Citation: Kristyn Alissa Bates. Gene-environment interactions in considering physical activity for the prevention of dementia[J]. AIMS Molecular Science, 2015, 2(3): 359-381. doi: 10.3934/molsci.2015.3.359
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Alzheimer’s disease (AD) is a devastating neurodegenerative disease named after the German Psychiatrist Dr Alois Alzheimer who first described the condition over 100 years ago [1]. Present estimates put the number of people living with dementia worldwide at 47 million and the majority of these people will have AD [2]. In the absence of an effective treatment or cure, that number is projected to triple by 2050, meaning that 1 in 85 adults will be living with AD [3], thus constituting a massive economic and emotional burden on society.
AD is characterised histopathologically by the abnormal deposition of two proteins, amyloid-beta (Aβ) [4,5] and hyperphosphorylated tau [6,7]. Traditionally, a definitive diagnosis of AD was only possible upon post-mortem analysis, but recent neuro-imaging techniques are making it possible to detect Aβ deposition decades before the onset of symptoms [8] and can therefore assist in identifying at-risk individuals and monitor disease progression. Tau radioisotopes for PET imaging are also an area of intense research activity (e. g. [9,10]. Clinically, AD is characterised by problems with specific aspects of learning and memory that progress to more global cognitive decline in the advanced stages, however accurate diagnosis based on clinical symptoms alone, particularly in the early stages of the disease is problematic [11].
Lastly, AD can be broadly categorised into two groups based on age of onset, late-onset AD, which occurs over the age of 65, and early-onset AD. Late-onset AD constitutes the vast majority of AD cases and is multifactorial in nature [12,13], however no known cause has yet been identified. Early-onset AD is much more rare and caused by autosomal dominant inheritance of mutations in three known genes, amyloid precursor protein (APP), presenilin-1 (PSEN1) and presenilin-2 (PSEN2) [14]. Down syndrome (trisomy 21) is also linked with AD, because a significant number of affected individuals develop the neuropathology of AD by the fifth decade of life. Over-production of APP and Aβ [15,16] by virtue of the location of the gene on Chromosome 21, is thought to contribute to the increased incidence of AD in people with Down syndrome.
It is clear that AD is a multifactorial disease, with a convergence of genetic, environmental and lifestyle factors involved in the disease process. Given the multitude of factors, it is useful to categorise them into modifiable or non-modifiable factors. For the purposes of this review, non-modifiable factors will include genetics, age and gender, whereas modifiable factors include lifestyle factors such as physical activity (PA), diet, cigarette smoking, depression, uncontrolled type 2 diabetes (T2D) and obesity.
In terms of non-modifiable factors, age is the biggest risk for AD [17,18], but it is important to remember that AD is not a part of normal ageing. The prevalence of AD increases with increasing age, where the latest rates from the United States indicate that 1 in 9 people over the age of 65 with AD, increasing to over 80% of people with AD being over the age of 75 years [18,19]. It is still unknown why the risk of AD increases with age, however reduced anti-oxidant capacity [20,21] and increased inflammation [22] are two age-related phenomena that may contribute to the pathogenesis of AD [23].
Women appear to be at greater risk of developing AD than men, even after controlling for sex-differences in life expectancy [24]. The risk may be age-dependent; with increasing age, women are more likely than men to develop AD [19]. Furthermore, the progression of AD in women may be faster than men, particularly at these older ages [25]. One hypothesis for this association is the reduction in gonadal hormones as a consequence of menopause, because gonadal hormones are known to have numerous neuroprotective actions in the CNS [26,27,28]. Though as is the case for ageing, the cause for this relationship is not completely understood.
Genetic polymorphism in the apolipoprotein E (APOE) gene is the strongest genetic risk factor for AD identified to date. The APOE ε4 allele is associated with increased risk for late-onset AD [29,30], in a gene-dose specific manner [31]. APOE ε4 has in turn been shown to influence elements of AD pathology including interactions with Aβ, tau and synaptic function [32,33,34,35,36,37] and also response to potential therapies [38,39,40]. Recent genome-wide association studies (GWAS) have identified numerous risk loci, however the risk conferred by these loci is much smaller than that of APOEε4 [41].
In 2011, Deborah Barnes and Kristine Yaffe published a review of the available literature pertaining to risk factors for AD. The paper suggested that up to half of all AD could be attributable to seven preventative risk factors [13]. Their findings were exciting not only because of the potential to prevent one, but multiple diseases, by modifying lifestyle choices. The seven factors identified by this study were diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity [13]. An updated analysis concluded that after taking into account the inter-relationships between these factors, approximately one third of AD could be prevented by improved access to educational opportunities and improved cardiovascular health [42]. Other important modifiable risk factors that have been identified in observational studies include traumatic brain injury [43] and cholesterol level fluctuations over the life span [44]. Exposure to environmental pollutants such as heavy metals and pesticides are also attracting attention as possible risk factors for neurodegenerative diseases, including AD [45].
PA is defined by the World Health Organization as “any bodily movement produced by skeletal muscles that requires energy expenditure” [46] and therefore includes exercise (a planned, structured, repetitive activity for the improvement or maintenance of physical fitness), but also activity that occurs as a consequence of house work chores, playing, working, active transportation and recreational activities. PA is an attractive target because this factor can contribute to reducing the risk of developing diabetes, preventing hypertension and obesity and also affects brain function—4 of the remaining 7 factors [47]. Because of this multitude of beneficial effects, PA is the focus of this review.
Exactly how regular PA confers protection against AD is not fully understood, however it is likely that PA has multiple direct and indirect beneficial effects that together contribute to brain health. Importantly, evidence is emerging that “its never too late” to benefit from increased PA in terms of AD prevention. A recent meta-analysis of 9 studies involving over 20, 000 participants confirmed that PA corresponds to a statistically significant reduction in risk of AD in older adults (over the age of 65 years). This meta-analysis also demonstrated a relationship between the level of PA and reduction in risk for AD in 6 out of the 9 studies analysed [48]. In other words, the more physically active you are, the less likely you are to develop AD. Furthermore, previous studies have reported long-lasting benefits, in terms of AD-risk reduction, of engaging in PA throughout the lifespan (as reviewed in [49]). It is apparent that PA exerts peripheral and central effects on brain function; outlined below are some of the ways that PA can influence brain function by altering psychological, biochemical and physiological parameters to ultimately improve cognitive performance.
Traditionally, studies have focussed on the relationship between PA and cardiovascular/aerobic fitness. However it is important to remember that improvements in health status can occur in the absence of measurable change in aerobic fitness such as cardiac output and oxidative potential [50]. For example, musculoskeletal fitness is strongly related to the ability of elderly people to maintain functional independence (reviewed in [47]) and reduces risks of falls [51], osteoporosis [52] and osteoarthritis [53]. Osteoporosis is also linked to increased risk for AD, possibly mediated by estrogen exposure in post-menopausal women [54,55,56].
Regular PA is known to reduce central adiposity and obesity, leading to reduced body fat and increased muscle mass (commonly measured as reduced body mass index-BMI) [49]. High BMI is in turn associated with poorer cognitive function and cerebral atrophy [57,58]. Central adiposity, as measured by waist-to-hip ratio is also associated with increased likelihood of neuropathological markers using brain imaging techniques [59]. Obesity at midlife significantly increases the risk of developing AD [60] and dementia [61]. Conversely, lean body mass and increased bone mineral density is associated with improved cognitive performance in healthy, older people [62]. The underlying mechanism linking body composition and brain health is not definitively known, however high-density lipoprotein (HDL) may be a major contributing factor. The evidence for this is four-fold; 1) HDL can bind to and facilitate clearance of Aβ [63,64], 2) PA can raise circulating HDL [65], 3) HDL is correlated with lower circulating Aβ [66] and 4) better cognitive performance in healthy aged people [67,68,69,70].
T2D and insulin resistance are also associated with increased risk for future AD [71]. There are many ways by which T2D may increase susceptibility to AD: through its association with other factors relating to “metabolic syndrome” (e. g. dyslipidemia, hypertension) [72], the toxic effects of prolonged exposure to high glucose levels [73] and through the neurobiological effects of insulin itself [74,75,76]. Regardless of the mechanism linking AD and T2D, studies suggest that PA has a role to play in the prevention of T2D [77,78], thus providing further support for the role of PA in the prevention of AD.
The beneficial effects of PA on the brain may also be mediated by increased production of growth factors such as brain derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF1) [79]. BDNF is a molecule central to the processes of learning and memory, hippocampal function and depression and anxiety [80]. PA has been consistently shown to up-regulate BDNF expression in several brain regions, particularly the hippocampus [81,82]. A series of elegant experiments over a number of years in animal models have demonstrated the central role of BDNF in mediating the improved learning response after PA. When rats are deprived of voluntary PA (i. e. wheel-running), the genes for both BDNF and its receptor (TrkB) are down-regulated [83]. Blocking the interaction of BDNF and TrkB receptors prevents the acquisition and retention of learning tasks [84] and also attenuates the induction of synaptic protein expression by PA in rodent models [85]. There may even be long-lasting effects of PA on BDNF signalling because mice that have been selectively bred for high wheel running have larger brain regions, higher BDNF levels, increased hippocampal neurogenesis and higher vascular endothelial growth factor (VEGF) levels and capillary density [86]. IGF1 is another growth factor that is up-regulated by PA [87]. Interestingly, IGF1 and BDNF act synergistically to mediate the effects of PA on the hippocampus [88,89]. Furthermore, IGF1 can also influence brain amyloidosis and tau hyperphosphorylation, key features of AD pathology [90].
