is heterogeneous in terms of risk factors, age of onset, presentation, progression, and pathology burden, designing a study to treat individuals as a homogenous population requires large sample sizes (thousands to tens of thousands) to be followed for long periods of time (years to decades).[22]

This results in large study costs, staff burden, and participant burden. In the absence of robust biomarkers that mark disease onset and progression, rather than just the presence of pathology, RCT design will remain a challenge.[23] Barriers to prevention studies include limited understanding of the real relationship between dementia risk factors and the effect of risk reduction; complexity of the effect of life course on dementia risk factors; lack of standardization of study design, definitions, and outcomes; difficulty translating RCT findings into real-world practice; cultural and social barriers to implementation; lack of research capacity to enroll large research cohorts for long periods of time; and pervasive social stigma associated with AD.[18]

Because effective prevention strategies are elusive despite significant advances in understanding of the biology and pathophysiology of AD, an alternative approach would be to take advantage of precision medicine designs used in oncology trials to tailor interventions to an individual’s phenotypic and genotypic expression. With better classification and phenotyping of individuals with AD, trial-ready cohorts can be targeted more appropriately with interventions (pharmacological and nonpharmacological) designed to ameliorate specific pathological mechanisms, based on specific biomarkers and individual characteristics.[23] Future trials could then be created to determine efficacy and safety (fast to fail) more quickly by moving away from one-size-fits-all approaches to person-specific precision treatments.

This would also require rethinking trial design for prevention measures, moving to more N-of-1 designs. N-of-1 trials consider the individual as the sole unit of observation to study the efficacy and adverse effects of an intervention[22] and are guided by objective data-driven criteria while leveraging the study designs and statistical techniques common to RCTs.[22] Because risk and molecular profiles of AD vary widely by person, grouping individuals into single entities (placebo vs treatment arm) may mix “super-responders” with “nonresponders,” washing out treatment effects that only become apparent in post hoc analyses.[24] Instead, comparing time-to-disease progression of an individual using a novel therapeutic approach to the time-to-disease progression for that same individuals for the immediately preceding treatment paradigm may be preferable.[25] N-of-1 trials may be less bound by threats to generalizability of large RCTs due to recruitment delays and challenges to translate significant p-values in large treatment groups to the care of an individual, which is the ultimate goal of clinical practice. In a metaanalyses of 70 N-of-1 trials, 50 of 57 completed trials provided definitive clinical or statistical answers, with 39% prompting physicians to change the plan of care.[26]

Another meta-analysis examined 108 trials involving 2,154 participants and found that 54% of participants had subsequent treatment decisions changed based on the results.[27] To create the platform for such trials, several conditions must be met (Table 2). Participants must be deeply phenotyped with characterization of sociodemographic, psychological, clinical, cognitive, functional, biomarker, and genetic traits. Ideally, these individuals would agree to be followed longitudinally, have samples banked for future analyses, and consent to autopsy to provide confirmation of diagnosis and treatment effects on brain pathology. Statistical considerations may take advantage of alternative time-series analyses and within- and between-subject comparisons. Lastly, an important concern is the cost of care when a high-cost intervention is planned—for example, off-label treatment with an expensive medication.[22]

Table 2. Basic Principles of a Dementia Prevention Program
Establish a longitudinal cohort of individuals without memory impairment and with prodromal disease
Develop a protocol that can measure person-centered and health-economic outcomes
Evaluate clinical, cognitive, functional, and behavioral features annually
Collect and bank biomarkers: blood, spinal fluid, deoxyribonucleic acid, cell lines, magnetic resonance imaging, positron emission tomography
Encourage autopsy participation
Perform deep phenotyping of individuals with near total participation in all biomarker collection protocols by all participants
Apply precision medicine–type interventions to match treatment to individual characteristics
Test customized N-of-1 interventions over a designated period to determine whether protocols alter biophysiological profiles, disease-relevant biomarkers, and outcome measures
Develop a statistical plan to incorporate immediate, intermediate, and long-term time-to-event analyses
Create a trial-ready cohort for large-scale pharmacological and nonpharmacological interventions


Example of a Personalized Medicine Approach to Dementia Prevention

As an example of how this may applied in a pragmatic sense, N-of-1 trials are being developed to personalize dementia prevention using an evidence-base derived from an extensive literature review and results of a National Institutes of Health–funded project to conduct dementia screening in multicultural communities (R01 AG0402–11-A1, study design reviewed[28, 29]). In addition to screening for cognitive impairment, broader medical screening for diabetes mellitus, hypertension, vascular risk factors, obesity, mobility, physical performance, frailty, and depression was incorporated into a “healthy body, healthy mind” approach to make the concept of dementia screening more acceptable and to understand the effect of comorbid disease on cognitive performance.

