Volume 20, Number 3, June 2010 - Special Issue "Basics of Alzheimer’s Disease Prevention" (Guest Editor: Jack de la Torre)

Pages 687-688
Jack de la Torre
Preface: Basics of Alzheimer’s Disease Prevention

Identification of Risk Factors

Pages 689-697
Review
Chengxuan Qiu, Weili Xu, Laura Fratiglioni
Vascular and Psychosocial Factors in Alzheimer’s Disease: Epidemiological Evidence Toward Intervention
Abstract: Alzheimer’s disease (AD), the most common cause of dementia, is posing serious threat to public health and health care system in both developed and developing nations due to a rapid increase in the aging population. Identification of etiological factors for AD and active implementation of interventions targeting those modifiable factors that may prevent or postpone clinical onset of the dementing disorder will provide an opportunity to cope with this challenge. Multidisciplinary research involving epidemiology, neuropathology, and neuroimaging has provided moderately strong evidence supporting the role of vascular factors and related disorders (e.g., midlife high blood pressure and obesity, diabetes, cerebral microvascular lesions, and smoking) as risk factors and the possible role of psychosocial factors (e.g., high educational achievements, mentally-stimulating activity, social engagement, and physical exercise) as protective factors in the development and clinical manifestation of the dementia syndrome, including AD. The implementation of long-term, multidomain interventions designed for the modification of multiple vascular risk factors and the maintenance of socially-integrated lifestyles and mentally-stimulating activities is expected to postpone the clinical onset of AD and dementia, and thus, substantially reduce the burden of the disease at both the individual and societal levels.

Pathology of Risk Factors and Their Modifiability

Pages 699-709
Review
David S. Knopman, Rosebud Roberts
Vascular Risk Factors: Imaging and Neuropathologic Correlates
Abstract: Cerebrovascular disease plays an important role in cognitive disorders in the elderly. Cerebrovascular disease and Alzheimer’s disease interact on several levels, with one important level being the overlap in risk factors. The major vascular risk factors such as diabetes and impaired glycemic control, hypertension, obesity, and hyper- or dyslipidemia have been associated both with Alzheimer’s disease and vascular dementia. The purpose of this review is to consider the context in which vascular dementia is diagnosed, place the pathophysiological consequences of cerebrovascular disease on cognition in the context of clinical and pathological Alzheimer’s disease, and then to consider the evidence for the role of major vascular risk factors in late-life cognitive impairment, changes in brain imaging and neuropathological changes. Midlife diabetes mellitus, hypertension, and obesity are established risk factors for clinically defined Alzheimer’s disease as well as vascular dementia. The basis for these relationships could either be that the risk factors lead to microvascular brain disease, promote Alzheimer pathology or both. The associations of late-life onset diabetes mellitus, hypertension, and obesity with cognitive impairment are either attenuated or reversed. The role of vascular risk factors in midlife should be the focus of public health efforts to reduce the burden of late-life cognitive impairment.

Pages 711-722
Review
Cynthia M. Carlsson
Type 2 Diabetes Mellitus, Dyslipidemia, and Alzheimer’s Disease
Abstract: The prevalence of Alzheimer’s disease (AD) is increasing rapidly, heightening the importance of finding effective preventive therapies for this devastating disease. Midlife vascular risk factors, including type 2 diabetes mellitus (T2DM), have been associated with increased risk of AD decades later and may serve as targets for AD prevention. Studies to date suggest that T2DM and hyperinsulinemia increase risk for AD, possibly through their effects on amyloid-β metabolism and cerebrovascular dysfunction—two early findings in preclinical AD pathology. This paper reviews the evidence supporting a relationship between T2DM, hyperinsulinemia, and diabetic dyslipidemia on the development of AD, discusses DM treatment trials and their preliminary results on cognitive function, and proposes some strategies for optimizing future AD prevention trial design.