Self-reported PA is associated with larger brain volumes, as measured by brain imaging techniques, compared to participants who report little or no PA [91]. Frontal lobe and medial temporal lobe structures are preferentially affected by PA in older adults [92]. The positive relationship between PA and brain volume also remains in patients with mild cognitive impairment (MCI) and AD [93]. Self-reported PA at midlife is associated with long-term benefits in terms of brain volume, particularly grey matter volume in the frontal areas, after a 21-year follow-up period [94], reinforcing the concept that lifetime engagement in PA can result in long-term health benefits. A randomised controlled trial utilising an aerobic-based PA program showed an increase in hippocampal volume and higher serum BDNF levels in the exercise compared to control groups in older adults [95]. In patients with early-stage AD, objective measures of PA (cardiovascular fitness) are associated with reduced brain atrophy [96] and preservation of medial temporal lobe structures [97], indicating that maintaining PA even through the onset of disease, can provide some benefit.
In rodents, voluntary PA has been shown to enhance hippocampal function by increasing learning rate in older animals [98,99]. A number of meta-analyses have been conducted to determine whether PA can influence cognitive performance (recently reviewed in [100]). The positive influence of PA on cognition remains for older adults with and without cognitive impairment [101] and appears to be greatest for executive functions, such as planning, working with memory and multi-tasking [102]. PA may also help prevent loss of spatial ability with age [103]. Recent studies have demonstrated that physically active younger adults have a higher degree of functional connectivity between brain regions than their more sedentary counterparts [104]. An aerobic exercise intervention program in older adults (aged 70-85 years) also resulted in greater brain network connectivity than sedentary controls over a 4 month period [105]. PA interventions can also induce plasticity in functional networks and brain activation patterns resulting in improved cognitive performance in cognitively healthy older adults [106]. Whilst these initial studies are on a small sample group, they do suggest that engaging in PA can enhance efficiency of brain networks, thus altering the functional connectivity and structure of the brain.
PA can influence mood and reduce depressive symptoms, both of which are known to influence cognitive performance and risk of later decline. PA has been shown to reduced the risk of both prevalent and incident depression in older adults over a 5 year follow-up period [107]. Reduced mobility is associated with increased risk of depression [108], indicating that keeping people active is an important intervention to be considered for people with disability [109]. The protective effect of PA against depression is also observed when objective measures of PA are used for elderly subjects [110]. PA is also associated with lower depressive symptoms and improved perception of quality of life for residents of institutionalised care facilities [111]. The protective benefit of PA remains after controlling for confounding demographic variables such as ethnicity, socioeconomic status, smoking and BMI [112]. Relatively simple PA interventions, for example, walking have been shown to reduce the severity of symptoms for older people with depression [113], and there is a suggestion that aerobic, rather than resistance exercise may be most beneficial for ameliorating depression [114]. PA can also reduce the severity of symptoms for elderly people with anxiety disorders [115].
Arguably, some of the most exciting data to date has shown that PA has disease-modifying capabilities. In 2005, Lazarov and colleagues demonstrated that environmental enrichment, including provision of running wheels, led to a reduction in Aβ load in a transgenic mouse model [116]. In the same year, Adlard and colleagues showed that voluntary exercise alone was sufficient to reduce amyloid load in transgenic mouse models [117], although to date, no studies have demonstrated that PA can remove pre-existing Aβ load.
Similar results are seen in human studies, where higher levels of physical activity are correlated with improved AD-associated biomarker panels such as CSF Aβ and tau and brain amyloid load as measured by carbon 11-labelled Pittsburgh Compound B-positron emission tomography [11C] PiB-PET [118,119,120] imaging [121], although not all studies find a relationship between PA and AD-associated biomarkers [122]. Subsequently, results from the Australian Imaging and Biomarkers and Lifestyle study of ageing demonstrated that higher self-reported levels of physical activity in cognitively healthy older adults is associated with lower blood plasma levels and reduced brain burden of Aβ [123]. PA has also been shown to attenuate age-related alterations in AD-associated biomarkers in people at risk for AD by nature of family history or APOEε4 polymorphism [124].
In summary, there is a large body of evidence to suggest that PA has multiple beneficial effects on cognitive function, through both direct and systemic/peripheral effects. PA is a factor that can be modified, but is there an interaction between PA and genetic risk for AD?
As discussed above, polymorphism in the APOE gene is the strongest genetic risk factor identified for AD. Apolipoprotein E has a further link to the relationship of PA to brain health because of its function as a lipid-transport protein [125,126,127,128]. A number of studies have sought to assess whether various potential protective strategies, for example estrogen replacement [38,129], anti-inflammatory [130] and antihypertensive [131] therapy can mitigate genetic risk of AD, in terms of APOEε4 carriage.
Similar analyses have also been conducted around the world to determine whether PA can still offer protection from AD in APOEε4 carriers. The results have been mixed with some studies finding greater benefit of PA in terms of cognitive health and reduced risk for AD for APOEε4 carriers [132,133,134,135,136,137,138,139], non-carriers [140] and no effect of APOE genotype [141,142,143]. The differences maybe due to methodological issues in assessing PA levels, the age of the cohorts, study design or the ethnicity of the various cohorts, however the overall protective effect of PA against cognitive decline remains.
More recent studies have begun to elucidate whether APOEε4 influences the impact of PA on potential AD-associated biomarkers. PA has been shown to confer protection against hippocampal atrophy in cognitively healthy older adults [144]. A recent analysis of cognitively normal older adults demonstrated that a sedentary lifestyle is associated with higher amyloid burden (PiB-PET imaging) amongst APOEε4 carriers but not non-carriers [145], suggesting that PA maybe particularly important in reducing AD-biological markers for people at genetic risk for AD. The greater improvement in cognitive performance and neuroplasticity as a result of PA for APOEε4 carriers is also found in transgenic mouse models [146].
It’s not entirely clear how possession of the APOEε4 allele confers increased risk for AD, however it is associated with reduced synaptic plasticity [37], reduced cholinergic functioning [147,148], reduced neuronal activity [149,150,151], impaired clearance of Aβ [152,153] and can also influence the inflammatory cascade and oxidative stress [32,154,155]. In addition to APOEε4 polymorphism, the levels of apolipoprotein E itself may be important in the pathogenesis of AD [156], with an APOE promoter polymorphism associated with increased risk for AD [157,158,159].
Given the effect of PA on BDNF levels, one may expect that genetic polymorphism in the BDNF gene may also influence the protective benefits conferred by PA. In humans, a Val66Met polymorphism in the BDNF gene (rs6265) has been associated with reduced secretion of BDNF, poorer cognitive performance and smaller hippocampal volume [160,161]. This particular polymorphism is also associated with increased risk for AD [162]. A recent cross-sectional analysis from the AIBL study group has found an associated between BDNF polymorphism, hippocampal volume and physical activity such that high levels of PA reduced the volume of the temporal lobe in BDNF Met carriers (i. e. the risk allele) [163]. This finding suggests that Val carriers are better able to derive the benefits of PA on BDNF levels than Met carriers, who may produce altered binding of BDNF to TrkB receptors, but not p75 receptors [164].
Genetic polymorphism for other molecules affected by PA, such as IDE [165] and IGF-1 [166] are also associated with increased risk for AD, but whether these polymorphisms also alter the efficacy of PA for preventing AD is unknown. Inflammation is another key process that is likely to be influenced by engaging in PA [79,167]. Because inflammatory genetic polymorphisms are also linked with AD risk [168,169,170,171,172,173,174,175,176,177,178], inflammation provides another avenue for investigation into the concept of genetic exercise. Lastly, a recent study has demonstrated that engaging in PA can reduce the risk conferred by other AD-risk alleles—https://www.aimspress.com/aimspress-data/aimsmoles/2015/3/PICALM, CLU and BIN1 [179], possibly by mediating Aβ clearance and tau pathology [180,181].
Another intriguing element to the concept of exercise genetics is the concept that PA can regulate epigenetic control of gene expression, in other words, exercise can change your DNA. Epigenetics is the study of changes in gene function that are heritable, but not related to a change in the sequence of DNA. Such modifications can occur through mechanisms such as DNA methylation and can either activate or suppress gene transcription. Exercise during pregnancy has been shown to mitigate AD-pathology in offspring of transgenic mice [182] and also to increase BDNF expression in rat pups [183]. Recent literature reviews have highlighted the link between PA and epigenetic control of a number of genes linked with AD including inflammatory genes and BDNF [184,185,186]. These studies suggest that PA may induce long-term and heritable alterations in DNA and offer new insights into how PA and interact with the genome to reduce risk for future AD (Figure1).
Despite numerous studies supporting the role for PA in the prevention of AD, there remain some issues that will need to be addressed before the full potential of PA can be realised. As a starting point, it is recommended by health authorities that people follow PA guidelines relevant to their age group. The Global Recommendations on Physical Activity, developed by the WHO are divided into three categories according to age group; children aged 5-17 years, adults aged 18-64 years and adults aged 65 and above, and are valid for all people unless specific medical conditions are contraindicated (Table1).