This cross-sectional study confirmed many findings of observational studies regarding the association between cognitive performance and diabetes mellitus, hypertension, obesity, vascular risk factors, and depression while providing novel findings linking cognitive performance to sarcopenia[28] and mobility.[29] These collective findings were prospectively applied to develop N-of-1 trials.

For example, a 68-year-old college-educated woman (although an actual case, some features were altered to preserve anonymity) presented with a 1-year history of subjective memory complaints (misplacing car keys, forgetting conversations, defensiveness about memory issues) but with independent functioning in everyday activities. Her relevant past history was significant for hypertension and hypercholesterolemia.

Physical examination findings included mild hypertension (blood pressure 132/92 mmHg) but normal cardiac and peripheral vascular examinations. Pertinent neurological findings included mild symmetric weakness, poor vibration sensation in the lower extremities, and mild postural instability. Cognitive testing revealed global deficits (Montreal Cognitive Assessment score 19/30), working memory and executive dysfunction, and episodic memory deficits on list learning that disappeared with cued recognition. Physical and functional testing revealed low lean muscle mass, at-risk nutritional status, modest daily physical activity, mild deficits in physical functionality (Short Physical Performance Battery score 7/12), and mild frailty (Fried Frailty Phenotype Score 3/5). Gait and balance testing revealed slowed gait speed (1.07 m/s), marked slowing (22.9%) with a dual-task challenge (walking while talking), and postural sway with eyes closed.

Blood-based biomarkers revealed an abnormal lipid profile (high total, low-density lipoprotein (LDL), and non–high-density lipoprotein (HDL) cholesterol; high LDL and small LDL particles; and low HDL particles), high inflammatory markers (high-sensitivity C-reactive protein and myeloperoxidase), apolipoprotein (Apo)E 3/4 genotype, and evidence of insulin resistance (high fasting glucose, glycosylated hemoglobin, and estimated average glucose).

Quantitative magnetic resonance imaging (MRI) revealed normal hippocampal size and lateral ventricle volume but confluent white matter hyperintensities with frontal lobe predominance. Auditory event–related potentials demonstrated slow median reaction times and low amplitude at the N200 peak (linked to impaired attention and executive function) and left–right asymmetry with frontal predominance (linked to vascular injury) but normal amplitudes and latencies at all other peaks, including the P50 peak associated with amyloid deposition.[30]

This deep phenotypic evaluation provided findings in cognitive testing (executive and working memory deficits with cued episodic memory improvements supporting intact hippocampal circuitry), physical testing (sarcopenia, at-risk nutritional status, poor physical functionality, and early frailty), gait testing (slowed gait speed, impaired dual tasks, postural instability with eyes closed), biomarker testing (lipid profile, inflammation, insulin resistance, ApoE4 genotype suggesting poor response to statins), MRI (preservation of hippocampal and cortical volume, extensive white matter disease), and electroencephalography (executive dysfunction and evidence of vascular injury) that could be treated and supported a diagnosis of vascular cognitive impairment.

A personalized treatment plan was then developed focusing on dietary counseling (Mediterranean-DASH Intervention for Neurodegenerative Delay diet, high-protein snacks, glycemic control); physical therapy for gait, balance, strengthening, and conditioning; referral to a personal trainer for aerobic, resistance, and flexibility training; mindfulness (yoga, meditation) for stress reduction; cognitive exercise focusing on problem-solving skills; omega-3 supplementation and possible resin therapy for cholesterol lowering; better blood pressure monitoring; and initiation of low-dose aspirin to improve blood flow. Longitudinal follow-up is needed to monitor adherence to recommendations and for evidence of improvement in outcomes. Such a trial could provide a direct estimate of individual treatment effects, fine-tune personalized care plans, enhance precision of future treatment decisions, improve person-centered outcomes, and if successful, reduce long-term healthcare costs.[25]


There is increasing evidence that multiple medical conditions increase the risk of neurodegeneration and subsequent development of dementia (Figure 1). It is also becoming clear that the majority of these risk factors act in amyloid- and tau-independent ways. Trials testing the amyloid hypothesis (β- and γ-secretase inhibitors, antiaggregation medications, mono- and polyclonal antibody approaches), antiinflammatory agents, and early-phase anti-tau therapies have failed to meet outcomes or have been discontinued because of safety concerns. While we wait for successful pharmacotherapy, these multiple pathways leading to AD can be taken advantage of to test hypotheses regarding risk reduction and mitigation.

In all likelihood, efforts to prevent cognitive decline and development of dementia may be more successful when they are multimodal and directed to at-risk individuals based on their personal health profile, rather than using “one-size-fits-all” approaches. The detection of and interventions addressing root causes may offer novel approaches to diagnosing, treating, curing, or preventing AD. AD offers a large array of potentially modifiable risk factors (lifestyle, exposure, environment, comorbid disease) that are excellent targets to personalize the approach to medical care.