Pages 723-736
Review
José A. Luchsinger
Type 2 Diabetes and Related Conditions in Relation to Dementia: An Opportunity for Prevention?
Abstract: This manuscript provides a comprehensive review of the epidemiologic evidence linking type 2 diabetes (T2D) and its precursor conditions, elevated adiposity and hyperinsulinemia, to dementia. The mechanisms relating these conditions to dementia may be vascular and non-vascular. Elevated adiposity in middle age is related to a higher risk of dementia but the data on this association in old age is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of dementia, including late onset Alzheimer’s disease (LOAD). Studies have consistently shown a relation of T2D with higher dementia risk, but the associations are stronger for vascular dementia compared to LOAD. A large proportion of the world population may be at increased risk of dementia given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and T2D. However, these associations may present a unique opportunity for prevention and treatment of dementia. There are several known modalities that are effective in the prevention and T2D and the reduction of hyperinsulinemia including lifestyle interventions, metformin, thiazolideniodones, and acarbose. Several studies in the prevention and treatment of T2D are currently measuring cognitive outcomes and will provide information on whether T2D treatment and prevention can prevent cognitive decline and dementia.

Pages 737-747
Review
John E. Morley and William A. Banks
Lipids and Cognition
Abstract: Cholesterol, omega-3 fatty acids, and triglycerides have been postulated to play roles in affecting cognition in Alzheimer’s disease (AD), the elderly, and obesity. Animal, human epidemiological, and in vitro studies each suggest an important role for cholesterol in the regulation of amyloid-β (Aβ) protein and the pathogenesis of AD. In contrast, well controlled studies have failed to show an effect of cholesterol lowering with statins on cognition, indicating that the cholesterol effect is spurious or indirect, possibly mediated through other lipids. Administration of diedocosahexanoic acid (DHA), a dietary omega-3 fatty acid derived primarily from fish and plants, improves cognition and reduces lipid peroxidation in animals, including in mouse models of AD. DHA also blocks Aβ-mediated tau phosphorylation. In humans, fish consumption or administration of DHA has been associated with cognitive improvement in many, but not all, studies. Both human and animal studies show that obesity is associated with cognitive impairments and that lowering triglycerides improves cognition. Administration of triglycerides to mice decreases learning and memory and impairs long-term potential. The effect of triglycerides may be mediated in part by inducing resistance to positive cognitive features of gastrointestinal hormones such as leptin. Overall, these studies strongly suggest that some lipids affect cognition in AD, the elderly, and obesity through a variety of mechanisms yet to be fully defined.

Pages 749-763
Review
Tânia Corrêa de Toledo Ferraz Alves, Luiz Kobuti Ferreira, Mauricio Wajngarten, Geraldo F. Busatto
Cardiac Disorders as Risk Factors for Alzheimer’s Disease
Abstract: Vascular risk factors can play an important role in determining the onset of non-genetic Alzheimer’s disease (AD). Most cases of AD are sporadic and late-onset, and a complex interaction between genetic predisposition and vascular risk factors has been proposed. Vascular risk factors for AD include stroke, hypertension, diabetes, homocysteine, smoking, hypercholesterolemia, heart failure, and atrial fibrillation; it is possible that these can trigger cerebrovascular dysfunction and AD pathology. Explanations for these associations include the coincidence of common disorders in the elderly where vascular and cerebrovascular disease can precipitate AD, implying that the onset of dementia is determined by a synergistic combination of risk factors. In this paper we review the role of cardiovascular risk factors in the pathogenesis of AD and discuss the associated brain mechanisms that can underlie the onset of AD. Cardiovascular diseases are a promising avenue of AD research because they are potentially modifiable in early adult life and provide a new perspective for the prevention of dementia.