Recommendations | Age Group | |
18-64 years |
65 year sand above |
|
At least 150 minutes of moderate-intensity OR At least 75 minutes of vigorous-intensity OR An equivalent combination of moderate- and vigorous-intensity aerobic PA/week. |
√ | √ |
Activity should be performed in bouts of at least 10 minutes duration. | √ | √ |
For additional health benefits, adults should increase their moderate-intensity to 300 minutes OR Engage in 150 minutes of vigorous-intensity OR An equivalent combination of moderate- and vigorous-intensity activity aerobic PA/week. |
√ | √ |
Muscle-strengthening activities should be done involving major muscle groups on 2 or more days a week. |
√ | √ |
Older adults, with poor mobility, should perform physical activity to enhance balance and prevent falls on 3 or more days per week. |
√ | |
When older adults cannot do the recommended amounts of physical activity due to health conditions, they should be as physically active as their abilities and conditions allow. |
√ | |
*PA includes leisure time physical activity, transportation (e. g. walking or cycling), occupational (i. e. work), household chores, or planned exercise/sports, in the context of daily, family, and community activities. |
Given the positive effects of PA on cognition, a number of randomised trials have been conducted that use an exercise intervention in patients at risk, or with dementia. A recent meta-analysis of 14 of such trials has indicated that PA intervention results in cognitive improvements across a range of domains including attention, executive function and fluid intelligence, as well as improvements on clinical dementia ratings [187]. The PA interventions included both aerobic and resistance exercises and also solely home-based interventions. PA interventions may also improve functional abilities and stabilise care-giver burden for patients with AD [188]. Clinical trials are currently underway to determine the effects of PA and genetics on cognitive performance in older adults [189], however there is currently no gold-standard for outcome measures in dementia prevention.
There are also some methodological issues that need to be resolved in order to better clarify and characterised the role of PA in the prevention of AD. To date, a number of studies rely on self-report questionnaires such as the Community Healthy Activities Model Program for Seniors (CHAMPS) (e. g. [190]) or International Physical Activity Questionnaire (e. g. [123]) versus objective measures (e. g. activity monitors [191] or aerobic fitness [134]). This is an important distinction because the results generated vary depending upon the measures used to assess PA engagement [192]. Additionally, the type of PA in regards to leisure-time versus other forms of PA such as occupational are important considerations when interpreting data. Leisure-time PA may include a cognitively stimulating and social-interaction component which may confer additional protective benefits than PA alone [136,193,194,195,196,197,198]. Lastly, there remains to be a detailed characterisation of the intensity and duration of PA that is required for maximal benefit. This is not only and important economic question for public health advocates, but it may be that too much PA could actually contribute to AD pathology, rather than mitigate it [92]. This knowledge will also assist in minimising environmental (such as feelings of safety, places to rest etc. [199]) and cultural barriers to engaging in PA [200].
Evidence from animal models suggests that a range of environmental enrichment opportunities result in the greatest protection of the brain from age and disease-related effects [201,202]. In this context, environments rich in motor, sensory and cognitive stimulation have been shown to enhance synaptic plasticity and cognitive performance as well as providing a disease-modification effect.
With this in mind, a number of studies have reported benefits from mentally stimulating activities on improving cognitive function and brain plasticity measures in healthy older people (e. g. [203,204,205], those with MCI [206] and with AD [207,208]. These sorts of cognitive training interventions are also associated with reduced risk for AD [209,210]. A recent Australian study showed that participation in a combination of PA and computerised cognitive stimulation improved cognitive performance and enhanced brain glucose metabolism for healthy older adults compared to single-mode stimulation or controls [211]. Whilst these studies are encouraging, they are still preliminary in nature and additional randomised, large-scale clinical trials are clearly warranted to determine the optimal intervention programs, whether there are long-lasting improvements and if any benefits of training are transferable to non-trained cognitive domains [212].
The idea that a multi-modal intervention may provide maximal benefit for AD has been taken one step further in the design of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)—a randomised controlled trial of diet, exercise, cognitive stimulation and blood pressure monitoring in older adults. This intervention resulted in a reduction in cognitive deterioration and a particular effect on executive functioning and processing speed and changes in lifestyle choices such as diet, PA and BMI [213]. Further follow-up studies are planned to determine whether the FINGER intervention had any effect on incident AD and dementia. In a similar vein, large prospective cohort studies such as AIBL [214] and the Alzheimer’s Disease Neuroimaging Initiative [215] provide further opportunities to interrogate the relationship between PA and AD. In addition, investigation of protective factors in cohorts of people who will develop AD by way of possessing an AD-causing genetic mutation (i. e. the Dominantly Inherited Alzheimer’s Network-DIAN) will provide valuable insights into the biological mechanisms affected by PA [216].
Evidence from animal models suggests that the effects of APOEε4 maybe more pronounced in females than males [217]. Indeed female APOEε4 carriers are at greater risk of future AD than male APOEε4 carriers [218]. Aerobic fitness in APOEε4 carriers is associated with better cognitive performance in healthy older women [134], yet APOEε4 carriage has no impact on the net protective benefit of PA in men [143]. This sex-genetic interaction needs to be better explored and characterised for PA intervention studies [24].
In summary, there are numerous lines of evidence strongly supportive for a role of PA in the prevention and possibly slowing the progression of AD. Research is now teasing apart the effect of various genetic factors on the ability of PA to act on various pathological aspects of AD. More studies are required to elucidate the mechanisms underlying the affect of PA on the brain in the hope that exercise prescription may one day become a reality for age-related diseases, including AD.
The author receives grant funding support from The Raine Foundation for Medical Research and the Neurotrauma Research Program of Western Australia.
There are no conflicts of interest to declare.
[1] |
Alzheimer A, Stelzmann RA, Schnitzlein HN, et al. (1995) An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat 8: 429-431. doi: 10.1002/ca.980080612
![]() |
[2] |
(2013) 2013 Alzheimer's disease facts and figures. Alzheimers Dement 9: 208-245. doi: 10.1016/j.jalz.2013.02.003
![]() |
[3] |
Brookmeyer R, Johnson E, Ziegler-Graham K, et al. (2007) Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 3: 186-191. doi: 10.1016/j.jalz.2007.04.381
![]() |
[4] |
Martins RN, Robinson PJ, Chleboun JO, et al. (1991) The molecular pathology of amyloid deposition in Alzheimer's disease. Mol Neurobiol 5: 389-398. doi: 10.1007/BF02935560
![]() |
[5] | Masters CL, Multhaup G, Simms G, et al. (1985) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. Embo J 4: 2757-2763. |
[6] |
Schweers O, Mandelkow EM, Biernat J, et al. (1995) Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments. Proc Natl Acad Sci U S A 92: 8463-8467. doi: 10.1073/pnas.92.18.8463
![]() |
[7] |
Goedert M, Jakes R, Spillantini MG, et al. (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383: 550-553. doi: 10.1038/383550a0
![]() |
[8] |
Villemagne VL, Pike KE, Darby D, et al. (2008) Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer's disease. Neuropsychologia 46: 1688-1697. doi: 10.1016/j.neuropsychologia.2008.02.008
![]() |
[9] | Chien DT, Bahri S, Szardenings AK, et al. (2013) Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis 34: 457-468. |
