Engagement in Pleasant Leisure Activities and Blood Pressure: A 5-Year Longitudinal Study in Alzheimer’s Caregivers

2017 May 31. doi: 10.1097/PSY.0000000000000497. [Epub ahead of print]

Engagement in pleasant leisure activities and blood pressure: A 5-year longitudinal study in Alzheimer’s caregivers.

Mausbach BT1, Romero-Moreno R, Bos T, von Känel R, Ziegler MG, Allison MA, Mills PJ, Dimsdale JE, Ancoli-Israel S, Losada A, Márquez-González M, Patterson TL, Grant I.



Elevated blood pressure is a significant public health concern, particularly given its association with cardiovascular disease risk, including stroke. Caring for a loved one with Alzheimer’s disease has been associated with physical health morbidity, including higher blood pressure. Engagement in adaptive coping strategies may help prevent blood pressure elevation in this population. This 5-year longitudinal study examined whether greater participation in pleasant leisure activities was associated with reduced blood pressure in caregivers.


Participants were 126 in-home spousal Alzheimer caregivers (mean age = 74.2 ± 7.9 years) that completed five yearly assessments. Linear mixed effects models analysis was used to examine the longitudinal relationship between pleasant leisure activities and caregiversblood pressure, after adjusting for demographic and health characteristics.


Greater engagement in pleasant leisure activities was associated with reduced mean arterial blood pressure (MAP; B = -0.08, SE = 0.04, p = 0.040). Follow-up analyses indicated engagement in activities was significantly associated with reduced diastolic (B = -0.07, SE = 0.03, p = 0.030) but not systolic blood pressure (B = -0.10, SE = 0.06, p = 0.114). In addition, MAP was significantly reduced when caregiving duties ended because of placement of care recipients in nursing homes (B = -3.10, SE = 1.11, p = 0.005) or death of the care-recipient (B = -2.64, SE = 1.14, p = 0.021).


Greater engagement in pleasant leisure activities was associated with lowered caregiversblood pressure over time. Participation in pleasant leisure activities may have cardiovascular health benefits for Alzheimer’s caregivers.




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.




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.


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.




Effects of Aerobic Exercise on Cognitive Function of Alzheimer’s Disease Patients

CNS Neurol Disord Drug Targets. 2015;14(10):1292-7.

The Effects of Aerobic Exercise on Cognitive Function of Alzheimer’s Disease Patients.

Yang SY, Shan CL, Qing H, Wang W, Zhu Y, Yin MM, Machado S, Yuan TF, Wu T1.


To evaluate the effect of moderate intensity of aerobic exercise on elderly people with mild Alzheimer’s disease, we recruited fifty volunteers aged 50 years to 80 years with cognitive impairment. They were randomized into two groups: aerobic group (n=25) or control group (n=25).

The aerobic group was treated with cycling training at 70% of maximal intensity for 40 min/d, 3 d/wk for 3 months. The control group was only treated with heath education.

Both groups were received cognitive evaluation, laboratory examination before and after 3 months. The results showed that the Minimum Mental State Examination score, Quality of Life Alzheimer’s Disease score and the plasma Apo-a1 level was significantly increased (P<0.05), the Alzheimer’s Disease Assessment Scale-cognition score, Neuropsychiatric Inventory Questionnaire score was significantly decreased.(P<0.05) in aerobic group before and after 3 months in aerobic group.

For the control group, there was no significant difference in scores of Alzheimer’s Disease Assessment Scale-cognition, Neuropsychiatric Inventory Questionnaire, Quality of Life Alzheimer’s Disease, Apo-a1 (P>0.05), while Minimum Mental State Examination scores decreased significantly after 3 months (P<0.05).

In conclusion, moderate intensity of aerobic exercise can improve cognitive function in patients with mild Alzheimer’s disease.



PMID: 26556080


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.


Physical Activity: A Viable Way to Reduce the Risks of Mild Cognitive Impairment, Alzheimer’s Disease, and Vascular Dementia in Older Adults

Brain Sci. 2017 Feb 20;7(2). pii: E22. doi: 10.3390/brainsci7020022.

Physical Activity: A Viable Way to Reduce the Risks of Mild Cognitive Impairment, Alzheimer’s Disease, and Vascular Dementia in Older Adults.

