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.



Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia

Stroke. 2017 Apr 20. pii: STROKEAHA.116.016027. doi: 10.1161/STROKEAHA.116.016027. [Epub ahead of print]

Sugar– and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study.

Pase MP1, Himali JJ2, Beiser AS2, Aparicio HJ2, Satizabal CL2, Vasan RS2, Seshadri S2, Jacques PF2.



Sugar– and artificiallysweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar– or artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort.


We studied 2888 participants aged >45 years for incident stroke (mean age 62 [SD, 9] years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 [SD, 6] years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991-1995), 6 (1995-1998), and 7 (1998-2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer’s disease).


After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer’s disease dementia. When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26-6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18-7.07) for Alzheimer’s disease. Sugarsweetened beverages were not associated with stroke or dementia.


Artificially sweetened soft drink consumption was associated with a higher risk of stroke and dementia.


© 2017 American Heart Association, Inc.


Risk of Pneumonia Associated with Incident Benzodiazepine Use Among Adults with Alzheimer Disease

CMAJ. 2017 Apr 10;189(14):E519-E529. doi: 10.1503/cmaj.160126.

Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease.

Taipale H1, Tolppanen AM2, Koponen M2, Tanskanen A2, Lavikainen P2, Sund R2, Tiihonen J2, Hartikainen S2.



Knowledge regarding whether benzodiazepines and similarly acting non-benzodiazepines (Z-drugs) are associated with an increased risk of pneumonia among older adults is lacking. We sought to investigate this association among community-dwelling adults with Alzheimer disease, a condition in which both sedative/hypnotic use and pneumonia are common.


We obtained data on all community-dwelling adults with a recent diagnosis of Alzheimer disease in Finland (2005-2011) from the Medication use and Alzheimer disease (MEDALZ) cohort, which incorporates national registry data on prescriptions, reimbursement, hospital discharges and causes of death. Incident users of benzodiazepines and Z-drugs were identified using a 1-year washout period and matched with nonusers using propensity scores. The association with hospital admission or death due to pneumonia was analyzed with the Cox proportional hazards model and adjusted for use of other psychotropic drugs in a time-dependent manner.


Among 49 484 eligible participants with Alzheimer disease, 5232 taking benzodiazepines and 3269 taking Z-drugs were matched 1:1 with those not taking these drugs. Collectively, use of benzodiazepines and Z-drugs was associated with an increased risk of pneumonia (adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.05-1.42). When analyzed separately, benzodiazepine use was significantly associated with an increased risk of pneumonia (adjusted HR 1.28, 95% CI 1.07-1.54), whereas Z-drug use was not (adjusted HR 1.10, 95% CI 0.84-1.44). The risk of pneumonia was greatest within the first 30 days of benzodiazepine use (HR 2.09, 95% CI 1.26-3.48).


Benzodiazepine use was associated with an increased risk of pneumonia among patients with Alzheimer disease. Risk of pneumonia should be considered when weighing the benefits and risks of benzodiazepines in this population.


© 2017 Canadian Medical Association or its licensors.


Association between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition

JAMA. 2017 Apr 11;317(14):1443-1450. doi: 10.1001/jama.2017.3090.

Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition.

Gottesman RF1, Schneider AL2, Zhou Y3, Coresh J4, Green E5, Gupta N6, Knopman DS7, Mintz A8, Rahmim A3, Sharrett AR4, Wagenknecht LE9, Wong DF10, Mosley TH11.



Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood.


To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET).

Design, Setting, and Participants

The Atherosclerosis Risk in Communities (ARIC)-PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015.


Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level.

Main Outcomes and Measures

Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable.


Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old.

Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65).

At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4% [n = 62], and 61.2% [n = 82], respectively).

In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69).

No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69).

Conclusions and Relevance

An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.


© 2017 American Medical Association. All Rights Reserved.