Lifestyle Risk Factors

Pages 765-775
Review
Patrick J.G.H. Kamphuis, Philip Scheltens
Can Nutrients Prevent or Delay Onset of Alzheimer's Disease?
Abstract: Age-related changes in nutritional status can play an important role in brain functioning. Specific nutrient deficiencies in the elderly, including omega-3 fatty acids, B-vitamins, and antioxidants among others, may exacerbate pathological processes in the brain. Consequently, the potential of nutritional intervention to prevent or delay cognitive impairment and the development of Alzheimer’s disease (AD) is a topic of growing scientific interest. This review summarizes epidemiological studies linking specific nutritional deficiencies to mild cognitive impairment (MCI), as well as completed and ongoing nutritional studies in prevention of MCI and AD. Processes that underlie AD pathogenesis include: membrane/synaptic degeneration, abnormal protein processing (amyloid-β, tau), vascular risk factors (hypertension, hypercholesterolemia), inflammation, and oxidative stress. Consideration of mechanistic evidence to date suggests that several nutritional components can effectively counteract these processes, e.g., by promoting membrane formation and synaptogenesis, enhancing memory/behavior, improving endothelial function, and cerebrovascular health. The literature reinforces the need for early intervention in AD and suggests that multi-nutritional intervention, targeting multiple aspects of the neurodegenerative process during the earliest possible phase in the development of the disease, is likely to have the greatest therapeutic potential.

Pages 777-783
Review
Zsolt Radak, Nikoletta Hart, Linda Sarga, Erika Koltai, Mustafa Atalay, Hideki Ohno, Istvan Boldogh
Exercise Plays a Preventive Role Against Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting the elderly population. It is predicted that the incidence of AD will be increased in the future making this disease one of the greatest medical, social, and economic challenges for individuals, families, and the health care system worldwide. The etiology of AD is multifactorial. It features increased oxidative state and deposition of amyloid plaques and neurofibrillary tangles of protein tau in the central cortex and limbic system of the brain. Here we provide an overview of the positive impacts of exercise on this challenging disease. Regular physical activity increases the endurance of cells and tissues to oxidative stress, vascularization, energy metabolism, and neurotrophin synthesis, all important in neurogenesis, memory improvement, and brain plasticity. Although extensive studies are required to understand the mechanism, it is clear that physical exercise is beneficial in the prevention of AD and other age-associated neurodegenerative disorders.

Pages 785-794
Review
Lana Arab and Marwan N. Sabbagh
Are Certain Lifestyle Habits Associated with Lower Alzheimer’s Disease risk?
Abstract: As the number of patients with Alzheimer’s disease (AD) is expected to grow, finding ways to prevent and lower the risk of AD becomes a crucial matter. Risk factors for developing AD have been identified including health conditions, dietary habits, genetics and heredity, gender, education, age, and lifestyle. Interventions targeted at some of these risk factors may offer opportunities for development of an optimal preventive strategy. Lifestyle habits which include dietary habits and physical activities appear to have positive effect on modifying many risk factors. Studies have shown controversial results when it comes to the relation between the adherence to a Mediterranean diet and /or physical activity and the incidence of AD. Many population-based studies reported the positive association between antioxidants intake (like vitamin E and C), and polyunsaturated fatty acids whether it is from the diet or supplements on the cognitive performance. Future investigations should aim to determine objectively whether lifestyle modification through diet, exercise, or vitamins/supplements truly exert risk reduction or outright prevention. In this review, lifestyle habits are reviewed as they pertain to influence on risk of developing AD as well as on cognitive decline. Epidemiological studies and animal studies are reviewed.

Pages 795-801
Review
Francesco Sofi, Claudio Macchi, Rosanna Abbate, Gian Franco Gensini, Alessandro Casini
Effectiveness of the Mediterranean Diet: Can It Help Delay or Prevent Alzheimer’s Disease?
Abstract: Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease manifested by cognitive and memory deterioration, with an increasing prevalence in the industrialized countries and an extraordinary cost of caring for patients. Due to the limited information available on the exact pathophysiology of the disease over the last years, there have been extensive efforts for the identification of possible risk factors, but no conclusive data have been obtained. Some risk factors have been identified but no clear evidence on what is clearly associated with the occurrence and progression of AD are available, and in particular no effective preventive strategies have been found. One of the most intriguing and appealing evidence of the recent literature is the association between lifestyle habits such as diet and dietary compounds and the occurrence of AD. In this review, we will focus on studies that investigated the association between nutrition and AD, with our attention on the role of a dietary pattern such as a Mediterranean-like diet on the occurrence of such disease. Studies in support of Mediterranean diet as an optimal diet for prevention of cardiovascular and major chronic diseases has rapidly evolved. A recent meta-analysis from our group, comprising prospective studies that investigated the association between adherence to Mediterranean diet and health status, showed a significant association between a greater adherence to Mediterranean diet and a reduced risk of major chronic degenerative diseases, including AD. Moreover, Mediterranean diet has been extensively reported to be associated with a favorable health outcome and a better quality of life.