Precision medicine approaches specifically target the heterogeneity of AD by identifying person-specific risk factors and applying a customized intervention directed against this risk profile. Even if these precision approaches do not cure or prevent AD, removing other pathways to neurodegeneration may greatly improve the likelihood that amyloid- or tau-specific therapies reach their endpoints. Perhaps it is time to abandon generalized approaches to AD and consider neurodegenerative disorders as diseases of a lifetime and that there may be individualized ways to build a better brain as we age.

Figure 1 Model of a dementia-prevention initiative.

(A) Hypothetical model of the development of clinical dementia. Before diagnosis, there would be evidence of cognitive decline, which reflects neurodegenerative changes including cellular dysfunction and loss, synaptic dysfunction, and loss of connectivity. Presumably, accumulation of one or more pathologies cause these downstream changes. If more than one pathology is present, each should have its own risk factor or factors (e.g., Risk Factor A causes Pathology A, Risk Factor B causes Pathology B). (B) Application of model in N-of-1 trial (described in detail in text). Six risk factors were identified during the clinical evaluation, presumably working through different pathways, with the end result being neurodegeneration, cognitive decline, and if unchecked, eventually clinical dementia. A personalized prevention plan directed at root causes of impairment, if successful, would prevent the conversion of cognitive decline to dementia (marked by X). Because root causes may interact or potentiate each other’s effect on neurodegeneration (connecting arrows on the left side), multimodal approaches are more likely to have an effect than single approaches.


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Dietary and Lifestyle Guidelines for the Prevention of Alzheimer’s Disease

Neurobiol Aging. 2014 Sep;35 Suppl 2:S74-8. doi: 10.1016/j.neurobiolaging.2014.03.033. Epub 2014 May 14.

Dietary and lifestyle guidelines for the prevention of Alzheimer’s disease.

Barnard ND1, Bush AI2, Ceccarelli A3, Cooper J4, de Jager CA5, Erickson KI6, Fraser G7, Kesler S8, Levin SM9, Lucey B10, Morris MC11, Squitti R12.


Risk of developing Alzheimer’s disease is increased by older age, genetic factors, and several medical risk factors. Studies have also suggested that dietary and lifestyle factors may influence risk, raising the possibility that preventive strategies may be effective. This body of research is incomplete. However, because the most scientifically supported lifestyle factors for Alzheimer’s disease are known factors for cardiovascular diseases and diabetes, it is reasonable to provide preliminary guidance to help individuals who wish to reduce their risk. At the International Conference on Nutrition and the Brain, Washington, DC, July 19-20, 2013, speakers were asked to comment on possible guidelines for Alzheimer’s disease prevention, with an aim of developing a set of practical, albeit preliminary, steps to be recommended to members of the public. From this discussion, 7 guidelines emerged related to healthful diet and exercise habits.


Alzheimer’s disease affected an estimated 4.7 million Americans in 2010, and its prevalence is expected to nearly triple in coming decades (Hebert et al., 2013). Several factors contribute to the risk of developing late-onset Alzheimer’s disease, including older age, genetic factors (especially the presence of the APOEε4 allele), family history, a history of head trauma, midlife hypertension, obesity, diabetes, and hypercholesterolemia (Bendlin et al., 2010).

In addition, recent prospective studies have shown that certain dietary and lifestyle factors, including saturated fat intake, vitamin E intake, and physical exercise, among others, are associated with Alzheimer’s risk, suggesting that prevention strategies may be applicable for these factors. In each of these areas, scientific evidence is less than complete. Nonetheless, individuals at risk for Alzheimer’s disease make decisions about dietary and lifestyle on a daily basis and need to act on the best evidence available to them, even when scientific consensus may not have been achieved.

In toxicology, the “precautionary principle” is invoked in situations in which there is a substantial basis for concern regarding the health consequences of an exposure and for which available data preclude a comprehensive evaluation of risk (European Commission, 2000). A similar approach can be applied to nutritional and other lifestyle-related exposures, particularly for conditions, such as cancer or Alzheimer’s disease, for which there may be a long latency period between exposure and disease manifestation and for which randomized controlled trials are impractical or are, for whatever reason, not rapidly forthcoming. Some have argued that the level of evidence required for making dietary recommendations for disease prevention may be different from that required for establishing the efficacy of medical treatments, such as pharmaceuticals (Blumberg et al., 2010).

At the International Conference on Nutrition and the Brain, Washington, DC, July 19–20, 2013, evidence regarding the influence of dietary factors, physical and mental exercise, and sleep on aspects of cognition was reviewed, and conference speakers were asked to comment on possible dietary and lifestyle guidelines for Alzheimer’s disease prevention, with an aim of developing a set of practical steps to be recommended to members of the public.