The Discovery of Alzheimer’s Disease

Dialogues Clin Neurosci. 2003 Mar; 5(1): 101–108.

The discovery of Alzheimer’s disease

Hanns Hippius, MD*
Hanns Hippius, Psychiatrische Klinik der LMU, Munich, Germany;

Gabriele Neundörfer, MD
Gabriele Neundörfer, Psychiatrische Klinik der LMU, Munich, Germany;


On Novembers, 1306, a clinical psychiatrist and neuroanatomist, Alois Alzheimer, reported “A peculiar severe disease process of the cerebral cortex” to the 37th Meeting of South-West German Psychiatrists in Tubingen, He described a 50-year-old woman whom he had followed from her admission for paranoia, progressive sleep and memory disturbance, aggression, and confusion, until her death 5 years later. His report noted distinctive plaques and neurofibrillary tangles in the brain histology. It excited little interest despite an enthusiastic response from Kraepelin, who promptly included “Alzheimer’s disease” in the 3ih edition of his text Psychiatrie in 1910. Alzheimer published three further cases in 1909 and a “plaque-only” variant in 1911, which reexamination of the original specimens in 1993 showed to be a different stage of the same process, Alzheimer died in 1915, aged 51, soon after gaining the chair of psychiatry in Breslau, and long before his name became a household word.

The 37th Meeting of South-West German Psychiatrists (37 Versammlung Sudwesideutscher Irrenarzte) was held in Tubingen on November 3, 1906. At the meeting, Alois Alzheimer (Figure 1), who was a lecturer(Privatdozent) at the Munich University Hospital and a coworker of Emil Kraepelin, reported on an unusual case study involving a “peculiar severe disease process of the cerebral cortex” (Uber einen eigenartigen, schweren Erkrankungsprozeβ der Hirnrinde).

Figure 1.

Figure 1. Alois Alzheimer. About 1909. © Archive for History of Psychiatry, Department of Psychiatry University of Munich. With permission.


Alzheimer described the long-term study of the female patient Auguste D., whom he had observed and investigated at the Frankfurt Psychiatric Hospital in November 1901 , when he was a senior assistant, there. Alzheimer had been interested in the symptomatology, progression, and course of the illness of Auguste D. from the time of her admission, and he documented the development of her unusual disease very precisely from the beginning.

In March 1901 , the husband of the 50-year-old woman had noticed an untreatable paranoid symptomatology in his wife and then – in fast progression and with increasing intensity – sleep disorders, disturbances of memory, aggressiveness, crying, and progressive confusion. Eventually, the husband was forced to take his wife to the Community Psychiatric Hospital at Frankfurt am Main, lite symptomatology increasingly deteriorated and so Auguste D. remained an inpatient of the hospital up to her death on April 8, 1906.

After the autopsy, Alzheimer was able to investigate the brain of Auguste D.both morphologically and histologically. These results and their relationship with the clinical findings recorded over more than 4 years were the basis for Alzheimer’s lecture at the Tubingen meeting.

The chairman of the session was the very prominent psychiatrist from the University of Freiburg, Alfred Hoche (1865-1943). Hoche was a scientific opponent of Kraepelin and his nosological concept and classification of psychiatric diseases. Kraepelin was not in the audience during Alzheimer’s presentation.

After Alzheimer’s lecture, Hoche, departing from the usual role of a chairman, did not comment on Alzheimer’s presentation and only once or twice asked the audience for comments or questions. He stated that, there was no need for discussion and invited the next, speakers to continue with their lectures. These were two contributions to psychoanalytical topics, and were followed by long and very lively discussions, including some active comments from the chairman.