[10] |
Maruyama M, Shimada H, Suhara T, et al. (2013) Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79: 1094-1108. doi: 10.1016/j.neuron.2013.07.037
![]() |
[11] |
Rentz DM, Parra Rodriguez MA, Amariglio R, et al. (2013) Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer's disease: a selective review. Alzheimers Res Ther 5: 58. doi: 10.1186/alzrt222
![]() |
[12] | Baumgart M, Snyder HM, Carrillo MC, et al. (2015) Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimers Dement. |
[13] |
Barnes DE, Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol 10: 819-828. doi: 10.1016/S1474-4422(11)70072-2
![]() |
[14] |
Selkoe DJ (1996) Amyloid beta-protein and the genetics of Alzheimer's disease. J Biol Chem 271: 18295-18298. doi: 10.1074/jbc.271.31.18295
![]() |
[15] |
Glenner GG, Wong CW (1984) Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122: 1131-1135. doi: 10.1016/0006-291X(84)91209-9
![]() |
[16] |
Mann DM, Esiri MM (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J Neurol Sci 89: 169-179. doi: 10.1016/0022-510X(89)90019-1
![]() |
[17] |
Jorm AF, Korten AE, Henderson AS (1987) The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 76: 465-479. doi: 10.1111/j.1600-0447.1987.tb02906.x
![]() |
[18] |
Hebert LE, Weuve J, Scherr PA, et al. (2013) Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 80: 1778-1783. doi: 10.1212/WNL.0b013e31828726f5
![]() |
[19] |
(2015) 2015 Alzheimer's disease facts and figures. Alzheimers Dement 11: 332-384. doi: 10.1016/j.jalz.2015.02.003
![]() |
[20] |
Lukiw WJ (2004) Gene expression profiling in fetal, aged, and Alzheimer hippocampus: a continuum of stress-related signaling. Neurochem Res 29: 1287-1297. doi: 10.1023/B:NERE.0000023615.89699.63
![]() |
[21] |
Smith MA, Nunomura A, Lee HG, et al. (2005) Chronological primacy of oxidative stress in Alzheimer disease. Neurobiol Aging 26: 579-580; discussion 587-595. doi: 10.1016/j.neurobiolaging.2004.09.021
![]() |
[22] |
Overmyer M, Helisalmi S, Soininen H, et al. (1999) Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol (Berl) 97: 383-392. doi: 10.1007/s004010051002
![]() |
[23] |
Currais A (2015) Ageing and inflammation - A central role for mitochondria in brain health and disease. Ageing Res Rev 21: 30-42. doi: 10.1016/j.arr.2015.02.001
![]() |
[24] | Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer's disease: assessing sex and gender differences. Clin Epidemiol 6: 37-48. |
[25] |
Chapman RM, Mapstone M, Gardner MN, et al. (2011) Women have farther to fall: gender differences between normal elderly and Alzheimer's disease in verbal memory engender better detection of Alzheimer's disease in women. J Int Neuropsychol Soc 17: 654-662. doi: 10.1017/S1355617711000452
![]() |
[26] |
Green PS, Simpkins JW (2000) Neuroprotective effects of estrogens: potential mechanisms of action. Int J Dev Neurosci 18: 347-358. doi: 10.1016/S0736-5748(00)00017-4
![]() |
[27] |
Jones KJ, Brown TJ, Damaser M (2001) Neuroprotective effects of gonadal steroids on regenerating peripheral motoneurons. Brain Res Brain Res Rev 37: 372-382. doi: 10.1016/S0165-0173(01)00107-2
![]() |
[28] | Wise PM, Dubal DB, Wilson ME, et al. (2001) Minireview: neuroprotective effects of estrogen-new insights into mechanisms of action. Endocrinology 142: 969-973. |
[29] |
Strittmatter WJ, Saunders AM, Schmechel D, et al. (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90: 1977-1981. doi: 10.1073/pnas.90.5.1977
![]() |
[30] |
Saunders AM, Strittmatter WJ, Schmechel D, et al. (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43: 1467-1472. doi: 10.1212/WNL.43.8.1467
![]() |
[31] |
Corder EH, Saunders AM, Strittmatter WJ, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261: 921-923. doi: 10.1126/science.8346443
![]() |
[32] |
McGeer PL, Walker DG, Pitas RE, et al. (1997) Apolipoprotein E4 (ApoE4) but not ApoE3 or ApoE2 potentiates beta- amyloid protein activation of complement in vitro. Brain Res 749: 135-138. doi: 10.1016/S0006-8993(96)01324-8
![]() |
[33] |
Prince JA, Zetterberg H, Andreasen N, et al. (2004) APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42. Neurology 62: 2116-2118. doi: 10.1212/01.WNL.0000128088.08695.05
![]() |
[34] |
Tiraboschi P, Hansen LA, Masliah E, et al. (2004) Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 62: 1977-1983. doi: 10.1212/01.WNL.0000128091.92139.0F
![]() |
[35] |
Lovestone S, Anderton BH, Hartley C, et al. (1996) The intracellular fate of apolipoprotein E is tau dependent and apoe allele-specific. Neuroreport 7: 1005-1008. doi: 10.1097/00001756-199604100-00010
![]() |
[36] |
Tesseur I, Van Dorpe J, Spittaels K, et al. (2000) Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol 156: 951-964. doi: 10.1016/S0002-9440(10)64963-2
![]() |
[37] | Arendt T, Schindler C, Bruckner MK, et al. (1997) Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele. J Neurosci 17: 516-529. |
[38] | Burkhardt MS, Foster JK, Laws SM, et al. (2004) Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4. J Alzheimers Dis 6: 221-228. |
[39] |
Patterson CE, Todd SA, Passmore AP (2011) Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease. Pharmacogenomics J 11: 444-450. doi: 10.1038/tpj.2010.61
![]() |
[40] |
Petersen RC, Thomas RG, Grundman M, et al. (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 352: 2379-2388. doi: 10.1056/NEJMoa050151
![]() |
[41] |
Bettens K, Sleegers K, Van Broeckhoven C (2013) Genetic insights in Alzheimer's disease. Lancet Neurol 12: 92-104. doi: 10.1016/S1474-4422(12)70259-4
![]() |
[42] |
Norton S, Matthews FE, Barnes DE, et al. (2014) Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol 13: 788-794. doi: 10.1016/S1474-4422(14)70136-X
![]() |
[43] |
Van Den Heuvel C, Thornton E, Vink R (2007) Traumatic brain injury and Alzheimer's disease: a review. Prog Brain Res 161: 303-316. doi: 10.1016/S0079-6123(06)61021-2
![]() |
[44] |
Solomon A, Kareholt I, Ngandu T, et al. (2007) Serum cholesterol changes after midlife and late-life cognition: twenty-one-year follow-up study. Neurology 68: 751-756. doi: 10.1212/01.wnl.0000256368.57375.b7
![]() |
[45] | Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B (2015) Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci 9: 124. |
[46] | Organization WH (2015) Global Strategy on Diet, Physical Activity and Health. |
[47] |
Warburton DE, Nicol CW, Bredin SS (2006) Health benefits of physical activity: the evidence. CMAJ 174: 801-809. doi: 10.1503/cmaj.051351
![]() |
[48] |
Beckett MW, Ardern CI, Rotondi MA (2015) A meta-analysis of prospective studies on the role of physical activity and the prevention of Alzheimer's disease in older adults. BMC Geriatr 15: 9. doi: 10.1186/s12877-015-0007-2
![]() |
[49] |
Reiner M, Niermann C, Jekauc D, et al. (2013) Long-term health benefits of physical activity--a systematic review of longitudinal studies. BMC Public Health 13: 813. doi: 10.1186/1471-2458-13-813
![]() |
[50] | Angevaren M, Aufdemkampe G, Verhaar HJ, et al. (2008) Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev: CD005381. |
[51] | Carter ND, Khan KM, McKay HA, et al. (2002) Community-based exercise program reduces risk factors for falls in 65- to 75-year-old women with osteoporosis: randomized controlled trial. CMAJ 167: 997-1004. |
[52] |
Lynch NA, Ryan AS, Evans J, et al. (2007) Older elite football players have reduced cardiac and osteoporosis risk factors. Med Sci Sports Exerc 39: 1124-1130. doi: 10.1249/01.mss.0b013e3180557466
![]() |
[53] |
Vuori IM (2001) Dose-response of physical activity and low back pain, osteoarthritis, and osteoporosis. Med Sci Sports Exerc 33: S551-586; discussion 609-510. doi: 10.1097/00005768-200106001-00026
![]() |
[54] |
Tan ZS, Seshadri S, Beiser A, et al. (2005) Bone mineral density and the risk of Alzheimer disease. Arch Neurol 62: 107-111. doi: 10.1001/archneur.62.1.107
![]() |
[55] |
Zhang Y, Seshadri S, Ellison RC, et al. (2001) Bone mineral density and verbal memory impairment: Third National Health and Nutrition Examination Survey. Am J Epidemiol 154: 795-802. doi: 10.1093/aje/154.9.795
![]() |
[56] |
Yaffe K, Browner W, Cauley J, et al. (1999) Association between bone mineral density and cognitive decline in older women. J Am Geriatr Soc 47: 1176-1182. doi: 10.1111/j.1532-5415.1999.tb05196.x
![]() |
[57] |
Gunstad J, Paul RH, Cohen RA, et al. (2007) Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. Compr Psychiatry 48: 57-61. doi: 10.1016/j.comppsych.2006.05.001
![]() |
[58] |
Gustafson D, Lissner L, Bengtsson C, et al. (2004) A 24-year follow-up of body mass index and cerebral atrophy. Neurology 63: 1876-1881. doi: 10.1212/01.WNL.0000141850.47773.5F