The following principles were applied to the development of guidelines:

  1. Guidelines were to be based on substantial, although not necessarily conclusive, evidence of benefit.
  2. Implementation of guidelines should present no reasonable risk of harm.
  3. The guidelines were to be considered to be subject to modification as scientific evidence evolves.


Seven guidelines emerged and are as follows:

  1. Minimize your intake of saturated fats and trans fats. Saturated fat is found primarily in dairy products, meats, and certain oils (coconut and palm oils). Trans fats are found in many snack pastries and fried foods and are listed on labels as “partially hydrogenated oils.”
  2. Vegetables, legumes (beans, peas, and lentils), fruits, and whole grains should replace meats and dairy products as primary staples of the diet.
  3. Vitamin E should come from foods, rather than supplements. Healthful food sources of vitamin E include seeds, nuts, green leafy vegetables, and whole grains. The recommended dietary allowance (RDA) for vitamin E is 15 mg per day.
  4. A reliable source of vitamin B12, such as fortified foods or a supplement providing at least the recommended daily allowance (2.4 μg per day for adults), should be part of your daily diet. Have your blood levels of vitamin B12 checked regularly as many factors, including age, may impair absorption.
  5. If using multiple vitamins, choose those without iron and copper and consume iron supplements only when directed by your physician.
  6. Although aluminum’s role in Alzheimer’s disease remains a matter of investigation, those who desire to minimize their exposure can avoid the use of cookware, antacids, baking powder, or other products that contain aluminum.
  7. Include aerobic exercise in your routine, equivalent to 40 minutes of brisk walking 3 times per week.


The rationale for each of these guidelines is briefly discussed as follows.

  1. Minimize your intake of saturated fats and trans fats.

As reviewed elsewhere in this supplement, several (although not all) prospective studies have indicated an association between intake of saturated or trans fats and incident Alzheimer’s disease (Barnard et al., 2014, Morris, 2014). Saturated fat is found especially in dairy products and meats; trans fats are found in many snack foods.

In the Chicago Health and Aging Project, individuals in the upper quintile of saturated fat intake had twice the risk of developing Alzheimer’s disease during a 4-year study period, compared with participants in the lowest quintile (Morris et al., 2003). In the Washington Heights-Inwood Columbia Aging Project in New York and the Cardiovascular Risk Factors, Aging, and Dementia study in Finland, Alzheimer’s disease risk was positively, but nonsignificantly, associated with saturated fat intake (Laitinen et al., 2006, Luchsinger et al., 2002). A number of well-controlled studies of cognitive decline have found that high saturated fat intake increases the rate of decline in cognitive abilities with age (Beydoun et al., 2007, Devore et al., 2009, Eskelinen et al., 2008, Heude et al., 2003, Morris et al., 2006b, Okereke et al., 2012).

Increased saturated fat intake is associated with risk of cardiovascular disease and type 2 diabetes (Mahendran et al., 2013, Mann, 2002), which, in turn, are associated with increased risk of Alzheimer’s disease (Ohara et al., 2011, Puglielli et al., 2003). A large study of Kaiser Permanente patients showed that participants with total plasma cholesterol levels ≥240 mg/dL in midlife had a 57% higher risk of Alzheimer’s disease 3 decades later, compared with participants with cholesterol levels <200 mg/dL (Solomon et al., 2009).

Additional evidence of mechanistic associations between saturated or trans fat intake and Alzheimer’s risk comes from the fact that the APOEε4 allele, which is strongly linked to Alzheimer’s risk, produces a protein that plays a key role in cholesterol transport (Puglielli et al., 2003) and from the observation that high-fat foods and/or the increases in blood cholesterol concentrations they may cause may contribute to beta-amyloid production or aggregation in brain tissues (Puglielli et al., 2001).

  1. Vegetables, legumes (beans, peas, and lentils), fruits, and whole grains should replace meats and dairy products as primary staples of the diet.

Vegetables, berries, and whole grains provide healthful micronutrients important to the brain and have little or no saturated fat or trans fats. In both the Chicago Health and Aging Project and the Nurses’ Health Study cohorts, high vegetable intakes were associated with reduced cognitive decline (Kang et al., 2005, Morris et al., 2006a). Legumes and fruits merit emphasis, not because of an association with reduced Alzheimer’s disease risk, but because, like grains and vegetables, they provide macronutrient nutrition that is essentially free of saturated and trans fats and are part of a dietary pattern associated with reduced risk of cardiovascular disease, weight problems, and type 2 diabetes (Fraser, 2009, Tonstad et al., 2009), which, in turn, have critical influences on brain health.