Gallaway PJ1, Miyake H2, Buchowski MS3, Shimada M4, Yoshitake Y5, Kim AS6, Hongu N7.


A recent alarming rise of neurodegenerative diseases in the developed world is one of the major medical issues affecting older adults. In this review, we provide information about the associations of physical activity (PA) with major age-related neurodegenerative diseases and syndromes, including Alzheimer’s disease, vascular dementia, and mild cognitive impairment. We also provide evidence of PA’s role in reducing the risks of these diseases and helping to improve cognitive outcomes in older adults. Finally, we describe some potential mechanisms by which this protective effect occurs, providing guidelines for future research.

1. Introduction

The alarming rise of neurodegenerative diseases in the developed world is becoming one of the major medical issues affecting older Americans. By the year 2030, >20% of Americans will be over 65 years of age [1,2]. There are now an estimated 5.4 million Americans (one in nine), aged 65 years and older, with Alzheimer’s disease (AD), the most common form of dementia, and this number is expected to almost triple by 2050, as the population ages [3]. AD has become the sixth leading cause of death in the U.S., and the fifth leading cause of death among Americans aged 65 years and older, with deaths due to AD increasing by 66% between 2000 and 2008; in contrast to the decline of most other leading causes of death during the same period [4]. AD will likely become a more prominent health issue in developing countries in the near future, as life expectancies of those populations are longer, due to improved medical care. The World Health Organization (WHO) estimates that 47.5 million people are living with dementia and 7.7 million new diagnoses are made every year, worldwide [5]. Psychological disorders, such as depression, are also common, and are the second leading cause of disability in older populations [6]. The Italian Longitudinal Study on Aging (ILSA) provided evidence in a prospective, cohort study, that depression and physical disability in older adults have a complex relationship [7]. Perhaps the most alarming aspect of the increase in dementia cases, is that there are currently no cures or new effective therapies [8]. However, some lifestyle factors, such as physical activity (PA), could lower the risk of certain forms of dementia [9]. In a recent Lancet Series on PA, Progress and Challenges (2016), Sallis and colleagues reported that regular PA could prevent almost 300,000 cases of dementia per year, worldwide, if everyone were physically active [10]. In this article, our goal is to explore the role of PA in reducing the risks of age-related AD, vascular dementia (VaD), and mild cognitive impairment (MCI). We define dementia, AD, VaD, and MCI and describe clinical and research-based assessment tools used to diagnose each disorder. Finally, we provide evidence of PA’s protective effects of cognition in older adults, and discuss some of the potential mechanisms of the protective effects of PA, proposing suggestions to guide future research on PA intervention programs in order to reduce the burden of dementia, primarily through prevention and improved health care. This review was based on searches of the US National Library of Medicine (PubMed), Ovid MEDLINE, Google Scholar, and Web of Science, using terms to identify the risk exposure (physical inactivity or sedentary), combined with terms to determine the outcomes of interest (cognitive impairment or decline or disorders or AD or dementia or MCI or VaD). A search filter was developed to include only human studies.

