Alzheimer’s disease (AD), as the most common cause of dementia, brings huge economic burden for patients and social health care systems, which motivates researchers to study multiple protective factors, among which physical activity and exercise have been proven to be both effective and economically feasible. A systematic literature search was performed for eligible studies published up to November 1st 2018 on three international databases (PubMed, Cochrane Library, and Embase) and two Chinese databases (Wanfang Data, China National Knowledge Infrastructure). All analyses were conducted using Stata 14.0. Due to heterogeneity between studies, a random-effects model was used for this meta-analysis. Meta-analysis was used to explore if physical activity and exercise can exert positive effects on cognition of elderly with AD and subgroup analyses were conducted to find out if there are dose-response effects. A total of 13 randomized controlled trials were included with a sample size of 673 subjects diagnosed with AD. Intervention groups showed a statistically significant improvement in cognition of included subjects measured by the MMSE score (SMD = 1.12 CI:0.66~1.59) compared to the control groups. Subgroup analyses showed different amounts of physical activity and exercise can generate different effects. As one of few meta-analyses comparing different quantities of physical activity and exercise interventions for AD in details, our study suggests that physical activity and exercise can improve cognition of older adults with AD. While the concomitant effects on cognition functions of high frequency interventions was not greater than that of low frequency interventions, the threshold remains to be settled. However, more RCTs with rigorous study design are needed to support our findings.

/pdf/effects-of-physical-activity-and-exercise-on-the-cognitive-wcl6ieemt5.pdf

Effects of physical activity and exercise on the cognitive function of patients with Alzheimer disease: a meta-analysis

Objective To estimate the effect of a moderate to high intensity aerobic and strength exercise training programme on cognitive impairment and other outcomes in people with mild to moderate dementia. Design Multicentre, pragmatic, investigator masked, randomised controlled trial. Setting National Health Service primary care, community and memory services, dementia research registers, and voluntary sector providers in 15 English regions. Participants 494 people with dementia: 329 were assigned to an aerobic and strength exercise programme and 165 were assigned to usual care. Random allocation was 2:1 in favour of the exercise arm. Interventions Usual care plus four months of supervised exercise and support for ongoing physical activity, or usual care only. Interventions were delivered in community gym facilities and NHS premises. Main outcome measures The primary outcome was score on the Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) at 12 months. Secondary outcomes included activities of daily living, neuropsychiatric symptoms, health related quality of life, and carer quality of life and burden. Physical fitness (including the six minute walk test) was measured in the exercise arm during the intervention. Results The average age of participants was 77 (SD 7.9) years and 301/494 (61%) were men. By 12 months the mean ADAS-cog score had increased to 25.2 (SD 12.3) in the exercise arm and 23.8 (SD 10.4) in the usual care arm (adjusted between group difference −1.4, 95% confidence interval −2.6 to −0.2, P=0.03). This indicates greater cognitive impairment in the exercise group, although the average difference is small and clinical relevance uncertain. No differences were found in secondary outcomes or preplanned subgroup analyses by dementia type (Alzheimer’s disease or other), severity of cognitive impairment, sex, and mobility. Compliance with exercise was good. Over 65% of participants (214/329) attended more than three quarters of scheduled sessions. Six minute walking distance improved over six weeks (mean change 18.1 m, 95% confidence interval 11.6 m to 24.6 m). Conclusion A moderate to high intensity aerobic and strength exercise training programme does not slow cognitive impairment in people with mild to moderate dementia. The exercise training programme improved physical fitness, but there were no noticeable improvements in other clinical outcomes. Trial registration Current Controlled Trials ISRCTN10416500.

https://www.bmj.com/content/bmj/361/bmj.k1675.full.pdf

Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the most cases of dementia, which is characterized by the deposition of dense plaques of amyloid beta (Aβ) plaques and neurofibrillary tangles consisting of hyperphosphorylated tau. The two main types of AD can be classified as early-onset AD (EOAD, onset < 65 years) and late-onset AD (LOAD, onset ≥ 65 years). Evidence from family and twin studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The first milestone with linkage analysis revealed the mutations in APP, PSEN1, and PSEN2 genes that cause EOAD. But pathogenic mutations in these three genes can only explain a small fraction of EOAD families. The additional disease-causing genes have not yet been identified. This review provides an overview of the genetic basis of EOAD and the relationship between the functions of these risk genes and the neuropathologic features of AD. A better understanding of genetic mechanisms underlying EOAD pathogenesis and the potentially molecular mechanisms of neurodegeneration will lead to the development of effective diagnosis and treatment strategies for this devastating disease.