Many plant-based foods are rich in several B-vitamins. Folate and vitamin B6 are noteworthy in that, along with vitamin B12, they act as cofactors for the methylation of homocysteine; elevated homocysteine levels are associated with higher risk of cognitive impairment in some studies (Morris, 2012, Smith et al., 2010, Vogel et al., 2009). Nonetheless, the efficacy of B-vitamins is not yet settled; in an Oxford University study of older individuals with elevated homocysteine levels and mild cognitive impairment, supplementation with these 3 vitamins maintained memory performance and reduced the rate of brain atrophy (de Jager et al., 2012, Douaud et al., 2013, Smith et al., 2010).

Healthful sources of folate include leafy green vegetables, such as broccoli, kale, and spinach, beans, peas, citrus fruits, and cantaloupe. The RDA for folate acid in adults is 400 μg per day. Vitamin B6 is found in green vegetables in addition to beans, whole grains, bananas, nuts, and sweet potatoes. The RDA for adults up to age 50 is 1.3 mg per day. For adults >50 years older, the RDA is 1.5 mg for women and 1.7 mg for men.

  1. Vitamin E should come from foods, rather than supplements. Healthful food sources of vitamin E include seeds, nuts, green leafy vegetables, and whole grains. The RDA for vitamin E is 15 mg per day.

In the Chicago Health and Aging Project, higher intakes of vitamin E from food sources were associated with reduced Alzheimer’s disease incidence (Morris et al., 2005). Similarly, in the Rotterdam study, high vitamin E intake was associated reduced dementia incidence (Devore et al., 2010).

Vitamin E occurs naturally in the form of tocopherols and tocotrienols and is found in many foods, including mangoes, papayas, avocadoes, tomatoes, red bell peppers, and spinach, and particularly in high quantities in nuts, seeds, and oils. The RDA for adults is 15 mg. A small handful of typical nuts or seeds contains ∼5 mg of vitamin E.

Vitamin E from supplements has not been shown to reduce Alzheimer’s disease risk. Many common supplements provide only α-tocopherol, and most do not replicate the range of vitamin E forms found in foods. A high intake of α-tocopherol has been shown to reduce serum concentrations of γ- and δ-tocopherols (Huang and Appel, 2003).

  1. A Reliable source of vitamin B12, such as fortified foods or a supplement providing at least the recommended dietary allowance (2.4 μg per day for adults) should be part of your daily diet. Have your blood levels of vitamin B12 checked regularly as many factors, including age, may impair absorption.

Vitamin B12 is essential for the health of the brain and nervous system and for blood cell formation. The RDA for adults is 2.4 μg. It is found in supplements and fortified foods, such as some breakfast cereals or plant milks. Vitamin B12 is also found in meats and dairy products, although absorption from these sources is limited in many individuals, particularly those older than 50 years, those with reduced stomach acid production, those taking certain medications (e.g., metformin and acid blockers), and individuals who have had gastrointestinal surgery (e.g., bariatric surgery) or who have Crohn disease or celiac disease.

The US Government recommends that vitamin B12 from supplements or fortified foods be consumed by all individuals older than 50 years. Individuals on plant-based diets or with absorption problems should take vitamin B12 supplements regardless of age. However, dietary sources and even vitamin B12 supplements may not be sufficient to sustain adequate blood levels. Some individuals require vitamin B12 injections. Every middle-aged or older adult should have his or her vitamin B12 status checked on a regular basis.

  1. If using multiple vitamins, choose those without iron and copper and consume iron supplements only when directed by your physician.

Iron is essential for formation of hemoglobin and certain other proteins, and copper plays an essential role in enzyme functions among many other aspects of health. However, some studies have suggested that excessive iron and copper intake may contribute to cognitive problems for some individuals (Brewer, 2009, Squitti et al., 2014, Stankiewicz and Brass, 2009). In recent meta-analyses (Schrag et al., 2013, Squitti et al., 2013, Ventriglia et al., 2012), circulating non-protein-bound copper was associated Alzheimer’s disease risk.

Other aspects of the diet may play a modulating role in the relationship between metals and cognitive effects. In the Chicago Health and Aging Project, individuals with a high intake of saturated fat along with a high copper intake were found to have cognitive decline equivalent to 19 additional years of aging (Morris et al., 2006b).

Most common multivitamins contain both iron and copper, sometimes exceeding the RDA (Physicians Committee for Responsible Medicine, 2013). However, most individuals in the United States meet the recommended intake of these minerals from everyday foods and do not require supplementation. The RDA for iron for women older than 50 years and for men at any age is 8 mg daily. For women of age 19–50 years, the RDA is 18 mg. The RDA for copper for men and women is 0.9 mg per day. For individuals who use multiple vitamins, it is prudent to favor products that deliver vitamins only, unless specifically directed by one’s personal physician. Some authorities also suggest specific clinical testing (e.g., to measure levels of non-ceruloplasmin copper) before initiating diet changes (Squitti et al., 2014).