![]() |
[59] | Jagust W, Harvey D, Mungas D, et al. (2005) Central obesity and the aging brain. Arch Neurol 62: 1545-1548. |
[60] | Kivipelto M, Ngandu T, Fratiglioni L, et al. (2005) Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 62: 1556-1560. |
[61] |
Whitmer RA, Gunderson EP, Barrett-Connor E, et al. (2005) Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. Bmj 330: 1360. doi: 10.1136/bmj.38446.466238.E0
![]() |
[62] | Sohrabi HR, Bates KA, Weinborn M, et al. (2015) Bone mineral density, adiposity, and cognitive functions. Front Aging Neurosci 7: 16. |
[63] |
Koudinov AR, Berezov TT, Kumar A, et al. (1998) Alzheimer's amyloid beta interaction with normal human plasma high density lipoprotein: association with apolipoprotein and lipids. Clin Chim Acta 270: 75-84. doi: 10.1016/S0009-8981(97)00207-6
![]() |
[64] |
Koudinov AR, Koudinova NV, Kumar A, et al. (1996) Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: Associations with high density lipoproteins. Biochem Biophys Res Commun 223: 592-597. doi: 10.1006/bbrc.1996.0940
![]() |
[65] | Eapen DJ, Kalra GL, Rifai L, et al. (2010) Raising HDL cholesterol in women. Int J Womens Health 1: 181-191. |
[66] | Bates KA, Sohrabi HR, Rodrigues M, et al. (2009) Association of Cardiovascular Factors and Alzheimer's Disease Plasma Amyloid-beta Protein in Subjective Memory Complainers. J Alzheimers Dis 17: 305-318. |
[67] |
Atzmon G, Gabriely I, Greiner W, et al. (2002) Plasma HDL levels highly correlate with cognitive function in exceptional longevity. J Gerontol A Biol Sci Med Sci 57: M712-715. doi: 10.1093/gerona/57.11.M712
![]() |
[68] |
Crichton GE, Elias MF, Davey A, et al. (2014) Higher HDL cholesterol is associated with better cognitive function: the Maine-Syracuse study. J Int Neuropsychol Soc 20: 961-970. doi: 10.1017/S1355617714000885
![]() |
[69] | Singh-Manoux A, Gimeno D, Kivimaki M, et al. (2008) Low HDL cholesterol is a risk factor for deficit and decline in memory in midlife. The Whitehall II study. Arterioscler Thromb Vasc Biol 28: 1557-1563. |
[70] | Ward MA, Bendlin BB, McLaren DG, et al. (2010) Low HDL Cholesterol is Associated with Lower Gray Matter Volume in Cognitively Healthy Adults. Front Aging Neurosci 2. |
[71] | Biessels GJ, Kappelle LJ (2005) Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem Soc Trans 33: 1041-1044. |
[72] |
Gatto NM, Henderson VW, St John JA, et al. (2008) Metabolic syndrome and cognitive function in healthy middle-aged and older adults without diabetes. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 15: 627-641. doi: 10.1080/13825580802036936
![]() |
[73] |
Tomlinson DR, Gardiner NJ (2008) Glucose neurotoxicity. Nat Rev Neurosci 9: 36-45. doi: 10.1038/nrn2294
![]() |
[74] |
Craft S, Asthana S, Newcomer JW, et al. (1999) Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 56: 1135-1140. doi: 10.1001/archpsyc.56.12.1135
![]() |
[75] |
Craft S, Newcomer J, Kanne S, et al. (1996) Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiol Aging 17: 123-130. doi: 10.1016/0197-4580(95)02002-0
![]() |
[76] |
Kulstad JJ, Green PS, Cook DG, et al. (2006) Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease. Neurology 66: 1506-1510. doi: 10.1212/01.wnl.0000216274.58185.09
![]() |
[77] |
Ibanez J, Izquierdo M, Arguelles I, et al. (2005) Twice-weekly progressive resistance training decreases abdominal fat and improves insulin sensitivity in older men with type 2 diabetes. Diabetes Care 28: 662-667. doi: 10.2337/diacare.28.3.662
![]() |
[78] |
Knowler WC, Barrett-Connor E, Fowler SE, et al. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346: 393-403. doi: 10.1056/NEJMoa012512
![]() |
[79] |
Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30: 464-472. doi: 10.1016/j.tins.2007.06.011
![]() |
[80] | Kuipers SD, Bramham CR (2006) Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy. Curr Opin Drug Discov Devel 9: 580-586. |
[81] |
Neeper SA, Gomez-Pinilla F, Choi J, et al. (1996) Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res 726: 49-56. doi: 10.1016/0006-8993(96)00273-9
![]() |
[82] |
Oliff HS, Berchtold NC, Isackson P, et al. (1998) Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in the rat hippocampus. Brain Res Mol Brain Res 61: 147-153. doi: 10.1016/S0169-328X(98)00222-8
![]() |
[83] |
Widenfalk J, Olson L, Thoren P (1999) Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain. Neurosci Res 34: 125-132. doi: 10.1016/S0168-0102(99)00051-6
![]() |
[84] |
Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20: 2580-2590. doi: 10.1111/j.1460-9568.2004.03720.x
![]() |
[85] |
Vaynman SS, Ying Z, Yin D, et al. (2006) Exercise differentially regulates synaptic proteins associated to the function of BDNF. Brain Res 1070: 124-130. doi: 10.1016/j.brainres.2005.11.062
![]() |
[86] |
Kolb EM, Rezende EL, Holness L, et al. (2013) Mice selectively bred for high voluntary wheel running have larger midbrains: support for the mosaic model of brain evolution. J Exp Biol 216: 515-523. doi: 10.1242/jeb.076000
![]() |
[87] | Carro E, Nunez A, Busiguina S, et al. (2000) Circulating insulin-like growth factor I mediates effects of exercise on the brain. J Neurosci 20: 2926-2933. |
[88] |
Ding Q, Vaynman S, Akhavan M, et al. (2006) Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience 140: 823-833. doi: 10.1016/j.neuroscience.2006.02.084
![]() |
[89] |
McCusker RH, McCrea K, Zunich S, et al. (2006) Insulin-like growth factor-I enhances the biological activity of brain-derived neurotrophic factor on cerebrocortical neurons. J Neuroimmunol 179: 186-190. doi: 10.1016/j.jneuroim.2006.06.014
![]() |
[90] |
Carro E, Torres-Aleman I (2004) The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer's disease. Eur J Pharmacol 490: 127-133. doi: 10.1016/j.ejphar.2004.02.050
![]() |
[91] |
Erickson KI, Raji CA, Lopez OL, et al. (2010) Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study. Neurology 75: 1415-1422. doi: 10.1212/WNL.0b013e3181f88359
![]() |
[92] |
Bugg JM, Head D (2011) Exercise moderates age-related atrophy of the medial temporal lobe. Neurobiol Aging 32: 506-514. doi: 10.1016/j.neurobiolaging.2009.03.008
![]() |
[93] | Boyle CP, Raji CA, Erickson KI, et al. (2015) Physical activity, body mass index, and brain atrophy in Alzheimer's disease. Neurobiol Aging 36 Suppl 1: S194-202. |
[94] |
Rovio S, Spulber G, Nieminen LJ, et al. (2010) The effect of midlife physical activity on structural brain changes in the elderly. Neurobiol Aging 31: 1927-1936. doi: 10.1016/j.neurobiolaging.2008.10.007
![]() |
[95] |
Erickson KI, Voss MW, Prakash RS, et al. (2011) Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A 108: 3017-3022. doi: 10.1073/pnas.1015950108
![]() |
[96] |
Burns JM, Cronk BB, Anderson HS, et al. (2008) Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology 71: 210-216. doi: 10.1212/01.wnl.0000317094.86209.cb
![]() |
[97] |
Honea RA, Thomas GP, Harsha A, et al. (2009) Cardiorespiratory fitness and preserved medial temporal lobe volume in Alzheimer disease. Alzheimer Dis Assoc Disord 23: 188-197. doi: 10.1097/WAD.0b013e31819cb8a2
![]() |
[98] |
van Praag H, Shubert T, Zhao C, et al. (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25: 8680-8685. doi: 10.1523/JNEUROSCI.1731-05.2005
![]() |
[99] |
Albeck DS, Sano K, Prewitt GE, et al. (2006) Mild forced treadmill exercise enhances spatial learning in the aged rat. Behav Brain Res 168: 345-348. doi: 10.1016/j.bbr.2005.11.008
![]() |
[100] |
Kramer AF, Erickson KI (2007) Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends Cogn Sci 11: 342-348. doi: 10.1016/j.tics.2007.06.009
![]() |
[101] |
Heyn P, Abreu BC, Ottenbacher KJ (2004) The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 85: 1694-1704. doi: 10.1016/j.apmr.2004.03.019
![]() |
[102] |
Colcombe S, Kramer AF (2003) Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci 14: 125-130. doi: 10.1111/1467-9280.t01-1-01430
![]() |
[103] |
Stones MJ, Kozma A (1989) Age, exercise, and coding performance. Psychol Aging 4: 190-194. doi: 10.1037/0882-7974.4.2.190
![]() |
[104] |
Kamijo K, Takeda Y, Hillman CH (2011) The relation of physical activity to functional connectivity between brain regions. Clin Neurophysiol 122: 81-89. doi: 10.1016/j.clinph.2010.06.007
![]() |
[105] | Burdette JH, Laurienti PJ, Espeland MA, et al. (2010) Using network science to evaluate exercise-associated brain changes in older adults. Front Aging Neurosci 2: 23. |
[106] | Voss MW, Prakash RS, Erickson KI, et al. (2010) Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front Aging Neurosci 2. |