Pages 803-811
Review
Leon Flicker
Modifiable Lifestyle Risk Factors for Alzheimer’s Disease
Abstract: There is increasing evidence that some lifestyle factors are linked to the development of Alzheimer’s disease. Many of these are potentially modifiable and include smoking, physical activity, education, social engagement, cognitive stimulation, and diet. Modification of most of these factors has other health advantages, increasing the potential benefits of modifying the individual’s lifestyle. Unfortunately, most of the current evidence is based on observational data, and where human trials have been performed they have used surrogate outcomes rather than the development of Alzheimer’s disease. For many of these modifiable lifestyle factors, such trials may never be performed, and an individual’s choice may need to be based on the available evidence.

Detection of Alzheimer’s Disease Risk Factors

Pages 813-821
Review
Angela L. Jefferson
Cardiac Output as a Potential Risk Factor for Abnormal Brain Aging
Abstract: Heart failure has served as a clinically useful model for understanding how cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to clinical brain injury. This review summarizes more recent data suggesting that subtle cardiac dysfunction or low normal levels of cardiac function, as quantified by cardiac output, are related to cognitive and neuroimaging markers of abnormal brain aging in the absence of heart failure or severe cardiomyopathy. Additional work is required, but such associations suggest that reduced cardiac output may be a risk factor for Alzheimer’s disease (AD) and abnormal brain aging through the propagation or exacerbation of neurovascular processes, microembolism due to thrombosis, and AD neuropathological processes. Such mechanistic pathways are discussed in the context of a theoretical model that posits a direct pathway of injury between cardiac output and abnormal brain aging (i.e., reduced systemic blood flow disrupts cerebral blood flow homeostasis), contributing to clinical brain injury, independent of shared risk factors for both cardiac dysfunction and abnormal brain aging.

Pages 823-832
Review
Mary C. Tierney, Miriam A. Lermer
Computerized Cognitive Assessment in Primary Care to Identify Patients with Suspected Cognitive Impairment
Abstract: The incidence and prevalence in those over age 65 of neurodegenerative disorders and chronic diseases, which often have deleterious effects on cognition, are rapidly increasing in western societies. Primary care physicians (PCPs) provide the majority of medical treatment for older people and in order to effectively care for their patients with suspected cognitive impairment, they must have tools that will allow them to accurately assess their patient’s cognitive function. This knowledge will assist the PCPs in formulating a diagnosis of dementia or cognitive impairment and provide an indication of risk of progression to dementia. It will also assist with monitoring response to treatment and care decisions, including medication management, capacity judgments, and the need for family involvement. Tests currently used in primary care, such as the Mini-Mental State Examination, do not accurately assess patients with mild cognitive impairments, and other tests more suitable for this purpose require further validation and may be too time-consuming in the primary care setting. A possible solution is the use of patient-administered computerized cognitive testing in the PCP’s office. This systematic review identified eleven test batteries and three were judged potentially appropriate for cognitive assessment in the PCP’s office. These three varied in their presentation format and the quality of cross-sectional validation studies, and none had longitudinal data for dementia prediction. Thus the existing test batteries show potential for use in primary care but further study is needed to demonstrate their feasibility and effectiveness in this setting.