The lack of interest from the numerous and well-known scientists in the audience was a great disappointment, for Alzheimer. Moreover, only a very short abstract, was printed in the official proceedings of the meeting.1 Tubingen’s public press commented extensively on the psychoanalytical lectures, whereas only two lines were devoted to Alzheimer’s lecture. Such was the beginning of communication on research into Alzheimer’s disease!2

Alois Alzheimer

Alois Alzheimer was born into a Catholic family on June 14, 1864, in the small town of Marktbreit in Lower Frankonia close to Würzburg on the river Main.24 His father was a royal notary in the Kingdom of Bavaria who had lost his first, wife 2 years previously to puerperal fever after giving birth to their first son. Alzheimer’s father married the sister of his dead wife and had six more children with her – the eldest child was Alois Alzheimer.

Alois Alzheimer went to elementary school in Marktbreit and later to classic secondary school in Aschaffenburg. After he left, school, Alzheimer became a college student in Berlin, Freiburg, and Wtirzburg (1883-1885). Very early on, in the first few academic trimesters, he became interested in anatomy and learned to work with microscopes.

As a young student, he attended some lectures on forensic psychiatry, but later during clinical training he was extensively occupied in all clinical disciplines, with one notable exception: he probably never attended clinical lectures in psychiatry! After a dissertation in anatomy, he finished his studies at Wtirzburg and obtained the official diploma in medicine with magna cum laude.

At this time, there were no indications that Alzheimer was destined to follow a career in psychiatry. However, a more or less accidental event after the end of his studies in medicine may have influenced him in this direction. At the end of the 19th century, some very wealthy German families had an unusual approach to the care of a mentally ill relative: they engaged a young medical doctor to travel with the patient. Alzheimer had such an offer and traveled for 5 months (May to October 1888) with a mentally ill female patient. Unfortunately, no information is known regarding this patient’s illness or identity, or the travel itinerary.

Upon returning from this journey, at the age of 24 years, Alzheimer applied for a position as assistant in the Community Hospital for Mental and Epileptic Patients (Städlische Anstalt fur Irre und Epileptiker) in Frankfurt am Main. The director of the Frankfurt Hospital, Emil Sioli (1852-1922), accepted Alzheimer’s application. Alzheimer worked with Sioli for 15 years (1888-1903) and was strongly influenced by him: Alzheimer thus became an all-round skilled clinician.

Sioli had held this position in Frankfurt since 1888 and he was the successor of the pediatrician H. Hoffmann (well known as the author of Shock-Headed Peter [Der StruwwelpeterJ).As a psychiatrist, Sioli directed the hospital with the main idea of nonrestraint psychiatry, an idea introduced from Great Britain, but at that time still controversial in Germany.

Today, many people believe that Alzheimer was a pure neuropathologist, but all information on his own selfassessment, as well as the summary of his scientific publications – after working with Sioli – demonstrate that he identified himself primarily as a clinical psychiatrist responsible for patients.

In addition to his development, as a clinician in Frankfurt, Alzheimer did not neglect. Ms interest in anatomy dating from his time as a young student in Berlin and Würzburg. This interest was enhanced by Franz Nissl (1860-1919), who came from Munich to work with Sioli in. Frankfurt 1 year after Alzheimer.

Nissl had already worked in neuroanatomy and neuropathology as a student, and had discovered a special histological staining technique (Nissl stain), which is still in use today. In Munich, Nissl had been a coworker of B. von Guddcn in his brain research laboratory. After the tragic death of von Gudden, who was found drowned with his patient Ludwig II, King of Bavaria, in 1886, Nissl sought, a new comparable position and, with the help of Sioli, became senior assistant at the Frankfurt Hospital in 1889.

From the beginning, Nissl and Alzheimer became good colleagues and close friends. The more senior Nissl encouraged young Alzheimer to actively continue research alongside his clinical work. Alzheimer followed Nissl’s advice and worked on topics such as general paresis in children and young adults,5 and brain atrophy in patients with cerebral arteriosclerosis,6 epilepsy,7 or dementia] diseases.8 He also published pioneering ideas on the contribution of the cortex to pathology, as the anatomical basis of some psychotic diseases.9

During his Frankfurt years, in 1895, Alzheimer married the very wealthy Cecilia Geisenheimer (née Wallerstein); Nissl was a witness at the marriage ceremony. Due to the prosperous financial background of his wife, Alzheimer was henceforth financially independent. His aim was to become an independent clinical director of a psychiatric hospital in which he could do research, but not exclusively Nissl left Frankfurt in 1896 because he had been invited by Emil Kraepelin (1856-1926) to work at the University Hospital of Heidelberg, which was directed by Kraepelin between 1890 and 1903.