2. Defining and Diagnosing MCI, Dementia, AD, and VaD

2.1. Mild Cognitive Impairment (MCI)

MCI is usually described as a transitional state between normal aging and dementia [11,12]. An individual with MCI experiences a cognitive decline that is not severe enough to significantly interfere with daily life, yet is worse than expected for one’s particular age [11]. Although studies on the MCI reversion to normality and MCI stability are limited, it is common for individuals with MCI to have no further deterioration of cognitive function for several years [13,14]. In a clinical setting, physicians may diagnose MCI based on self-reported symptoms or cognitive tests, but a wide variety of operational definitions of MCI have resulted in unreliability, although progress toward an objective standard continues to be made [15]. Cognitive tests, such as the mini-mental state examination (MMSE) [16] and the Montreal Cognitive Assessment (MoCA) [17], have been developed to help screen for MCI and/or dementia. Point scores in the MMSE range from zero (severe dementia) to 30 (lack of cognitive impairment) [16]. The MMSE provides a measurement of the overall cognitive functioning, including attention and orientation, memory, registration, recall, calculation, language, and the ability to draw, to health professionals and researchers, but does not give clinicians the ability to predict if those with MCI will experience further cognitive decline due to dementia [18,19]. The MoCA was specifically developed to assist with MCI diagnosis. In a validation study, it detected 90% of MCI cases with previously established criteria for MCI, a standardized mental status test, and subjective complaints about memory loss by participants or families, over at least six months. The MoCA significantly outperformed the MMSE, which detected only 18% of the MCI cases [17]. In addition, the MoCA has been shown to be a sensitive tool for cognitive impairment associated with other clinical conditions, such as Parkinson’s disease [20], Huntington’s disease [21], and multiple sclerosis [22]. Although progress has been made toward making the MCI diagnosis objective, the concept of MCI still remains somewhat vague and controversial, and issues such as clinical criteria for practitioners need to be investigated [23]. Since MCI is a syndrome with multiple etiologies, it is not considered a disease, but an aggregate of cognitive symptoms, attributable to either an underlying precursory stage of a serious disease, or an idiopathic acceleration of cognitive decline, when compared to a normal state [19]. To signify this distinction, MCI due to AD is typically separated as the prodromal stage of AD, and it is diagnosed using criteria specific to the early stages of AD, including specific biomarkers that are not evident in other causes of MCI [24]. Although MCI sometimes persists as only a minor annoyance if it is of the non-AD variety, more often than not, it progresses to AD or another form of dementia [25]. MCI has become an important risk factor and indicator of the early stages of dementia, that has resulted in the testing of medications meant for AD treatment [26]. With MCI serving as a link between dementia and normal aging [27], it can potentially help us investigate the effect of, not only medications, but also lifestyle programs, such as regular PA, social activity, and diet, on age-related cognitive decline and dementia—both for improving cognition and delaying cognitive decline [28,29,30].

2.2. Dementia

Dementia is not a specific disease, but rather it refers to the symptomatic outcome of a number of serious neurodegenerative diseases that adversely affect cognitive function. Worldwide prevalence of people with dementia is estimated at 47.5 million, and is expected to double by 2030 and triple by 2050 [5]. Most patients with dementia display behavioral and psychological symptoms [31], such as memory loss and difficulty organizing or planning, and psychological changes, such as personality changes (aggression—verbal/physical), agitation, anxiety, depression, social withdrawal, and hallucinations [32]. Dementia is the result of serious neurodegeneration in the brain, significantly hinders daily activities, and can require a complete reliance on caregivers in later stages [32]. The most common form of dementia is AD, which causes 50%–75% of all dementia cases [33]. VaD is the second most common primary cause of dementia—at least 20% of dementia cases are due to VaD, and it is often present alongside AD or another form of dementia [34]. Although a definitive percentage is not available, due to many cases of dementia going undiagnosed, AD and VaD are estimated to be responsible for 70%–95% of dementia cases. Dementia is typically diagnosed by a healthcare provider in a clinical setting, by determining the extent of cognitive impairment, although this can be a difficult task due to dementia’s progressive nature—there is a range of severity in symptoms, depending on how far the disease has progressed when the patient is examined, and this largely relies on the examining physician’s discretion [35]. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are both brain imaging methods that are most commonly used to make a dementia diagnosis by examining the physical condition of the brain [36]. However, even with these tools, the difficulties of recognizing and diagnosing dementia are apparent, and approximately half of dementia cases are currently undiagnosed [37]. The distinctions between regular aging and the first signs of dementia may be difficult for a clinician to distinguish, and PET and SPECT scans may be expensive, which could discourage widespread testing. The changes may also happen slowly and subtly, and may thus be indiscernible to family members or caretakers. Currently, there is no cure for dementia.