  1. Although aluminum’s role in Alzheimer’s disease remains a matter of investigation, those who desire to minimize their exposure can avoid the use of cookware, antacids, baking powder, or other products that contain aluminum.

Aluminum’s role in Alzheimer’s disease remains controversial. Some researchers have called for caution, citing aluminum’s known neurotoxic potential when entering the body in more than modest amounts (Kawahara and Kato-Negishi, 2011) and the fact that aluminum has been demonstrated in the brains of individuals with Alzheimer’s disease (Crapper et al., 1973, Crapper et al., 1976). Studies in the United Kingdom and France found increased Alzheimer’s prevalence in areas where tap water contained higher aluminum concentrations (Martyn et al., 1989, Rondeau et al., 2009). However, because of the limited number of relevant studies, most experts regard current evidence as insufficient to indict aluminum as a contributor to Alzheimer’s disease risk.

Because aluminum plays no role in human biology, it may be prudent to avoid aluminum exposure to the extent possible, although its role in cognitive disorders remains under investigation. Aluminum is found in some brands of baking powder, antacids, certain food products, and antiperspirants.

  1. Include aerobic exercise in your routine, equivalent to 40 minutes of brisk walking 3 times per week.

Observational studies have shown that individuals who exercise regularly are at reduced risk for Alzheimer’s disease (Erickson et al., 2012). Adults who exercised in midlife were found to be less likely to develop dementia after age 65, compared with their sedentary peers (DeFina et al., 2013). In controlled trials, aerobic exercise—such as brisk walking for 40 minutes 3 times per week—reduces brain atrophy and improves memory and other cognitive functions (Hotting and Roder, 2013).

In addition to the foregoing guidelines, other steps merit further investigation for possible inclusion in future iterations of prevention guidelines. These could include recommendations as follows:

  • Maintain a sleep routine that will provide an appropriate amount of sleep each night, approximately 7–8 hours for most individuals.

It is important to evaluate and treat any underlying sleep disorders, such as obstructive sleep apnea. Sleep disturbances have been associated with cognitive impairment in older adults (Blackwell et al., 2011, Lim et al., 2013, Tworoger et al., 2006, Yaffe et al., 2011).

  • Engage in regular mental activity that promotes new learning, for example, 30 minutes per day, 4–5 times per week.

Several studies have suggested that individuals who are more mentally active have reduced risk for cognitive deficits later in life (Curlik and Shors, 2013, Hotting and Roder, 2013, Robertson, 2013, Stern, 2012, Tucker and Stern, 2011).


Although current scientific evidence is incomplete, substantial evidence suggests that, a combination of healthful diet steps and regular physical exercise may reduce the risk of developing Alzheimer’s disease. These lifestyle changes present additional benefits, particularly for body weight, cardiovascular health, and diabetes risk, and essentially no risk of harm. As investigations into Alzheimer’s disease bear additional fruit, these guidelines should be modified accordingly.


Copyright © 2015 Elsevier Inc. All rights reserved.


Mediterranean Diet and Cognitive Health

2017 Aug 1;12(8):e0182048. doi: 10.1371/journal.pone.0182048. eCollection 2017.

Mediterranean diet and cognitive health: Initial results from the Hellenic Longitudinal Investigation of Ageing and Diet.

Anastasiou CA1,2, Yannakoulia M1, Kosmidis MH3, Dardiotis E4, Hadjigeorgiou GM4, Sakka P5, Arampatzi X3, Bougea A6, Labropoulos I7, Scarmeas N2,8.



The Mediterranean dietary pattern has been associated with a decreased risk of many degenerative diseases and cognitive function in particular; however, relevant information from Mediterranean regions, where the prototype Mediterranean diet is typically adhered to, have been very limited.

Additionally, predefined Mediterranean diet (MeDi) scores with use of a priori cut-offs have been used very rarely, limiting comparisons between different populations and thus external validity of the associations.

Finally, associations between individual components of MeDi (i.e., food groups, macronutrients) and particular aspects of cognitive performance have rarely been explored. We evaluated the association of adherence to an a priori defined Mediterranean dietary pattern and its components with dementia and specific aspects of cognitive function in a representative population cohort in Greece.


Participants from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD), an on-going population-based study, exploring potential associations between diet and cognitive performance in a representative sample from Greek regions, were included in this analysis.

Diagnosis of dementia was made by a full clinical and neuropsychological evaluation, while cognitive performance was assessed according to five cognitive domains (memory, language, attention-speed, executive functioning, visuospatial perception) and a composite cognitive score. Adherence to MeDi was evaluated by an a priori score (range 0-55), derived from a detailed food frequency questionnaire.


Among 1,865 individuals (mean age 73±6 years, 41% male), 90 were diagnosed with dementia and 223 with mild cognitive impairment.