[107] |
Strawbridge WJ, Deleger S, Roberts RE, et al. (2002) Physical activity reduces the risk of subsequent depression for older adults. Am J Epidemiol 156: 328-334. doi: 10.1093/aje/kwf047
![]() |
[108] |
Lampinen P, Heikkinen E (2003) Reduced mobility and physical activity as predictors of depressive symptoms among community-dwelling older adults: an eight-year follow-up study. Aging Clin Exp Res 15: 205-211. doi: 10.1007/BF03324501
![]() |
[109] |
Lee Y, Park K (2008) Does physical activity moderate the association between depressive symptoms and disability in older adults? Int J Geriatr Psychiatry 23: 249-256. doi: 10.1002/gps.1870
![]() |
[110] |
Yoshiuchi K, Nakahara R, Kumano H, et al. (2006) Yearlong physical activity and depressive symptoms in older Japanese adults: cross-sectional data from the Nakanojo study. Am J Geriatr Psychiatry 14: 621-624. doi: 10.1097/01.JGP.0000200602.70504.9c
![]() |
[111] |
Salguero A, Martinez-Garcia R, Molinero O, et al. (2011) Physical activity, quality of life and symptoms of depression in community-dwelling and institutionalized older adults. Arch Gerontol Geriatr 53: 152-157. doi: 10.1016/j.archger.2010.10.005
![]() |
[112] |
Lee H, Lee JA, Brar JS, et al. (2014) Physical activity and depressive symptoms in older adults. Geriatr Nurs 35: 37-41. doi: 10.1016/j.gerinurse.2013.09.005
![]() |
[113] |
Maki Y, Ura C, Yamaguchi T, et al. (2012) Effects of intervention using a community-based walking program for prevention of mental decline: a randomized controlled trial. J Am Geriatr Soc 60: 505-510. doi: 10.1111/j.1532-5415.2011.03838.x
![]() |
[114] |
Penninx BW, Rejeski WJ, Pandya J, et al. (2002) Exercise and depressive symptoms: a comparison of aerobic and resistance exercise effects on emotional and physical function in older persons with high and low depressive symptomatology. J Gerontol B Psychol Sci Soc Sci 57: P124-132. doi: 10.1093/geronb/57.2.P124
![]() |
[115] |
Teixeira CM, Vasconcelos-Raposo J, Fernandes HM, et al. (2013) Physical Activity, Depression and Anxiety Among the Elderly. Social Indicators Research 113: 307-318. doi: 10.1007/s11205-012-0094-9
![]() |
[116] |
Lazarov O, Robinson J, Tang YP, et al. (2005) Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120: 701-713. doi: 10.1016/j.cell.2005.01.015
![]() |
[117] |
Adlard PA, Perreau VM, Pop V, et al. (2005) Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J Neurosci 25: 4217-4221. doi: 10.1523/JNEUROSCI.0496-05.2005
![]() |
[118] |
Kemppainen NM, Aalto S, Wilson IA, et al. (2006) Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease. Neurology 67: 1575-1580. doi: 10.1212/01.wnl.0000240117.55680.0a
![]() |
[119] |
Klunk WE, Engler H, Nordberg A, et al. (2004) Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 55: 306-319. doi: 10.1002/ana.20009
![]() |
[120] |
Klunk WE, Lopresti BJ, Ikonomovic MD, et al. (2005) Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain. J Neurosci 25: 10598-10606. doi: 10.1523/JNEUROSCI.2990-05.2005
![]() |
[121] |
Liang KY, Mintun MA, Fagan AM, et al. (2010) Exercise and Alzheimer's disease biomarkers in cognitively normal older adults. Ann Neurol 68: 311-318. doi: 10.1002/ana.22096
![]() |
[122] |
Vemuri P, Lesnick TG, Przybelski SA, et al. (2012) Effect of lifestyle activities on Alzheimer disease biomarkers and cognition. Ann Neurol 72: 730-738. doi: 10.1002/ana.23665
![]() |
[123] |
Brown BM, Peiffer JJ, Taddei K, et al. (2013) Physical activity and amyloid-beta plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing. Mol Psychiatry 18: 875-881. doi: 10.1038/mp.2012.107
![]() |
[124] |
Okonkwo OC, Schultz SA, Oh JM, et al. (2014) Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology 83: 1753-1760. doi: 10.1212/WNL.0000000000000964
![]() |
[125] |
Bennet AM, Di Angelantonio E, Ye Z, et al. (2007) Association of apolipoprotein E genotypes with lipid levels and coronary risk. Jama 298: 1300-1311. doi: 10.1001/jama.298.11.1300
![]() |
[126] | Mahley RW, Nathan BP, Pitas RE (1996) Apolipoprotein E. Structure, function, and possible roles in Alzheimer's disease. Ann N Y Acad Sci 777: 139-145. |
[127] |
Weisgraber KH (1994) Apolipoprotein E: structure-function relationships. Adv Protein Chem 45: 249-302. doi: 10.1016/S0065-3233(08)60642-7
![]() |
[128] | Weisgraber KH, Mahley RW (1996) Human apolipoprotein E: the Alzheimer's disease connection. Faseb J 10: 1485-1494. |
[129] |
Yaffe K, Haan M, Byers A, et al. (2000) Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology 54: 1949-1954. doi: 10.1212/WNL.54.10.1949
![]() |
[130] |
Szekely CA, Breitner JC, Fitzpatrick AL, et al. (2008) NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology 70: 17-24. doi: 10.1212/01.wnl.0000284596.95156.48
![]() |
[131] |
Qiu C, Winblad B, Fastbom J, et al. (2003) Combined effects of APOE genotype, blood pressure, and antihypertensive drug use on incident AD. Neurology 61: 655-660. doi: 10.1212/WNL.61.5.655
![]() |
[132] |
Rovio S, Kareholt I, Helkala EL, et al. (2005) Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 4: 705-711. doi: 10.1016/S1474-4422(05)70198-8
![]() |
[133] |
Deeny SP, Poeppel D, Zimmerman JB, et al. (2008) Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in epsilon4 carriers. Biol Psychol 78: 179-187. doi: 10.1016/j.biopsycho.2008.02.007
![]() |
[134] |
Etnier JL, Caselli RJ, Reiman EM, et al. (2007) Cognitive performance in older women relative to ApoE-epsilon4 genotype and aerobic fitness. Med Sci Sports Exerc 39: 199-207. doi: 10.1249/01.mss.0000239399.85955.5e
![]() |
[135] |
Kivipelto M, Rovio S, Ngandu T, et al. (2008) Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study. J Cell Mol Med 12: 2762-2771. doi: 10.1111/j.1582-4934.2008.00296.x
![]() |
[136] | Niti M, Yap KB, Kua EH, et al. (2008) Physical, social and productive leisure activities, cognitive decline and interaction with APOE-epsilon 4 genotype in Chinese older adults. Int Psychogeriatr 20: 237-251. |
[137] | Schuit AJ, Feskens EJ, Launer LJ, et al. (2001) Physical activity and cognitive decline, the role of the apolipoprotein e4 allele. Med Sci Sports Exerc 33: 772-777. |
[138] | Yang SY, Weng PH, Chen JH, et al. (2014) Leisure activities, apolipoprotein E e4 status, and the risk of dementia. J Formos Med Assoc. |
[139] |
Luck T, Riedel-Heller SG, Luppa M, et al. (2014) Apolipoprotein E epsilon 4 genotype and a physically active lifestyle in late life: analysis of gene-environment interaction for the risk of dementia and Alzheimer's disease dementia. Psychol Med 44: 1319-1329. doi: 10.1017/S0033291713001918
![]() |
[140] |
Podewils LJ, Guallar E, Kuller LH, et al. (2005) Physical Activity, APOE Genotype, and Dementia Risk: Findings from the Cardiovascular Health Cognition Study. Am J Epidemiol 161: 639-651. doi: 10.1093/aje/kwi092
![]() |
[141] |
Lindsay J, Laurin D, Verreault R, et al. (2002) Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 156: 445-453. doi: 10.1093/aje/kwf074
![]() |
[142] |
Sabia S, Kivimaki M, Kumari M, et al. (2010) Effect of Apolipoprotein E epsilon4 on the association between health behaviors and cognitive function in late midlife. Mol Neurodegener 5: 23. doi: 10.1186/1750-1326-5-23
![]() |
[143] |
Taaffe DR, Irie F, Masaki KH, et al. (2008) Physical activity, physical function, and incident dementia in elderly men: the Honolulu-Asia Aging Study. J Gerontol A Biol Sci Med Sci 63: 529-535. doi: 10.1093/gerona/63.5.529
![]() |
[144] | Smith JC, Nielson KA, Woodard JL, et al. (2014) Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease. Front Aging Neurosci 6: 61. |
[145] |
Head D, Bugg JM, Goate AM, et al. (2012) Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. Arch Neurol 69: 636-643. doi: 10.1001/archneurol.2011.845
![]() |
[146] |
Nichol K, Deeny SP, Seif J, et al. (2009) Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice. Alzheimers Dement 5: 287-294. doi: 10.1016/j.jalz.2009.02.006
![]() |
[147] | Buttini M, Yu GQ, Shockley K, et al. (2002) Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. J Neurosci 22: 10539-10548. |
[148] |
Allen SJ, MacGowan SH, Tyler S, et al. (1997) Reduced cholinergic function in normal and Alzheimer's disease brain is associated with apolipoprotein E4 genotype. Neurosci Lett 239: 33-36. doi: 10.1016/S0304-3940(97)00872-0
![]() |
[149] | Scarmeas N, Habeck C, Anderson KE, et al. (2004) Altered PET functional brain responses in cognitively intact elderly persons at risk for Alzheimer disease (carriers of the epsilon4 allele). Am J Geriatr Psychiatry 12: 596-605. |
