The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques-which are frequently surrounded by dystrophic neurites-and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.

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Epidemiology of Alzheimer disease

More than 25 million people in the world today are affected by dementia, most suffering from Alzheimer's disease. In both developed and developing nations, Alzheimer's disease has had tremendous impact on the affected individuals, caregivers, and society. The etiological factors, other than older age and genetic susceptibility, remain to be determined. Nevertheless, increasing evidence strongly points to the potential risk roles of vascular risk factors and disorders (eg, cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions) and the possible beneficial roles of psychosocial factors (eg, high education, active social engagement, physical exercise, and mentally stimulating activity) in the pathogenetic process and clinical manifestation of the dementing disorders. The long-term multidomain interventions toward the optimal control of multiple vascular risk factors and the maintenance of socially integrated lifestyles and mentally stimulating activities are expected to reduce the risk or postpone the clinical onset of dementia, including Alzheimer's disease.

Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention

Background
This is an update of a Cochrane review first published in 2001 and then updated in 2009. Vascular risk factors including high cholesterol levels increase the risk of dementia due to Alzheimer's disease and of vascular dementia. Some observational studies have suggested an association between statin use and lowered incidence of dementia.

Objectives
To evaluate the efficacy and safety of statins for the prevention of dementia in people at risk of dementia due to their age and to determine whether the efficacy and safety of statins for this purpose depends on cholesterol level, apolipoprotein E (ApoE) genotype or cognitive level.

Search methods
We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) Portal on 11 November 2015.

Selection criteria
We included double-blind, randomised, placebo-controlled trials in which statins were administered for at least 12 months to people at risk of dementia.

Data collection and analysis
We used standard methodological procedures expected by Cochrane.

Main results
We included two trials with 26,340 participants aged 40 to 82 years of whom 11,610 were aged 70 or older. All participants had a history of, or risk factors for, vascular disease. The studies used different statins (simvastatin and pravastatin). Mean follow-up was 3.2 years in one study and five years in one study. The risk of bias was low. Only one study reported on the incidence of dementia (20,536 participants, 31 cases in each group; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.61 to 1.65, moderate quality evidence, downgraded due to imprecision). Both studies assessed cognitive function, but at different times using different scales, so we judged the results unsuitable for a meta-analysis. There were no differences between statin and placebo groups on five different cognitive tests (high quality evidence). Rates of treatment discontinuation due to non-fatal adverse events were less than 5% in both studies and there was no difference between statin and placebo groups in the risk of withdrawal due to adverse events (26,340 participants, 2 studies, OR 0.94, 95% CI 0.83 to 1.05).

Authors' conclusions
There is good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia. Biologically, it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising. However, indication bias may have been a factor in these studies and the evidence from subsequent RCTs has been negative. There were limitations in the included studies involving the cognitive assessments used and the inclusion of participants at moderate to high vascular risk only.

Statins for the prevention of dementia

BACKGROUND: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD.METHODS: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks.RESULTS: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated.CONCLUSIONS: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. Classification of evidence: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.

Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease LEADe

Cognitive function is an important component of aging and predicts quality of life, functional independence, and risk of institutionalization. Advances in our understanding of the role of cardiovascular risks have shown them to be closely associated with cognitive impairment and dementia. Because many cardiovascular risks are modifiable, it may be possible to maintain brain health and to prevent dementia in later life. The purpose of this American Heart Association (AHA)/American Stroke Association presidential advisory is to provide an initial definition of optimal brain health in adults and guidance on how to maintain brain health. We identify metrics to define optimal brain health in adults based on inclusion of factors that could be measured, monitored, and modified. From these practical considerations, we identified 7 metrics to define optimal brain health in adults that originated from AHA’s Life’s Simple 7: 4 ideal health behaviors (nonsmoking, physical activity at goal levels, healthy diet consistent with current guideline levels, and body mass index 2 ) and 3 ideal health factors (untreated blood pressure