2.3. Alzheimer’s Disease

Alzheimer’s disease (AD) has dramatically risen in the last couple of decades, becoming the sixth leading cause of death in the U.S., and the fifth leading cause of death among older adults, with deaths due to AD increasing by an astounding 66% between 2000 and 2008, in sharp contrast to the general decline of most other leading causes of death during the same period of time [38]. Alzheimer’s disease is a neurodegenerative, dementia-causing disease, with no known cure. Around 70% of AD cases occur after the age of 65 [39]. Amyloid-beta (Aβ) is a polypeptide—a chain of amino acids that is a protein precursor—that can build up on brain cells, causing plaques that are found in abundance in AD patients; these Aβ plaques are thought to be one of the major contributors to dementia caused by AD [40]. In addition to plaques, AD also appears to be related to tangles in the brain, which are structural abnormalities due to defective or deficient tau proteins; tau proteins support microtubules, which help provide cell structure and movement. AD is typically diagnosed by biomarkers, such as Aβ in cerebrospinal fluid, tau proteins, and regional brain volumes; these measurable substances can be used to predict AD progression in patients with MCI. However, cognitive markers, such as the symptoms reported by an examining physician, appear to be more effective predictors of the future development of AD, especially at baseline MCI, when it is first noticed and diagnosed [41]. To recognize the asymptomatic pre-clinical stage (up to a decade before the clinical onset of AD), standardized criteria for preclinical [42] and prodromal (amnestic MCI) stages [43] of the diagnostic criteria for AD, have been recommended for both clinical and research purposes.

2.4. Vascular Dementia

Vascular dementia (VaD) is the second most common form of dementia after AD, and is the result of impaired blood supply to the brain, which damages brain tissue when oxygen and nutrients are cut off. There are a number of possible causes of VaD [44]. It is often the result of a number of small, focal cerebral infarcts (small strokes) that may go unnoticed individually, but have an additive detrimental effect as more and more small areas of the brain are destroyed by ischemic events; however, there are also a number of other causal subtypes of cerebrovascular disease [45]. VaD may also be present along with other forms of dementia, such as AD, which can further complicate the condition, aggravating dementia symptoms, as access to more areas of the brain are lost. Diagnosing VaD is therefore no simple matter; there is currently a lack of validated criteria for establishing a diagnosis, and many of the various pathologies that reduce the brain’s blood supply are complex [46]. Although cerebrovascular lesions can be seen using brain imaging techniques, the diagnosis of VaD remains difficult, since such lesions may or may not be contributing to dementia symptoms, and this can lead to over-diagnosis of VaD as the cause of dementia [47].

2.5. Progression of a Neurodegenerative Disorder

Age-related neurodegenerative disorders, such as AD and VaD, generally show the same patterns in their progressions from normal aging to dementia. First, symptoms of MCI develop. MCI symptoms may improve if the condition is transient, and the patient may even go back to experiencing normal aging. The subject may also experience and remain in the MCI stage, without the condition progressing to dementia [13,14,25,26,27]. However, if there is an underlying cause, such as AD or VaD, MCI will eventually progress to dementia, and this step is irreversible. Intervention before irreversible brain damage occurs, is the best clinical practice for reducing the impact of dementia [28,29,30].

Numerous studies have revealed the connections between frailty, a pathological aging process that is reversible [48], and neurodegenerative disorders [49]. Cognitive frailty was first proposed by Panza and colleagues, who reported the risks of decreased cognitive functions, modulated by vascular factors [50]. In 2013, the International Academy on Nutrition and Aging and the International Association of Gerontology and Geriatrics, defined cognitive frailty as the heterogeneous clinical syndrome condition in older adults with both physical frailty and cognitive impairment, but excluding those with AD and other dementias [51]. Cognitive frailty is further refined into two subtypes; reversible and potentially reversible cognitive frailty [52]. The cognitive impairment of reversible cognitive frailty is subjective cognitive decline (SCD), a type of cognitive decline that may appear as the first symptom of preclinical AD, and/or positive biomarkers resulting from physical factors. [52]. MCI is the cognitive impairment of potentially reversible cognitive frailty. Recently, a longitudinal population-based study reported that reversible cognitive frailty in older adults increased the risk of developing dementia, particularly VaD, but not AD, and all-cause mortality [53]. The authors suggested that older adults with reversible cognitive frailty could benefit from a cognitive impairment intervention that may include regular PA, diet (e.g., Mediterranean diet), smoking cessation, and an active social lifestyle [53]. More research is required to determine the clinical screening criterion of cognitive frailty and the effectiveness of interventions for individuals with other geriatric disorders.