[150] | Rimajova M, Lenzo NP, Wu J-S, et al. (2007) Fluoro-2-deoxy-D-glucose (FDG)-PET in APOEε4 carriers in the Australian population. Journal of Alzheimer's disease 13: 137-146. |
[151] |
Mosconi L, De Santi S, Brys M, et al. (2008) Hypometabolism and altered cerebrospinal fluid markers in normal apolipoprotein E E4 carriers with subjective memory complaints. Biol Psychiatry 63: 609-618. doi: 10.1016/j.biopsych.2007.05.030
![]() |
[152] | Hone E, Martins IJ, Fonte J, et al. (2003) Apolipoprotein E influences amyloid-beta clearance from the murine periphery. J Alzheimers Dis 5: 1-8. |
[153] | Hone E, Martins IJ, Jeoung M, et al. (2005) Alzheimer's disease amyloid-beta peptide modulates apolipoprotein E isoform specific receptor binding. J Alzheimers Dis 7: 303-314. |
[154] |
Mazur-Kolecka B, Frackowiak J, Kowal D, et al. (2002) Oxidative protein damage in cells engaged in beta-amyloidosis is related to apoE genotype. Neuroreport 13: 465-468. doi: 10.1097/00001756-200203250-00021
![]() |
[155] |
Overmyer M, Helisalmi S, Soininen H, et al. (1999) Astrogliosis and the ApoE genotype. an immunohistochemical study of postmortem human brain tissue. Dement Geriatr Cogn Disord 10: 252-257. doi: 10.1159/000017128
![]() |
[156] |
Taddei K, Clarnette R, Gandy SE, et al. (1997) Increased plasma apolipoprotein E (apoE) levels in Alzheimer's disease. Neurosci Lett 223: 29-32. doi: 10.1016/S0304-3940(97)13394-8
![]() |
[157] |
Laws SM, Hone E, Gandy S, et al. (2003) Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. J Neurochem 84: 1215-1236. doi: 10.1046/j.1471-4159.2003.01615.x
![]() |
[158] |
Laws SM, Hone E, Taddei K, et al. (2002) Variation at the APOE -491 promoter locus is associated with altered brain levels of apolipoprotein E. Mol Psychiatry 7: 886-890. doi: 10.1038/sj.mp.4001097
![]() |
[159] | Casadei VM, Ferri C, Veglia F, et al. (1999) APOE-491 promoter polymorphism is a risk factor for late-onset Alzheimer's disease. Neurology 53: 1888-1889. |
[160] |
Bueller JA, Aftab M, Sen S, et al. (2006) BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59: 812-815. doi: 10.1016/j.biopsych.2005.09.022
![]() |
[161] |
Lim YY, Villemagne VL, Laws SM, et al. (2014) Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal Alzheimer's disease: a preliminary study. PLoS One 9: e86498. doi: 10.1371/journal.pone.0086498
![]() |
[162] |
Feher A, Juhasz A, Rimanoczy A, et al. (2009) Association between BDNF Val66Met polymorphism and Alzheimer disease, dementia with Lewy bodies, and Pick disease. Alzheimer Dis Assoc Disord 23: 224-228. doi: 10.1097/WAD.0b013e318199dd7d
![]() |
[163] |
Brown BM, Bourgeat P, Peiffer JJ, et al. (2014) Influence of BDNF Val66Met on the relationship between physical activity and brain volume. Neurology 83: 1345-1352. doi: 10.1212/WNL.0000000000000867
![]() |
[164] |
Teng HK, Teng KK, Lee R, et al. (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25: 5455-5463. doi: 10.1523/JNEUROSCI.5123-04.2005
![]() |
[165] |
Zhang Y, Wang B, Wan H, et al. (2013) Meta-analysis of the insulin degrading enzyme polymorphisms and susceptibility to Alzheimer's disease. Neurosci Lett 541: 132-137. doi: 10.1016/j.neulet.2013.01.051
![]() |
[166] | Vargas T, Martinez-Garcia A, Antequera D, et al. (2011) IGF-I gene variability is associated with an increased risk for AD. Neurobiol Aging 32: 556 e553-511. |
[167] |
Braskie MN, Boyle CP, Rajagopalan P, et al. (2014) Physical activity, inflammation, and volume of the aging brain. Neuroscience 273: 199-209. doi: 10.1016/j.neuroscience.2014.05.005
![]() |
[168] | Licastro F, Porcellini E, Caruso C, et al. (2006) Genetic risk profiles for Alzheimer's disease: Integration of APOE genotype and variants that up-regulate inflammation. Neurobiol Aging. |
[169] |
Culpan D, MacGowan SH, Ford JM, et al. (2003) Tumour necrosis factor-alpha gene polymorphisms and Alzheimer's disease. Neurosci Lett 350: 61-65. doi: 10.1016/S0304-3940(03)00854-1
![]() |
[170] |
Du Y, Dodel RC, Eastwood BJ, et al. (2000) Association of an interleukin 1 alpha polymorphism with Alzheimer's disease. Neurology 55: 480-483. doi: 10.1212/WNL.55.4.480
![]() |
[171] |
Grimaldi LM, Casadei VM, Ferri C, et al. (2000) Association of early-onset Alzheimer's disease with an interleukin-1alpha gene polymorphism. Ann Neurol 47: 361-365. doi: 10.1002/1531-8249(200003)47:3<361::AID-ANA12>3.0.CO;2-N
![]() |
[172] |
Hedley R, Hallmayer J, Groth DM, et al. (2002) Association of interleukin-1 polymorphisms with Alzheimer's disease in Australia. Ann Neurol 51: 795-797. doi: 10.1002/ana.10196
![]() |
[173] |
Koivisto AM, Helisalmi S, Pihlajamaki J, et al. (2005) Interleukin-6 promoter polymorphism and late-onset Alzheimer's disease in the Finnish population. J Neurogenet 19: 155-161. doi: 10.1080/01677060600569721
![]() |
[174] |
Laws SM, Perneczky R, Wagenpfeil S, et al. (2005) TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels. Hum Mutat 26: 29-35. doi: 10.1002/humu.20180
![]() |
[175] |
Lio D, Annoni G, Licastro F, et al. (2006) Tumor necrosis factor-alpha -308A/G polymorphism is associated with age at onset of Alzheimer's disease. Mech Ageing Dev 127: 567-571. doi: 10.1016/j.mad.2006.01.015
![]() |
[176] |
Nicoll JA, Mrak RE, Graham DI, et al. (2000) Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Ann Neurol 47: 365-368. doi: 10.1002/1531-8249(200003)47:3<365::AID-ANA13>3.0.CO;2-G
![]() |
[177] |
Sciacca FL, Ferri C, Licastro F, et al. (2003) Interleukin-1B polymorphism is associated with age at onset of Alzheimer's disease. Neurobiol Aging 24: 927-931. doi: 10.1016/S0197-4580(03)00011-3
![]() |
[178] |
Shibata N, Ohnuma T, Takahashi T, et al. (2002) Effect of IL-6 polymorphism on risk of Alzheimer disease: genotype-phenotype association study in Japanese cases. Am J Med Genet 114: 436-439. doi: 10.1002/ajmg.10417
![]() |
[179] |
Ferencz B, Laukka EJ, Welmer AK, et al. (2014) The benefits of staying active in old age: physical activity counteracts the negative influence of PICALM, BIN1, and CLU risk alleles on episodic memory functioning. Psychol Aging 29: 440-449. doi: 10.1037/a0035465
![]() |
[180] | Holler CJ, Davis PR, Beckett TL, et al. (2014) Bridging integrator 1 (BIN1) protein expression increases in the Alzheimer's disease brain and correlates with neurofibrillary tangle pathology. J Alzheimers Dis 42: 1221-1227. |
[181] | Xu W, Tan L, Yu JT (2014) The Role of PICALM in Alzheimer's Disease. Mol Neurobiol. |
[182] |
Herring A, Donath A, Yarmolenko M, et al. (2012) Exercise during pregnancy mitigates Alzheimer-like pathology in mouse offspring. Faseb J 26: 117-128. doi: 10.1096/fj.11-193193
![]() |
[183] |
Parnpiansil P, Jutapakdeegul N, Chentanez T, et al. (2003) Exercise during pregnancy increases hippocampal brain-derived neurotrophic factor mRNA expression and spatial learning in neonatal rat pup. Neurosci Lett 352: 45-48. doi: 10.1016/j.neulet.2003.08.023
![]() |
[184] | Horsburgh S, Robson-Ansley P, Adams R, et al. (2015) Exercise and inflammation-related epigenetic modifications: focus on DNA methylation. Exerc Immunol Rev 21: 26-41. |
[185] |
Kaliman P, Parrizas M, Lalanza JF, et al. (2011) Neurophysiological and epigenetic effects of physical exercise on the aging process. Ageing Res Rev 10: 475-486. doi: 10.1016/j.arr.2011.05.002
![]() |
[186] | Ntanasis-Stathopoulos J, Tzanninis JG, Philippou A, et al. (2013) Epigenetic regulation on gene expression induced by physical exercise. J Musculoskelet Neuronal Interact 13: 133-146. |
[187] | Hess NCL, Dieberg G, McFarlane JR, et al. (2014) The effect of exercise intervention on cognitive performance in persons at risk of, or with, dementia: A systematic review and meta-analysis. Healthy Aging Research 3: 1-10. |
[188] |
Holthoff VA, Marschner K, Scharf M, et al. (2015) Effects of physical activity training in patients with Alzheimer's dementia: results of a pilot RCT study. PLoS One 10: e0121478. doi: 10.1371/journal.pone.0121478
![]() |
[189] | Etnier JL, Labban JD, Karper WB, et al. (2015) Innovative Research Design Exploring the Effects of Physical Activity and Genetics on Cognitive Performance in Community-Based Older Adults. J Aging Phys Act. |
[190] |
Lautenschlager NT, Cox KL, Flicker L, et al. (2008) Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 300: 1027-1037. doi: 10.1001/jama.300.9.1027
![]() |
[191] |
Buchman AS, Boyle PA, Yu L, et al. (2012) Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology 78: 1323-1329. doi: 10.1212/WNL.0b013e3182535d35
![]() |
[192] | Zlatar ZZ, McGregor KM, Towler S, et al. (2015) Self-reported physical activity and objective aerobic fitness: differential associations with gray matter density in healthy aging. Front Aging Neurosci 7: 5. |