Nissl accepted the invitation because he thus achieved a position at a university with better conditions for research. Both Nissl and Alzheimer regretted that they could no longer work together at the same hospital. However, they continued their friendship and their scientific exchange for the rest of their lives.

On the other hand, Nissl’s move to Heidelberg brought about an improvement in Alzheimer’s position at the Frankfurt Hospital. Sioli recommended Alzheimer to the authorities as Nissl’s successor as first assistant and deputy director of the hospital.

The official appointment to this position was in July 1896. This appointment represented an important step for Alzheimer toward his professional target: to become the director of a psychiatric hospital.

The following years were satisfactory for Alzheimer not only with regard to his professional situation, but also with respect, to his particularly harmonious family life with his wife and three children born between 1895 and 1900.2


For Alzheimer, the year 1901 marked a difficult turning point in his life. Some months after the birth of their third child, his 41 -year-old wife died. Alzheimer was now a widower and had to take care of three children. Although his income from Ms position at the hospital was small, he had his wife’s extensive inheritance. One of his unmarried sisters moved to Frankfurt to look after the household because Alzheimer wanted to live with his family and to work at, or near to, Frankfurt. He planned to apply for leading positions in this area.

To overcome the grief of his wife’s death, Alzheimer worked more intensively at the hospital than ever before. He saw all newly admitted patients and made a detailed and extensive documentation of his findings. On November 26, 1901, he investigated the newly admitted female patient Auguste D., not imagining for one moment, that the clinical investigation of this patient would be the starting point for a development that would make him famous throughout the world!

From Frankfurt to Munich via Heidelberg

Apart from his very intensive clinical work, Alzheimer – together with Sioli – organized the establishment of a special branch hospital for mental patients close to Frankfurt in the Taunus mountains. In addition, he began to write a so-called Habilitationssdirift (postdoctoral thesis for a university lecturing qualification) as a basis for an application at a medical faculty of a German university.

He was in possession of the clinical and the postmortem findings of 320 patients with the diagnosis of “Progressive Paralyse” (general paresis), investigated at the Frankfurt Hospital since 1888. (Around 1900, more than 25% of chronic psychiatric inpatients suffered from this disease and were hospitalized up to their death. The relationship between syphilis and general paresis was still controversial: Treponema pallidum, [Spirochaela pallida] had not yet been discovered and no effective treatment was available.)

In the summer of 1902, little more than one year after the death of Alzheimer’s wife, Emil Kraepelin invited him to join the Heidelberg research team as assistant to the Heidelberg Hospital. This was a great honor because Kraepelin was at the time one of the most, prominent and influential psychiatrists in Germany.

In addition, Alzheimer’s great friend Nissl had then been working in the Heidelberg Hospital for 7 years. In spite of many reasons in favor of Heidelberg, Alzheimer refused Kraepelin’s invitation and applied – unsuccessfully – for the leading position in a Hessian state hospital.

When Nissl heard about, this, he persuaded Kraepelin to repeat his offer of a position at the Heidelberg Hospital to Alzheimer. Kraepelin did so and Alzheimer accepted; he moved to Heidelberg at the end of 1902.10

Sioli and the Frankfurt, authorities explicitly regretted the departure of Alzheimer. However, Sioli approved of Alzheimer’s decision, since it led to a university position (the University of Frankfurt was only established in 1914). Sioli promised Alzheimer that he would tell him of the fate of all the patients who had been of special interest to Alzheimer from a scientific point of view. Thus, some years later, Alzheimer obtained information on the course of Auguste D.’s illness and her death at the Frankfurt Hospital in April 1906.