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3. Risk Factors for AD, VaD, and MCI

There are a number of risk factors for AD, the most obvious of which is advanced age. In addition to environmental factors, genetic causes are implicated, as several genes that have been associated with AD; the most undisputed and well-known of which is the gene that encodes apolipoprotein E (APOE). The APOE gene is the strongest genetic risk factor for the development of late-onset AD, which accounts for >95% of all AD cases [54,55,56]. Many epidemiological studies suggest that the APOE ε4 allele carrier status of individuals have associations between modifiable lifestyle risk factors, and dementia and AD [57,58,59,60]. Accumulating data suggest the APOE ε4 allele plays an important role in Aβ plaques and clearance, tau protein tangle formations, oxidation, neurotoxicity, and dysfunction in lipid transport, which are the major hypotheses of AD pathogenesis [61]. The epidemiological population-based study which had an average of 21 years of follow-up times before the diagnosis of dementia, showed that APOE ε4 allele carriers’ risk of dementia may be more affected by lifestyle factors such as PA, dietary fat and fish oil intake, alcohol drinking, and smoking. The authors suggested that adopting a healthy lifestyle, including increased PA, should be utilized as a major preventive strategy to decrease the risk or postpone the onset of dementia among APOE ε4 allele carriers [62]. The genetics of AD is advancing quickly, as new AD-related genes continue to be found [63]. However, to date, no therapeutic interventions targeting the APOE or other genes have been successfully established [64,65].

Cardiovascular disease (CVD) is another apparent risk factor for AD, particularly peripheral arterial disease—a form of atherosclerosis [66,67]. According to a number of studies, depression in later life also presents a significant risk for acquiring AD [68,69]. Within a three-year period, depressed MCI patients had a twofold higher risk of developing AD than non-depressed MCI patients [70]. Hypertension [71], diabetes [72], hypotension [73], and hypercholesterolemia [74], are all additional risk factors for AD [75,76]. Poor sleep quality and sleep deficiency may present yet another risk factor, as sleep deprivation induces more Aβ buildup in the brain, while adequate sleep reduces it—moreover, Aβ buildup may also cause poor sleep patterns and increased wakefulness [77]. Poor sleeping patterns may therefore lead to increased Aβ formation, to further deteriorate sleep quality, resulting in positive feedback that may increase AD risk. There are a number of risk factors for VaD that are also risk factors for AD, including hypertension, diabetes, excessive adiposity, and dyslipidemia [78]. Although the effect of these conditions on VaD may be obvious due to their cardiovascular or metabolic nature, the link to AD may be more indirect, as the resultant disruption of vascular functions in the brain could be compounding the neurodegeneration caused by the Aβ plaques or neurofibrillary tangles of AD, by disrupting cerebral autoregulation [75,76,79]. The risk factors for MCI are generally the same as those for AD—this is to be expected because MCI can also be the prodromal stage of AD. The most significant risk factors for MCI are older age and hypertension [80]. Now that we have addressed the potential risk factors for the most common age-related neurodegenerative diseases, we can explore the role of PA as a protective or risk-reducing behavior.

4. Physical Activity’s Effect on Future Risk of MCI, Dementia, AD, and VaD

PA is beneficial for both physical fitness (e.g., changes in the cardiovascular system, bone and muscle) and mental health (e.g., emotional functioning—depression, moods, cognitive functioning, social functioning) in almost all older adults [9,81], and its effects have been extensively studied in healthy older adults and those with cognitive impairment, including MCI, dementia, AD, and VaD.

4.1. Long-Term Cognitive Effects of PA on Healthy Older Adults

PA throughout one’s life can enhance cognitive function later in life, so it should be encouraged at every age. In contrast, sedentary behaviors, such as viewing television for extended periods over the course of years, can negatively affect cognitive function later in life. A longitudinal study over 25 years, that measured the PA and television viewing habits of 3247 healthy adults (aged 18–30 years at the start of the study), found that higher levels of PA and lower amounts of television viewing, resulted in significantly better processing speeds and executive functions in cognitive tests at midlife [82]. Moreover, those who were physically active in midlife had a reduced risk of developing depression in late life [83]. Depression in late life has also been linked to dementia, particularly in those carrying the ε4 variant of the APOE gene that predisposes to AD in depressed individuals [84]. According to the findings of a 10-year longitudinal study involving 470 participants aged 79–98 years, PA can also help engage older adults in cognitive and social activities, which may be one of the factors that helps prevent cognitive decline [85]. Ideally, all adults should remain physically active throughout life [10,86], starting at a young age, to achieve optimal cognitive health as an older adult. However, there may be shorter-term benefits to increased PA levels [87,88,89,90].