[193] |
Akbaraly TN, Portet F, Fustinoni S, et al. (2009) Leisure activities and the risk of dementia in the elderly: results from the Three-City Study. Neurology 73: 854-861. doi: 10.1212/WNL.0b013e3181b7849b
![]() |
[194] |
Scarmeas N, Levy G, Tang MX, et al. (2001) Influence of leisure activity on the incidence of Alzheimer's disease. Neurology 57: 2236-2242. doi: 10.1212/WNL.57.12.2236
![]() |
[195] |
Schooler C, Mulatu MS (2001) The reciprocal effects of leisure time activities and intellectual functioning in older people: a longitudinal analysis. Psychol Aging 16: 466-482. doi: 10.1037/0882-7974.16.3.466
![]() |
[196] |
Verghese J, Lipton RB, Katz MJ, et al. (2003) Leisure activities and the risk of dementia in the elderly. N Engl J Med 348: 2508-2516. doi: 10.1056/NEJMoa022252
![]() |
[197] |
Barnes LL, Mendes de Leon CF, Wilson RS, et al. (2004) Social resources and cognitive decline in a population of older African Americans and whites. Neurology 63: 2322-2326. doi: 10.1212/01.WNL.0000147473.04043.B3
![]() |
[198] |
Bennett DA, Schneider JA, Tang Y, et al. (2006) The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study. Lancet Neurol 5: 406-412. doi: 10.1016/S1474-4422(06)70417-3
![]() |
[199] |
Trost SG, Owen N, Bauman AE, et al. (2002) Correlates of adults' participation in physical activity: review and update. Med Sci Sports Exerc 34: 1996-2001. doi: 10.1097/00005768-200212000-00020
![]() |
[200] |
Dergance JM, Calmbach WL, Dhanda R, et al. (2003) Barriers to and benefits of leisure time physical activity in the elderly: differences across cultures. J Am Geriatr Soc 51: 863-868. doi: 10.1046/j.1365-2389.2003.51271.x
![]() |
[201] |
Kempermann G, Gast D, Gage FH (2002) Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol 52: 135-143. doi: 10.1002/ana.10262
![]() |
[202] |
Hannan AJ (2014) Environmental enrichment and brain repair: harnessing the therapeutic effects of cognitive stimulation and physical activity to enhance experience-dependent plasticity. Neuropathol Appl Neurobiol 40: 13-25. doi: 10.1111/nan.12102
![]() |
[203] |
Ball K, Berch DB, Helmers KF, et al. (2002) Effects of cognitive training interventions with older adults: a randomized controlled trial. Jama 288: 2271-2281. doi: 10.1001/jama.288.18.2271
![]() |
[204] | Calero MD, Navarro E (2007) Cognitive plasticity as a modulating variable on the effects of memory training in elderly persons. Arch Clin Neuropsychol 22: 63-72. |
[205] |
Engvig A, Fjell AM, Westlye LT, et al. (2010) Effects of memory training on cortical thickness in the elderly. Neuroimage 52: 1667-1676. doi: 10.1016/j.neuroimage.2010.05.041
![]() |
[206] |
Rozzini L, Costardi D, Chilovi BV, et al. (2007) Efficacy of cognitive rehabilitation in patients with mild cognitive impairment treated with cholinesterase inhibitors. Int J Geriatr Psychiatry 22: 356-360. doi: 10.1002/gps.1681
![]() |
[207] |
Zanetti O, Binetti G, Magni E, et al. (1997) Procedural memory stimulation in Alzheimer's disease: impact of a training programme. Acta Neurol Scand 95: 152-157. doi: 10.1111/j.1600-0404.1997.tb00087.x
![]() |
[208] |
Zanetti O, Zanieri G, Di Giovanni G, et al. (2001) Effectiveness of procedural memory stimulation in mild Alzheimer's disease patients: A controlled study. Neuropsychol Rehabil 11: 263-272. doi: 10.1080/09602010042000088
![]() |
[209] |
Wilson RS, Mendes De Leon CF, Barnes LL, et al. (2002) Participation in cognitively stimulating activities and risk of incident Alzheimer disease. Jama 287: 742-748. doi: 10.1001/jama.287.6.742
![]() |
[210] |
Wilson RS, Scherr PA, Schneider JA, et al. (2007) Relation of cognitive activity to risk of developing Alzheimer disease. Neurology 69: 1911-1920. doi: 10.1212/01.wnl.0000271087.67782.cb
![]() |
[211] |
Shah T, Verdile G, Sohrabi H, et al. (2014) A combination of physical activity and computerized brain training improves verbal memory and increases cerebral glucose metabolism in the elderly. Transl Psychiatry 4: e487. doi: 10.1038/tp.2014.122
![]() |
[212] | Gates NJ, Sachdev P (2014) Is cognitive training an effective treatment for preclinical and early Alzheimer's disease? J Alzheimers Dis 42 Suppl 4: S551-559. |
[213] |
Ngandu T, Lehtisalo J, Solomon A, et al. (2015) A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385: 2255-2263. doi: 10.1016/S0140-6736(15)60461-5
![]() |
[214] |
Ellis KA, Bush AI, Darby D, et al. (2009) The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease. Int Psychogeriatr 21: 672-687. doi: 10.1017/S1041610209009405
![]() |
[215] |
Mueller SG, Weiner MW, Thal LJ, et al. (2005) Ways toward an early diagnosis in Alzheimer's disease: the Alzheimer's Disease Neuroimaging Initiative (ADNI). Alzheimers Dement 1: 55-66. doi: 10.1016/j.jalz.2005.06.003
![]() |
[216] |
Bateman RJ, Xiong C, Benzinger TL, et al. (2012) Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 367: 795-804. doi: 10.1056/NEJMoa1202753
![]() |
[217] |
Raber J, Wong D, Buttini M, et al. (1998) Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc Natl Acad Sci U S A 95: 10914-10919. doi: 10.1073/pnas.95.18.10914
![]() |
[218] |
Ungar L, Altmann A, Greicius MD (2014) Apolipoprotein E, gender, and Alzheimer's disease: an overlooked, but potent and promising interaction. Brain Imaging Behav 8: 262-273. doi: 10.1007/s11682-013-9272-x
![]() |
1. | Najada Stringa, Natasja M van Schoor, Yuri Milaneschi, M Arfan Ikram, Vieri Del Panta, Chantal M Koolhaas, Trudy Voortman, Stefania Bandinelli, Frank J Wolters, Martijn Huisman, Anne Newman, Physical Activity as Moderator of the Association Between APOE and Cognitive Decline in Older Adults: Results from Three Longitudinal Cohort Studies, 2020, 75, 1079-5006, 1880, 10.1093/gerona/glaa054 | |
2. | Song‐Yi Park, Veronica Wendy Setiawan, Lon R. White, Anna H. Wu, Iona Cheng, Christopher A. Haiman, Lynne R. Wilkens, Loїc Le Marchand, Unhee Lim, Modifying effects of race and ethnicity and APOE on the association of physical activity with risk of Alzheimer's disease and related dementias , 2023, 19, 1552-5260, 507, 10.1002/alz.12677 |
Recommendations | Age Group | |
18-64 years |
65 year sand above |
|
At least 150 minutes of moderate-intensity OR At least 75 minutes of vigorous-intensity OR An equivalent combination of moderate- and vigorous-intensity aerobic PA/week. |
√ | √ |
Activity should be performed in bouts of at least 10 minutes duration. | √ | √ |
For additional health benefits, adults should increase their moderate-intensity to 300 minutes OR Engage in 150 minutes of vigorous-intensity OR An equivalent combination of moderate- and vigorous-intensity activity aerobic PA/week. |
√ | √ |
Muscle-strengthening activities should be done involving major muscle groups on 2 or more days a week. |
√ | √ |
Older adults, with poor mobility, should perform physical activity to enhance balance and prevent falls on 3 or more days per week. |
√ | |
When older adults cannot do the recommended amounts of physical activity due to health conditions, they should be as physically active as their abilities and conditions allow. |
√ | |
*PA includes leisure time physical activity, transportation (e. g. walking or cycling), occupational (i. e. work), household chores, or planned exercise/sports, in the context of daily, family, and community activities. |
Recommendations | Age Group | |
18-64 years |
65 year sand above |
|
At least 150 minutes of moderate-intensity OR At least 75 minutes of vigorous-intensity OR An equivalent combination of moderate- and vigorous-intensity aerobic PA/week. |
√ | √ |
Activity should be performed in bouts of at least 10 minutes duration. | √ | √ |
For additional health benefits, adults should increase their moderate-intensity to 300 minutes OR Engage in 150 minutes of vigorous-intensity OR An equivalent combination of moderate- and vigorous-intensity activity aerobic PA/week. |
√ | √ |
Muscle-strengthening activities should be done involving major muscle groups on 2 or more days a week. |
√ | √ |
Older adults, with poor mobility, should perform physical activity to enhance balance and prevent falls on 3 or more days per week. |
√ | |
When older adults cannot do the recommended amounts of physical activity due to health conditions, they should be as physically active as their abilities and conditions allow. |
√ | |
*PA includes leisure time physical activity, transportation (e. g. walking or cycling), occupational (i. e. work), household chores, or planned exercise/sports, in the context of daily, family, and community activities. |