Alzheimer moved to Heidelberg expecting to work there for a long time. However, just one month later in April 1903, the Professor of Psychiatry in Munich, A. Bumm (1849-1903), died at the age of 54. For some years, Bumm had been responsible for the planning and construction of a new modern, large university hospital for psychiatry. At the time of Bumm’s unexpected death, the building was not yet finished and the Munich chair suddenly became vacant. On the recommendation of the Faculty of Medicine, the chair and directorship were offered to Kraepelin.

After only momentary hesitation, Kraepelin agreed to soon take up the position and moved in autumn 1902. He was accompanied by three coworkers from his Heidelberg team, one of whom was Alzheimer. Kraepelin used the remaining year till the official opening of the hospital in November 1904 to work on his textbooks and undertook a long voyage to explore Indonesia.

During this time, Alzheimer’s task in Munich was the supervision of the completion of the building and the organization of hospital equipment. After his return, Kraepelin stated that. Alzheimer had done an excellent job.10 With regard to hospital equipment, a very modern and spacious histopathological laboratory with the most modem microscopes and other apparatus was established (Figure 2), enabling Alzheimer to continue his histopathological research.

Figure 2.

Figure 2. Alzheimer’s modern histopathological laboratory in the Psychiatric University Hospital in Munich, 1904. © Archive for History of Psychiatry, Department of Psychiatry University of Munich. With permission.

After the opening of the hospital in November 1904, R. Gaupp (1870-1953) (Figure 3) was appointed senior assistant and Alzheimer became Kraepelin’s first, research assistant. In this position, Alzheimer received no payment, but he could devote all his time to research. Alzheimer’s remarkable private fortune enabled him to work under these peculiar conditions.

Figure 3.

Figure 3. (Left to right) A. Alzheimer, E. Kraepelin, R. Gaupp, and F. Nissl. About 1906. © Archive for History of Psychiatry, Department of Psychiatry University of Munich. With permission.

Alzheimer was head of the histopathological laboratory until 1912. During these 8 years, numerous young scientists from many countries were trained by Alzheimer and later became famous neuropathologists or clinical psychiatrists. The list, of Alzheimer’s coworkers (Figure 4) includes many prominent names – N. Achucarro, I. Bonfiglio, L. Casamaior, U. Cerletti, H-G Crcutzfeld, C. v. Econome, A. Jakob, K. Kleist, F. H. Lewy, L. Merzbacher, G. Perusini, and W. Spielmeyer – a who’s who of contemporary neuropathology!

Figure 4.

Figure 4. Alzheimer and coworkers in Munich. Back (left to right); F. Lotmar; unknown; St Rosental; Allers (?); unknown; A. Alzheimer; M. Achucarro, F H. Levy. Front (left to right); Frau Grombach; U. Cerletti; unknown; F Bonfiglio; G. Perusini. About 1909.

In October 1903, a short time after moving to Munich, Alzheimer arranged for his children to follow him and they all lived in a large house near the hospital, together with his sister as housekeeper. Furthermore, at the end of 1904, he bought, a big weekend house beside a small lake near Munich.

An important step in Alzheimer’s academic career came in November 1903 when he presented hisHabilitationsschrift in Munich. ‘Ill e manuscript, entitled Differential diagnosis of general paresis on the basis of histological studies (Histologische Studien zur Differ entialdiagnose der progressiven Paralyse) , was printed as an almost 300-page book soon afterwards 11and Alzheimer was appointed Privatdozent (lecturer) in August 1904.


The case of Auguste D.