4.2. Short-Term Cognitive Effects of PA on Healthy Older Adults

For healthy older adults, the short-term effects of PA need further investigation. One study found that the cognitive functions of memory and independence were improved in older adults (aged > 75) by a single session of low-intensity, range-of-motion exercise, but the effect might also be short-lived [87]. Another study found that healthy older adults practicing Tai Chi, or simple stretching and toning exercises, can improve global cognitive function, improve recall, and reduce subjective cognitive complaints after a one-year intervention [88]. Certain exercises, such as range-of-motion and Tai Chi, may show short-term benefits in cognitive ability in healthy older adults [87,88]. Aerobic exercise has been shown to attenuate cognitive decline, reduce brain atrophy, and improve physical health in healthy older adults [89,90], although there is some evidence that short-term cognitive effects are not as pronounced [89]. A review of 12 trials lasting from eight to 26 weeks, and included 754 older adults with no cognitive impairment, showed no short-term cognitive benefits from aerobic exercise [89]. However, the age of the older adult may also factor into the efficacy of aerobic exercise. One study showed that adults between 60 and 70 years old displayed significant cognitive benefits in spatial object recall and recognition from a three-month aerobic PA intervention that increased hippocampal perfusion—blood flow to the hippocampus. However, the positive effect of aerobic PA on perfusion may decline with age [91].

In recent years, there has been growing interest in resistance training (e.g., weight lifting, strength training) to improve cognition [92,93,94,95] and prevent brain volume loss in older adults [96]. The long-term impact on cognition and white matter volume in older women was reported in a 52-week randomized clinical trial of resistance training program that included machine exercises Keiser pressurized air system, free weights, non-machine exercises, or balance-and-toning training program that included stretching, range-of-motion, core-strength, balance, and relaxation exercises. Both interventions were performed twice per week. The resistance training program promoted memory, reduced cortical white matter atrophy, and increased peak muscle power after 2-year follow-up, relative to the balance-and-toning training program [96]. Also, it has been reported that cortical white matter volume is reduced among older adults with dementia, when compared to their healthy counterparts [97]. Thus, maintaining cortical white matter volume might be important for maintaining cognitive functions in older adults [96].

There are several studies supporting the hypothesis that resistance training has similar positive effects on cognitive function among older adults, to aerobic-based exercise training. However, there is no clear consensus on the underlying mechanisms by which resistance training promotes cognitive function and brain tissue integrity [9,95,96]. More research is needed to examine the variables of resistance training (i.e., intensity, frequency) and the possible mechanisms by which resistance training may prevent cognitive decline. A recent meta-analysis found that combined aerobic exercise and resistance training, had greater effects on reducing cognitive decline than these programs alone [98]. Current understanding of how PA promotes cognitive function is largely from aerobic training studies. Further research is required to identify the underlying changes in the body and brain (e.g., changes in brain volume) that improve cognitive function, using neuroimaging, physiological assessment, and circulating levels of various neurotrophins (e.g., IGF-1). Subsequent research should also determine how and what types of PA could help both healthy and frail older adults gain cognitive benefits in social and environmental settings of daily life.