Defining Optimal Brain Health in Adults: A Presidential Advisory From the American Heart Association/American Stroke Association

Background Growing evidence suggests that elevated cholesterol levels in mid-life are associated with increased risk of developing Alzheimer’s disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily). Methods This is an international, multicenter, double-blind, randomized, parallel-group study with a double-blind randomized withdrawal phase of patients with mild to moderate AD (Mini-Mental State Examination [MMSE] score, 13 to 25). Inclusion criteria included age 50 to 90 years, receiving donepezil 10 mg for at least 3 months before randomization, and low-density lipoprotein cholesterol levels (LDL-C) 2.5 to 3.5 mmol/L (95 to 195 mg/dL). Co-primary end points are changes in AD Assessment Scale-cognitive subscale (ADAS-cog) and AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale scores. A confirmatory end point is rate of change in whole brain and hippocampal volumes in patients who enrolled in the magnetic resonance imaging substudy. Results Enrollment of 641 subjects is complete. The baseline mean data are age 74 ± 8 years, 53% women, MMSE 22 ± 3, ADAS-cog 23 ± 10, AD Functional Assessment and Change Scale (ADFACS) 13 ± 9, Neuropsychiatric Inventory (NPI) 10 ± 11, and Clinical Dementia Rating-Sum of Boxes (CDR-SB) 6 ± 3. Mean prior donepezil treatment was 409 ± 407 days. Mean baseline lipid levels are total cholesterol 5.8 ± 0.8 mmol/L (224 ± 33 mg/dL), LDL-C 3.7 ± 0.7 mmol/L (143 ± 26 mg/dL), triglycerides 1.5 ± 0.7 mmol/L (132 ± 64 mg/dL), and high-density lipoprotein cholesterol 1.6 ± 0.5 mmol/L (64 ± 18 mg/dL). Conclusions LEADe will report in 2008 and is expected to provide a more definitive evaluation of the potential for statins in the treatment of people with AD.

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics.

2 The efficacy of statins for treating dyslipidemia and preenting complications of coronary artery disease such as myoardial infarctions is well established [1–5], and has lead to apid adoption worldwide. Statins act by inhibiting 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, and are rst-line agents for reducing serum total cholesterol and lowensity lipoprotein cholesterol (LDL-C). AD and cardiovascular disease (CVD) share several comon risk factors, and observational studies have suggested that he risk of AD is reduced in patients who receive statin therapy n mid-life. Lowering cholesterol with statins has been shown o reduce -amyloid production and could provide a mechaism for modifying the progression of AD. Alzheimer’s disase (AD) is characterized pathologically by the deposition of xtracellular -amyloid and the accumulation of neurofibrilary tangles. Strategies to delay the onset of progression of AD ave largely targeted the plaques formed by the deposition of -amyloid.. Cholesterol may play an important role in the evelopment and progression of AD. One proposed benefit of tatins is the prevention of Alzheimer’s disease (AD), potenially related to cholesterol reducing [6] and/or anti-inflammaory properties [7]. In animal models, elevated cholesterol evels have been shown to increase processing of amyloid recursor protein (APP) and associated -amyloid production. Randomized, double-blind, placebo-controlled, clinical rials (RCT) sufficiently large to provide definitive evidence or the benefits of statin therapy in AD have not yet been onducted, although a recent pilot RCT suggested that atorastatin improved AD symptoms [8]. Most observational tudies have also reported that statin exposure protects gainst AD [9–13], but two recent studies found no signifcant association between statin use and subsequent onset of ementia or AD [14,15]. The latter two studies controlled

Commentary on "Cytoskeletal modulators and pleiotropic strategies for Alzheimer drug discovery." Atorvastatin's effect in Alzheimer's dementia (LEADe) study.

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The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics.

Commentary on "Cytoskeletal modulators and pleiotropic strategies for Alzheimer drug discovery." Atorvastatin's effect in Alzheimer's dementia (LEADe) study.