Each unit increase in the Mediterranean dietary score (MedDietScore) was associated with a 10% decrease in the odds for dementia. Adherence to the MeDi was also associated with better performance in memory, language, visuospatial perception and the composite cognitive score; the associations were strongest for memory.

Fish consumption was negatively associated with dementia and cognitive performance positively associated with non-refined cereal consumption.


Our results suggest that adherence to the MeDi is associated with better cognitive performance and lower dementia rates in Greek elders. Thus, the MeDi in its a priori constructed prototype form may have cognitive benefits in traditional Mediterranean populations.



Physical Exercise as a Preventive or Disease-Modifying Treatment of Dementia and Brain Aging

Mayo Clin Proc. 2011 Sep;86(9):876-84. doi: 10.4065/mcp.2011.0252.

Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging.

Ahlskog JE1, Geda YE, Graff-Radford NR, Petersen RC.


A rapidly growing literature strongly suggests that exercise, specifically aerobic exercise, may attenuate cognitive impairment and reduce dementia risk. We used PubMed (keywords exercise and cognition) and manuscript bibliographies to examine the published evidence of a cognitive neuroprotective effect of exercise.

Meta-analyses of prospective studies documented a significantly reduced risk of dementia associated with midlife exercise; similarly, midlife exercise significantly reduced later risks of mild cognitive impairment in several studies.

Among patients with dementia or mild cognitive impairment, randomized controlled trials (RCTs) documented better cognitive scores after 6 to 12 months of exercise compared with sedentary controls.

Meta-analyses of RCTs of aerobic exercise in healthy adults were also associated with significantly improved cognitive scores.

One year of aerobic exercise in a large RCT of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise.

Cross-sectional studies similarly reported significantly larger hippocampal or gray matter volumes among physically fit seniors compared with unfit seniors.

Brain cognitive networks studied with functional magnetic resonance imaging display improved connectivity after 6 to 12 months of exercise. Animal studies indicate thatexercise facilitates neuroplasticity via a variety of biomechanisms, with improved learning outcomes. Induction of brain neurotrophic factors byexercise has been confirmed in multiple animal studies, with indirect evidence for this process in humans.

Besides a brain neuroprotective effect, physical exercise may also attenuate cognitive decline via mitigation of cerebrovascular risk, including the contribution of small vessel disease to dementia. 

Exercise should not be overlooked as an important therapeutic strategy.



Environmental Risk Factors for Dementia

BMC Geriatr. 2016 Oct 12;16(1):175.

Environmental risk factors for dementia: a systematic review.

Killin LO, Starr JM, Shiue IJ, Russ TC



Dementia risk reduction is a major and growing public health priority. While certain modifiable risk factors for dementiahave been identified, there remains a substantial proportion of unexplained risk. There is evidence that environmental risk factors may explain some of this risk. Thus, we present the first comprehensive systematic review of environmental risk factors for dementia.


We searched the PubMed and Web of Science databases from their inception to January 2016, bibliographies of reviewarticles, and articles related to publically available environmental data. Articles were included if they examined the association between an environmental risk factor and dementia. Studies with another outcome (for example, cognition), a physiological measure of the exposure, case studies, animal studies, and studies of nutrition were excluded. Data were extracted from individual studies which were, in turn, appraised for methodological quality. The strength and consistency of the overall evidence for each risk factor identified was assessed.


We screened 4784 studies and included 60 in the review. Risk factors were considered in six categories: air quality, toxic heavy metals, other metals, other trace elements, occupational-related exposures, and miscellaneous environmental factors. Few studies took a life course approach. There is at least moderate evidence implicating the following risk factors: air pollution; aluminium; silicon; selenium; pesticides; vitamin D deficiency; and electric and magnetic fields.


Studies varied widely in size and quality and therefore we must be circumspect in our conclusions. Nevertheless, this extensive review suggests that future research could focus on a short list of environmental risk factors for dementia. Furthermore, further robust, longitudinal studies with repeated measures of environmental exposures are required to confirm these associations.


© 2016 BioMed Central Ltd unless otherwise stated. Part of Springer Nature.


Efficacy of Antidepressants for Depression in Alzheimer’s Disease

2017;58(3):725-733. doi: 10.3233/JAD-161247.

Efficacy of Antidepressants for Depression in Alzheimer’s Disease: Systematic Review and Meta-Analysis.

Orgeta V, Tabet N, Nilforooshan R, Howard R.



Depression is common in people with Alzheimer’s disease (AD) affecting overall outcomes and decreasing quality of life. Although depression in AD is primarily treated with antidepressants, there are few randomized controlled trials (RCTs) assessing efficacy and results have been conflicting.


To systematically review evidence on efficacy of antidepressant treatments for depression in AD.