After the Munich Hospital had opened (November 11, 1904), Alzheimer hoped to again have more time for his research. This happened only for a short time, but with great effect. In April 1906, Sioli, with whom Alzheimer worked in .Frankfurt, informed him of the death of the patient Auguste D., arranged an autopsy, and gave him brain material for investigation. By this means, epoch-making research was enabled.12,13

Alzheimer discovered and described the histological alterations later known as plaques and neurofibrillary tangles.14 He presented these findings to Kraepelin and the other scientists in the Munich research team, convincing all of them that, such histopathological findings in connection with such a clinical symptomatology and course of illness had never been seen before.

Kraepelin encouraged Alzheimer to present the case of Auguste D. as soon as possible at the next scientific congress of German psychiatrists in the autumn of 1906 in Tubingen. The lack of response to this discovery at this meeting was very disappointing for Alzheimer, but he did not give up his search for comparable cases. He felt, satisfied that his lecture, which had not been mentioned at Tubingen, was published one year after the conference.15

Due to changes at the Munich Hospital, Alzheimer’s hopes of being able to devote all his time to research in the histopathological laboratory were dashed. Robert Gaupp, who had moved together with Kraepelin and Alzheimer from Heidelberg to Munich, was offered the chair of psychiatry and the directorship of the Medical Faculty of the University of Tubingen (1906-1939). Gaupp accepted this appointment and left Munich in October 1906. Kraepelin entrusted Alzheimer, as Gaupp’s successor, with the position of deputy director.

Alzheimer was now occupied with many additional obligations: care of patients, training of young psychiatrists, teaching of students, expert reports in psychiatry, and administrative duties. Therefore, Alzheimer delegated the research in the histopathological laboratory to his team of coworkers, which every year was becoming bigger.

Notably, Gactano Perusini from Italy specialized in research on cases with dementing processes. After 1906, Perusini and Alzheimer observed three additional cases comparable to that of Auguste D., and Perusini published these four cases, together with all clinical and histopathological details in 1909.16

Between 1906 and 1909, Kraepelin prepared the 8th edition of his famous textbook Psychiatrie A As he had soon recognized the fundamental significance of Alzheimer’s findings, he included a report, on the case history of Auguste D. in the written text of 1908 and proposed calling this peculiar illness Alzheimer’s disease. Both volumes of the new edition of Kraepelin ‘s textbook came out in 1910.

In this way, very soon after the description of the first case, the diagnostic term Alzheimer’s disease was introduced by Kraepelin’s authority and, since that time, has been generally used. However, in spite of this fact, because this disease – presenile dementia with some unusual histological signs (plaques and neurofibrillary tangles) – was very rare, the name of Alois Alzheimer was almost forgotten for more than 50 years. During the last, few decades, the situation has changed considerably.

The case of Josef F.

In 1911, Alzheimer himself published again in a broader context on presenile and senile dementing processes.18 He described how the male patient Josef F. died after 3 years of hospitalization in Munich in 1910. Kraepelin had already mentioned the case of Josef F. in his textbook, and had diagnosed him as having Alzheimer’s disease17 before death. The histological investigation confirmed the clinical diagnosis, but there was one important difference. Alzheimer noticed that there were no neurofibrillary tangles in the slide preparations of Josef F.’s brain, only plaques.

For a long time, it was considered to be contradictory if “plaque-only” cases belonged to the same category as cases with plaques and neurofibrillary tangles. A singular situation in research in recent years has provided a solution to this problem. In 1995, after an intensive search of the Frankfurt archives, K. Maurer discovered the documentation of the clinical findings of Auguste D.19

Histopathological slide preparations of her brain were subsequently found in the Munich Institute of Neuropathology. Documentation on the illness of Josef F. up to his death was found in clinical archives of the Munich Psychiatric Hospital and, after a long search, M. B. Graeber finally discovered the brain slide preparation in the depot of the Munich Institute of Neuropathology, where it had been stored since 1911.19

The material of both cases (Auguste D. and Josef F.) was reinvestigated with modern ncurohistochcmical techniques. The results of this investigation and analysis of all findings together with a summary on literature and conceptual interpretations were published by H-J. Moller and M. B. Graeber.2

Their conclusion was that plaque-only cases and cases with plaques and neurofibrillary tangles are simply different stages in the development of the same disease process.20 This means that – in addition to his pioneering discovery of the case of Auguste D. in 1906 – a few years later, Alzheimer was the first person to describe an important stage of development of the illness associated with his name with the case of Josef F. also.