Pages 833-842
Review
Shari R. Waldstein, Carrington Rice Wendell
Neurocognitive Function and Cardiovascular Disease
Abstract: Cardiovascular (CV) diseases and their risk factors negatively impact the brain and neurocognitive function prior to stroke, dementia, or mild cognitive impairment (MCI). Indeed, a progression of neurocognitive and neurobiological impairments may be associated with increasingly severe manifestations of CV risk and disease. In samples ranging from children to elderly, a broad spectrum of CV risk factors, and both subclinical and clinical CV diseases have been related to decrements in cognitive function and cognitive decline across multiple domains of performance including executive functions, attention, learning and memory, perceptuo-motor speed, and others. In contrast to the MCI literature, the possibility of distinct subgroups has not been explored. Further, it remains unknown whether neurocognitive performance (or its pattern) per se can predict conversion to MCI and later dementia. We suggest that neurocognitive function may contribute to such prediction in concert with relevant radiological, genetic, biomedical, sociodemographic, and other data. To best do so, future research would benefit from inclusion of a breadth of neurocognitive tests that tap multiple domains of function with historical sensitivity to vascular and neurodegenerative pathology, in addition to biological or radiological assessment of such pathology. Aggressive efforts at prevention and early intervention with CV risk may play a critical role in the prevention of MCI or dementia.

Pages 843-854
Review
Lisa Mosconi, Valentina Berti, Lidia Glodzik, Alberto Pupi, Susan De Santi, Mony J. de Leon
Pre-Clinical Detection of Alzheimer’s Disease Using FDG-PET, with or without Amyloid Imaging
Abstract: The development of prevention therapies for Alzheimer’s disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring in the preclinical stage of the disease. Early diagnostics is necessary to identify and treat at risk individuals before irreversible neuronal loss occurs. In vivo imaging has long been used to evaluate brain structural and functional abnormalities as predictors of future AD in non-demented persons. Prior to development of amyloid-β (Aβ) tracers for positron emission tomography (PET), the most widely utilized PET tracer in AD was 2-[P18PF]fluoro-2-Deoxy-D-glucose (PFDG) PET. For over 20 years, FDG-PET has been used to measure cerebral metabolic rates of glucose (CMRglc), a proxy for neuronal activity, in AD. Many studies have shown that CMRglc reductions occur early in AD, correlate with disease progression, and predict histopathological diagnosis. This paper reviews reports of clinical and preclinical CMRglc reductions observed in association with genetic and non-genetic risk factors for AD. We then briefly review brain Aβ PET imaging studies in AD and discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Aβ-PET to improve the early detection of AD.

Pages 855-859
Review
Kazuo Kitagawa
Cerebral Blood Flow Measurement by PET in Hypertensive Subjects as a Marker of Cognitive Decline
Abstract: Recent epidemiological studies have shown that hypertension is a significant risk factor for Alzheimer’s disease (AD). Cerebral small vessel disease (CSVD) including silent cerebral infarction and white matter lesions could represent hypertensive target organ damages in the brain and may be reliable predictors for incident dementia. However, there have been few measures to classify those patients with CSVD who are at high risk for cognitive decline and dementia. Although cerebral hypoperfusion is central to the vascular hypothesis of AD, there have been no studies linking cerebral blood flow (CBF) and future cognitive decline. Using positron emission tomography, we have demonstrated a moderate association between CBF under baseline conditions and cognitive decline during a 3-year follow-up study in 27 hypertensive patients (r = 0.53, P = 0.003). Findings from randomized clinical trials together with our results suggest that the preservation or improvement of CBF by anti-hypertensive treatment might be effective for the prevention of cognitive decline and dementia, especially in hypertensive patients with CSVD.

Pages 861-870
Review
Jack C. de la Torre
Alzheimer’s Disease is Incurable but Preventable
Abstract: The dramatic rising incidence and costs of Alzheimer’s disease (AD) require that research efforts and funding be primarily directed on either finding a cure or applying preventive measures to curb this disorder. A cure for AD appears unlikely when significant cognitive loss has occurred because the neuronal networks that controlled the perturbed cognitive abilities are either dead or irreversibly damaged and replacing them, even if it were technically possible, would not reconstruct the intellectual identity of the host. Prevention of risk factors to sporadic AD is a more realistic stratagem and treatment, when indicated, ideally should begin in cognitively intact individuals as part of a mass screening effort. Prevention of modifiable risk factors to AD is cost-effective because it reduces hospice or hospital stay, repeated doctor visits, and long-term care. Presently, neurocognitive and neuroimaging tests are used with partial success in identifying persons at higher risk of AD but these tests can not pinpoint either a cause or a specific intervention that could attenuate disease progress. We previously proposed that carotid artery ultrasound +echocardiography together with ankle-brachail index (CAUSE+ABI) as mass screening tests in asymptomatic persons could detect not only cardio-cerebrovascular risk factors to AD, but also identify an indicated intervention. CAUSE+ABI are simple to perform, cost-effective, non-invasive, and reasonably accurate for the intended purpose. Additionally, detection of cardio-cerebrovasacular abnormalities long before expression of cognitive deterioration allows higher success rate with earlier treatment. Evidence-based medicine is recommended for optimizing clinical decision-making in evaluating AD risk factors and their treatment.