Systematic review and meta-analysis of double blind RCTs comparing antidepressants versus placebo for depression in AD. We searched MEDLINE, CINAHL, EMBASE, PsycINFO, the Cochrane Controlled Trials Register and on line national and international registers. Primary outcomes were treatment response and depressive symptoms. Secondary outcomes were cognition, acceptability, and tolerability. Risk of bias was also assessed.


Seven studies met inclusion criteria. Three compared sertraline with placebo; one compared both sertraline and mirtazapine to placebo; imipramine, fluoxetine, and clomipramine were evaluated in one study each. In terms of response to treatment (6 studies, 297 patients treated with antidepressants and 223 with placebo), no statistically significant difference between antidepressants and placebo was found (odds ratio (OR) 1.95, 95% CI 0.97-3.92). We found no significant drug-placebo difference for depressive symptoms (5 studies, 311 patients, SMD -0.13; 95% CI -0.49 to 0.24). Overall quality of the evidence was moderate because of methodological limitations in studies and the small number of trials.


Despite the importance of depression in people with AD, few RCTs are available on efficacy of antidepressants, limiting clear conclusions of their potential role. There is a need for further high quality RCTs.



Survival and Causes of Death Among People with Parkinson, Dementia with Lewy Bodies

JAMA Neurol. 2017 May 15. doi: 10.1001/jamaneurol.2017.0603. [Epub ahead of print]

Survival and Causes of Death Among People With Clinically Diagnosed Synucleinopathies With Parkinsonism: A Population-Based Study.

Savica R1, Grossardt BR2, Bower JH3, Ahlskog JE3, Boeve BF3, Graff-Radford J3, Rocca WA1, Mielke MM1.



To our knowledge, a comprehensive study of the survival and causes of death of persons with synucleinopathies compared with the general population has not been conducted. Understanding the long-term outcomes of these conditions may inform patients and caregivers of the expected disease duration and may help with care planning.


To compare survival rates and causes of death among patients with incident, clinically diagnosed synucleinopathies and age- and sex-matched referent participants.

Design, Setting, and Participants:

This population-based study used the Rochester Epidemiology Project medical records-linkage system to identify all residents in Olmsted County, Minnesota, who received a diagnostic code of parkinsonism from 1991 through 2010. A movement-disorders specialist reviewed the medical records of each individual to confirm the presence of parkinsonism and determine the type of synucleinopathy. For each confirmed patient, an age- and sex-matched Olmsted County resident without parkinsonism was also identified.

Main Outcomes and Measures:

We determined the age- and sex-adjusted risk of death for each type of synucleinopathy, the median time from diagnosis to death, and the causes of death.


Of the 461 patients with synucleinopathies, 279 (60.5%) were men, and of the 452 referent participants, 272 (60.2%) were men. From 1991 through 2010, 461 individuals received a diagnosis of a synucleinopathy (309 [67%] of Parkinson disease, 81 [17.6%] of dementia with Lewy bodies, 55 [11.9%] of Parkinson disease dementia, and 16 [3.5%] of multiple system atrophy with parkinsonism). During follow-up, 68.6% (n = 316) of the patients with synucleinopathies and 48.7% (n = 220) of the referent participants died. Patients with any synucleinopathy died a median of 2 years earlier than referent participants. Patients with multiple system atrophy with parkinsonism (hazard ratio, 10.51; 95% CI, 2.92-37.82) had the highest risk of death compared with referent participants, followed by those with dementia with Lewy bodies (hazard ratio, 3.94; 95% CI, 2.61-5.94), Parkinson disease with dementia (hazard ratio, 3.86; 95% CI, 2.36-6.30), and Parkinson disease (hazard ratio, 1.75; 95% CI, 1.39-2.21). Neurodegenerative disease was the most frequent cause of death listed on the death certificate for patients, and cardiovascular disease was the most frequent cause of death among referent participants.

Conclusions and Relevance:

Individuals with multiple system atrophy with parkinsonism, dementia with Lewy bodies, and Parkinson disease dementia have increased mortality compared with the general population. The mortality among persons with Parkinson disease is only moderately increased compared with the general population.


© 2017 American Medical Association. All Rights Reserved.


Rivastigmine for Alzheimer’s Disease

Cochrane Database Syst Rev. 2015 Apr 10;(4):CD001191. doi: 10.1002/14651858.CD001191.pub3.

Rivastigmine for Alzheimer’s disease.

Birks JS1, Grimley Evans J.



Alzheimer’s disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer’s disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts.

Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity.

Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.


To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer’s type.


We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR “SDZ ENA 713”. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources.


We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer’s type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared.


One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data.


A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.

Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns.

All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer’s disease with a mean age of about 75 years.

All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).

Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies).

Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies).


Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer’s disease.

In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician’s global assessment.

There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy.

The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.