From Munich to Breslau

Kraepelin had promised Alzheimer that, after the departure of Gaupp (1906), he would only be in charge as deputy director for a short time. However, this state of affairs lasted 3 years until E. Rtidin (1874-1952) was appointed to take over all of Alzheimer’s routine duties. Since he now had more time for research, Alzheimer was mainly occupied from 1909 onwards with histopathological studies on all kinds of psychotic mental diseases, including dementia praccox (schizophrenia) and manicdepressive psychoses. The aim was to also find a neuropath ological basis for these so-called endogenous psychoses.

Kraepelin was especially hopeful that Alzheimer would be successful, in order to demonstrate that his concept of dichotomy of these psychotic diseases was right. Alzheimer intended to publish all his findings in a comprehensive book, but he was not able to finish this project. He was also occupied with more general problems of research in psychiatric illness, notably with the difficulties in correlating clinical diagnosis and postmortem findings.21

In addition, on Kraepclin’s advice, in 1910, together with 3 the neurologist M.Lewandowsky (1876-1918), Alzheimer established a new scientific journal Zeitschrift für die gesamte Neurologie und Psychiatrie. The first introductory contribution of this new journal was written by Alzheimer himself.21

In 1912, he was appointed Chair of Psychiatry at the University of Breslau. This position was the realization of his dreams as a young assistant at the psychiatric hospital at Frankfurt, for his professional life: to work as clinician and director responsible for a psychiatric hosr pital. Unfortunately, he had very few years left to work in Breslau, for he died there at the age of 51 on December 19,1915.


National Center for Biotechnology Information, U.S. National Library of Medicine


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.



Prolonged Sleep Duration as Marker of Early Neurodegeneration Predicting Dementia

Neurology. 2017 Feb 22. pii: 10.1212/WNL.0000000000003732. doi:[Epub ahead of print]

Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia.

Westwood AJ1, Beiser A1, Jain N1, Himali JJ1, DeCarli C1, Auerbach SH1, Pase MP2, Seshadri S2.



To evaluate the association between sleep duration and the risk of incident dementia and brain aging.


Self-reported total hours of sleep were examined in the Framingham Heart Study (n = 2,457, mean age 72 ± 6 years, 57% women) as a 3-level variable: <6 hours (short), 6-9 hours (reference), and >9 hours (long), and was related to the risk of incident dementia over 10 years, and cross-sectionally to total cerebral brain volume (TCBV) and cognitive performance.


We observed 234 cases of all-cause dementia over 10 years of follow-up. In multivariable analyses, prolonged sleep duration was associated with an increased risk of incident dementia (hazard ratio [HR] 2.01; 95% confidence interval [CI] 1.24-3.26). These findings were driven by persons with baseline mild cognitive impairment (HR 2.83; 95% CI 1.06-7.55) and persons without a high school degree (HR 6.05; 95% CI 3.00-12.18).

Transitioning to sleeping >9 hours over a mean period of 13 years before baseline was associated with an increased risk of all-cause dementia (HR 2.43; 95% CI 1.44-4.11) and clinical Alzheimer disease (HR 2.20; 95% CI 1.17-4.13). Relative to sleeping 6-9 hours, long sleep duration was also associated cross-sectionally with smaller TCBV (β ± SE, -1.08 ± 0.41 mean units of TCBV difference) and poorer executive function (β ± SE, -0.41 ± 0.13 SD units of Trail Making Test B minus A score difference).