/pdf/the-genes-associated-with-early-onset-alzheimer-s-disease-4h2bvu6lcz.pdf

The genes associated with early-onset Alzheimer's disease.

The present study was designed to investigate the role of β-amyloid (Aβ1-42 ) in inducing neuronal pyroptosis and its mechanism. Mice cortical neurons (MCNs) were used in this study, LPS + Nigericin was used to induce pyroptosis in MCNs (positive control group), and Aβ1-42 was used to interfere with MCNs. In addition, propidium iodide (PI) staining was used to examine cell permeability, lactate dehydrogenase (LDH) release assay was employed to detect cytotoxicity, immunofluorescence (IF) staining was used to investigate the expression level of the key protein GSDMD, Western blot was performed to detect the expression levels of key proteins, and enzyme-linked immunosorbent assay (ELISA) was utilized to determine the expression levels of inflammatory factors in culture medium, including IL-1β, IL-18 and TNF-α. Small interfering RNA (siRNA) was used to silence the mRNA expression of caspase-1 and GSDMD, and Aβ1-42 was used to induce pyroptosis, followed by investigation of the role of caspase-1-mediated GSDMD cleavage in pyroptosis. In addition, necrosulfonamide (NSA), an inhibitor of GSDMD oligomerization, was used for pre-treatment, and Aβ1-42 was subsequently used to observe the pyroptosis in MCNs. Finally, AAV9-siRNA-caspase-1 was injected into the tail vein of APP/PS1 double transgenic mice (Alzheimer's disease mice) for caspase-1 mRNA inhibition, followed by observation of behavioural changes in mice and measurement of the expression of inflammatory factors and pyroptosis-related protein. As results, Aβ1-42 could induce pyroptosis in MCNs, increase cell permeability and enhance LDH release, which were similar to the LPS + Nigericin-induced pyroptosis. Meanwhile, the expression levels of cellular GSDMD and p30-GSDMD were up-regulated, the levels of NLRP3 inflammasome and GSDMD-cleaved protein caspase-1 were up-regulated, and the levels of inflammatory factors in the medium were also up-regulated. siRNA intervention in caspase-1 or GSDMD inhibited Aβ1-42 -induced pyroptosis, and NSA pre-treatment also caused the similar inhibitory effects. The behavioural ability of Alzheimer's disease (AD) mice was relieved after the injection of AAV9-siRNA-caspase-1, and the expression of pyroptosis-related protein in the cortex and hippocampus was down-regulated. In conclusion, Aβ1-42 could induce pyroptosis by GSDMD protein, and NLRP3-caspase-1 signalling was an important signal to mediate GSDMD cleavage, which plays an important role in Aβ1-42 -induced pyroptosis in neurons. Therefore, GSDMD is expected to be a novel therapeutic target for AD.

New mechanism of nerve injury in Alzheimer's disease: β-amyloid-induced neuronal pyroptosis.

Ageing of the population, together with population growth, has brought along an ample increase in the number of older individuals living with dementia and disabilities. Dementia is the main cause of disability in old age, and promoting healthy brain ageing is considered as a key element in diminishing the burden of age-related disabilities. The World Health Organization recently launched the first risk reduction guidelines for cognitive impairment and dementia. According to recent estimates, approximately 40% of dementia cases worldwide could be attributable to 12 modifiable risk factors: low education; midlife hypertension and obesity; diabetes, smoking, excessive alcohol use, physical inactivity, depression, low social contact, hearing loss, traumatic brain injury and air pollution indicating clear prevention potential. Dementia and physical disability are closely linked with shared risk factors and possible shared underlying mechanisms supporting the possibility of integrated preventive interventions. FINGER trial was the first large randomized controlled trial indicating that multidomain lifestyle-based intervention can prevent cognitive and functional decline amongst at-risk older adults from the general population. Within the World-Wide FINGERS network, the multidomain FINGER concept is now tested and adapted worldwide proving evidence and tools for effective and easily implementable preventive strategies. Close collaboration between researchers, policymakers and healthcare practitioners, involvement of older adults and utilization of new technologies to support self-management is needed to facilitate the implementation of the research findings. In this scoping review, we present the current scientific evidence in the field of dementia and disability prevention and discuss future directions in the field.

How can dementia and disability be prevented in older adults: where are we today and where are we going?

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.

https://www.mdpi.com/2076-3425/7/2/22/pdf

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

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