4.3. Effects of PA on the Risk of Developing MCI and Dementia in Older Adults

PA is effective in reducing risk for developing MCI in older adults, but the optimizing of exercise training (i.e., types of PA, intensity, duration), cardiorespiratory fitness, age, level of cognition, medications, and social environments, may all play roles in the outcome [9]. The studies mentioned above showed that stretching and toning exercises hold the most promise for improving cognitive function in the healthy adults aged 75 years and older [87,88], while aerobic [90,91,99] and resistance exercise [92,93,94,95] also have positive effects. It seems that the risk of developing MCI may also be improved by exercise intensity. In older adults (aged ≥ 65 years), moderate exercise was shown to reduce the risk for MCI, while vigorous or light exercise did not show similar effect [100]. Increased PA in older adults also appears to reduce the risk of dementia due to AD and VaD, although more research must be done to explore the mechanisms of this effect [90,95,96]. In one study, adults of 65 years and older, participating in the Cardiovascular Health Cognition Study who regularly participated in four or more physical activities per week, had about half the risk of developing dementia as those participating in zero to one physical activities. However, those carrying the ε4 variant of the APOE gene—the greatest genetic risk factor for late onset AD—the risk was not affected by PA levels [101]. The frequency of the APOE ε4 gene is 19.0% in African American, 13.6% in Caucasian, 11.0% in Hispanic, and 8.9% in Japanese populations [102]. As mentioned earlier, for the majority of the population—those without the APOE ε4 gene—PA may have protective effects against the development of dementia [62]. This finding is supported by other studies showing a significant reduction of dementia found in older adults who exercised three or more times per week, when compared to those who did not [103]. Nevertheless, the mechanisms by which different types and frequencies of PA reduce dementia risk in older adults warrant further research.

4.4. Effects of PA on Older Adults with Cognitive Impairment

For older adults who have already developed a form of cognitive impairment, whether mild, such as those with MCI, or moderate to severe, as with dementia, PA can improve cognitive function, when compared to those with cognitive impairment who are not physically active [104]. Studies show that six to 12 months of exercise for those with MCI or dementia results in better cognitive scores than sedentary controls [105]. The positive effect of PA on cognitive function may be more apparent in older adults with MCI than in those with dementia, according to one review, but this may be due to the methodological issues of the performed studies; thus, more research is needed on the effect of PA on cognitive function in older adults with dementia [105]. However, the meta-analysis showed that aerobic exercise helps improve cognition in older adults with both AD and non-AD dementia, when combined with other standard medical treatments for dementia, and higher frequency interventions did not result in additional effects on cognition [106]. The results offer supporting evidence that PA intervention, with or without pharmacotherapy, is beneficial for cognition in patients with dementia.

5. Potential Mechanisms for PA’s Protective Effects

While the protective effect of PA on the aging brain is supported by numerous studies, the exact mechanisms are less clear. A recent review examined many possible mechanisms for how PA is linked to a reduced risk of age-related cognitive impairments, including MCI, AD, and VaD [107]. In this section, we will examine some of these potential mechanisms.

5.1. Increasing Blood Flow to the Brain

PA can increase blood flow to the brain, both during and shortly after a PA event, in response to increased needs for oxygen and energetic substrate [108,109]. The increased brain/cerebral blood flow triggers various neurobiological reactions, which provide an increased supply of nutrients. Moreover, cerebral angiogenesis—the development of new blood vessels in the brain—is increased by PA, and the brain’s vascular system is plastic, even in old age [110]. The increased vascularization of the brain, as well as the regular increases in blood flow that periods of PA provide, may reduce the risks of MCI and AD, by nourishing more brain cells and helping to remove metabolic waste or AD-inducing Aβ. The potential risk-reducing effect of increased blood flow on the development of VaD is more obvious, since VaD involves an impaired blood supply to the brain, while PA increases the blood supply. For instance, if a small artery in the brain is occluded by an embolus, this can often lead to an ischemic stroke, but blood can sometimes reach affected brain cells from an alternative path. Increased vascularization in the brain from PA can increase these alternative sources of blood during arterials occlusions, possibly limiting the damage [111]. There is strong evidence that cerebrovascular health may also play a large role in the severity of AD, as cases with brain infarctions, in addition to AD, showed worse symptoms of dementia than those with only AD [112]. More research is needed to determine the extent to which increasing vascularization of the brain may help reduce the risk of age-related neurodegenerative diseases.