Prolonged sleep duration may be a marker of early neurodegeneration and hence a useful clinical tool to identify those at a higher risk of progressing to clinical dementia within 10 years.


© 2017 American Academy of Neurology.


Vitamin E for Alzheimer’s Dementia and Mild Cognitive Impairment

Cochrane Database Syst Rev. 2017 Jan 27;1:CD002854. doi: 10.1002/14651858.CD002854.pub4. [Epub ahead of print]

Vitamin E for Alzheimer’s dementia and mild cognitive impairment.

Farina N1, Llewellyn D2, Isaac MG3, Tabet N1.



Vitamin E occurs naturally in the diet. It has several biological activities, including functioning as an antioxidant to scavenge toxic free radicals. Evidence that free radicals may contribute to the pathological processes behind cognitive impairment has led to interest in the use of vitamin E supplements to treat mild cognitive impairment (MCI) and Alzheimer’s disease (AD). This is an update of a Cochrane Review first published in 2000, and previously updated in 2006 and 2012.


To assess the efficacy of vitamin E in the treatment of MCI and dementia due to AD.

Search Methods

We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources on 22 April 2016 using the terms: “Vitamin E”, vitamin-E, alpha-tocopherol.

Selection Criteria

We included all double-blind, randomised trials in which treatment with any dose of vitamin E was compared with placebo in people with AD or MCI.

Data Collection and Analysis

We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. Where appropriate we attempted to contact authors to obtain missing information.

Main Results

Four trials met the inclusion criteria, but we could only extract outcome data in accordance with our protocol from two trials, one in an AD population (n = 304) and one in an MCI population (n = 516). Both trials had an overall low to unclear risk of bias. It was not possible to pool data across studies owing to a lack of comparable outcome measures.

In people with AD, we found no evidence of any clinically important effect of vitamin E on cognition, measured with change from baseline in the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog) over six to 48 months (mean difference (MD) -1.81, 95% confidence interval (CI) -3.75 to 0.13, P = 0.07, 1 study, n = 272; moderate quality evidence).

There was no evidence of a difference between vitamin E and placebo groups in the risk of experiencing at least one serious adverse event over six to 48 months (risk ratio (RR) 0.86, 95% CI 0.71 to 1.05, P = 0.13, 1 study, n = 304; moderate quality evidence), or in the risk of death (RR 0.84, 95% CI 0.52 to 1.34, P = 0.46, 1 study, n = 304; moderate quality evidence). People with AD receiving vitamin E showed less functional decline on the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory than people receiving placebo at six to 48 months (mean difference (MD) 3.15, 95% CI 0.07 to 6.23, P = 0.04, 1 study, n = 280; moderate quality evidence).

There was no evidence of any clinically important effect on neuropsychiatric symptoms measured with the Neuropsychiatric Inventory (MD -1.47, 95% CI -4.26 to 1.32, P = 0.30, 1 study, n = 280; moderate quality evidence).

We found no evidence that vitamin E affected the probability of progression from MCI to probable dementia due to AD over 36 months (RR 1.03, 95% CI 0.79 to 1.35, P = 0.81, 1 study, n = 516; moderate quality evidence). Five deaths occurred in each of the vitamin E and placebo groups over the 36 months (RR 1.01, 95% CI 0.30 to 3.44, P = 0.99, 1 study, n = 516; moderate quality evidence).

We were unable to extract data in accordance with the review protocol for other outcomes. However, the study authors found no evidence that vitamin E differed from placebo in its effect on cognitive function, global severity or activities of daily living . There was also no evidence of a difference between groups in the more commonly reported adverse events.

Author’s Conclusions

We found no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD. However, there is moderate quality evidence from a single study that it may slow functional decline in AD.

Vitamin E was not associated with an increased risk of serious adverse events or mortality in the trials in this review. These conclusions have changed since the previous update, however they are still based on small numbers of trials and participants and further research is quite likely to affect the results.