5.2. Improving Cardiovascular and Metabolic Health

Earlier, we discussed how hypertension is one of the main risk factors for MCI, AD, and VaD [71,79]. Hypertension can increase the risk of strokes, as well as small strokes that are often the cause of VaD. Since strokes can complicate AD and aggravate dementia symptoms, it follows that hypertensive individuals could benefit by lowering their blood pressure, regardless of their level of cognitive impairment. Even low-intensity PA for 30 min, three to six times a week for nine months, can significantly lower blood pressure in elderly adults [112]. Because hypertension is a prominent risk factor, lowering blood pressure may be one of the mechanisms by which PA reduces the risk of many age-related neurodegenerative diseases. Diabetes is also a very significant risk factor for MCI, AD, and VaD [72]. The excess blood glucose levels found in those with diabetes causes tissue damage [113], inflammation [114], and microvascular disease [115], which possibly affect brain tissue, consequently increasing the chance of stroke. Regular PA can prevent type 2 diabetes and also helps manage blood glucose levels in those with diabetes [116]. By reducing the risk of diabetes and improving health conditions, improvement of metabolic health may be a secondary mechanism by which PA decreases the chances of MCI, AD, and VaD. Another risk factor for cognitive impairment in older adults that we have previously discussed is hyperlipidemia, or abnormally high lipid (cholesterol and triglycerides) blood concentration [74,78]. Regular PA can increase blood level high-density lipoproteins (HDL) that help carry cholesterol out of the bloodstream and into the liver, reducing hyperlipidemia. Thus, it seems plausible that PA reduces neurodegeneration risk through general cardiovascular and metabolic health improvement [117].

5.3. Preventing and Treating Depression

Depression is a known risk factor for developing dementia. Depression also appears to reduce certain cognitive functions in adults who are otherwise not cognitively impaired [118]. Although midlife depression doubles the chances of acquiring dementia later in life, it is harder to distinguish whether late-life depression is a risk factor for dementia, or vice versa; it could be a result of the early stages of dementia or MCI [119]. PA is effective for both treating and preventing depression [120], and therefore, it would stand to reason that reducing depression could be one of the means by which PA reduces the risk of AD, MCI, and other cognitive disorders. Even in cases where late-life depression is caused by the early dementia symptoms, PA could still be encouraged as part of a treatment for the depressive symptoms. Future research is needed to determine how health care professionals can deliver a PA program to healthy or physically/cognitively frail older adults. There is a need to determine the external factors of PA intervention, such as timing, dose, type, structure, and use of mindfulness that best ameliorate depression, and thereby reduce the risk of cognitive decline and prevent dementia.

5.4. Improving Sleep Quality

PA is associated with a reduction of insomnia symptoms, and other sleep quality and quantity problems, including problems with sleep onset (being able to fall asleep quickly) and sleep maintenance (staying asleep throughout the night) in older adults [121]. We previously noted a study showing that poor sleep quality is a potential risk factor for AD in particular [61], as sleep disturbances occur frequently in older adults with dementia [122] A specific mechanism by which sleep may reduce the risk of AD is through metabolic waste clearance in the brain, that occurs during sleep; this process also clears Aβ from the brain [123]. Aβ buildup results in plaques that contribute to AD, so clearing it from the brain during the deep stages of sleep may be the reason why adequate sleep reduces the risk of developing AD. This may also be a potential mechanism of the protective effect of PA on brain health in older age; PA promotes better sleep quality, which may in turn, helps clear harmful wastes, such as Aβ from the brain, thereby reducing the risk of dementia.

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6. Conclusions

Several studies demonstrate the protective effect of PA on brain health, particularly by reducing the risk for the neurodegenerative dementia-causing diseases, AD and VaD, as well as their precursor, MCI. We have described potential direct and indirect mechanisms of this protective effect. More research is warranted to explore the relationships between PA and the aging brain. Other factors, including genetics, may affect the development of neurological disorders. However, in most cases, moderate PA is beneficial for both physical and mental health in older adults. Moderate-intensity aerobic exercise, resistance training, stretching, toning, and a range of motion exercises, may yield cognitive benefits in older adults. Although the exact mechanisms by which PA decreases the risk for dementia is not fully understood, PA should be encouraged [124], since it improves the quality of life for all older adults. The existing evidence shows that rates of dementia could be reduced, if people were physically active [10]. There is a possibility that PA may become the most important behavioral factor in facilitating healthy mental and physical aging (Figure 1). Current evidence supports PA’s short and long term cognitive benefits, regardless of age. Many mechanisms responsible for the PA’s protective effect against age-related cognitive impairment are still not fully understood.