Pages 871-880
Review
David C. Alsop, Weiying Dai, Murray Grossman, John A. Detre
Arterial Spin Labeling Blood Flow MRI: Its Role in the Early Characterization of Alzheimer’s Disease
Abstract: Arterial spin labeling (ASL) enables the noninvasive, quantitative imaging of cerebral blood flow using standard magnetic resonance imaging (MRI) equipment. Because it requires no contrast injection, ASL can add resting functional information to MRI studies measuring atrophy and signs of ischemic injury. Key features of ASL technology that may affect studies in Alzheimer’s disease are described. The existing literature describing ASL blood flow imaging applied to Alzheimer’s disease and related dementia is reviewed and the potential role of ASL in treatment and prevention studies of early Alzheimer’s disease is discussed.

Pages 881-891
Review
Ineke A van Rossum, Stephanie Vos, Ron Handels, Pieter Jelle Visser
Biomarkers as Predictors for Conversion from Mild Cognitive Impairment to Alzheimer-Type Dementia: Implications for Trial Design
Abstract: Disease modifying drugs for Alzheimer’s disease (AD) are likely to be most effective when given in non-demented subjects. In this review we summarized biomarkers in cerebrospinal fluid (CSF) and blood that can predict AD-type dementia in subjects with mild cognitive impairment (MCI). In addition we investigated whether these markers could reduce sample size and costs if used to select subjects for trials on the prevention of AD in subjects with MCI. A meta-analysis of markers that had been investigated in multiple studies showed that the combination of amyloid-β (Aβ)1-42 and tau in CSF had the best predictive accuracy for AD (odds ratio (OR) 18.1, 95% confidence interval (CI) 9.6-32.4). Aβ1-42, total tau, and phosphorylated tau in CSF also predicted conversion, but with lower accuracy (OR 7.5 to 8.1). Plasma level of Aβ1-40 tended to predict conversion to AD (Cohen’s delta 0.23, 95% CI -0.01-0.48, p 0.07). Plasma levels of Aβ1-42, the ratio Aβ1-42/Aβ1-40 and homocysteine did not predict outcome. In a fictive trial design, the use of the combination of Aβ1-42 and tau in CSF in the selection of subjects could reduce sample size by 67% and trial costs by 60% compared to a trial in which unselected subjects with MCI would be enrolled. In conclusion, the combination of Aβ1-42 and tau in CSF is useful to select subjects for trials that aim to slow down the progression from MCI to AD-type dementia.

Interventions to Prevent Cognitive Decline

Pages 893-901
Review
Simona Luzzi, Lucia Vella, Marco Bartolini, Leandro Provinciali and Mauro Silvestrini
Atherosclerosis in the Evolution of Alzheimer’s Disease: Can Treatment Reduce Cognitive Decline?
Abstract: The relationship between cerebrovascular impairment and Alzheimer’s disease is a controversial debate. An important and topical aspect in clinical research is the attempt to define the role of atherosclerosis and its determinants in the presentation and evolution of dementia. In this article, we discuss the evidence of the interaction between degenerative and vascular mechanisms in the pathogenesis of dementia. Moreover, we present data about the influence of hypertension and dyslipidemia, usually considered among the most important risk factors for atherosclerosis, on the evolution of Alzheimer’s disease. The effects of antihypertensive and lipid-lowering drugs on cognitive impairment will be also discussed.

Pages 903-914
Review
Emmanuelle Duron, Olivier Hanon
Antihypertensive Treatments, Cognitive Decline, and Dementia
Abstract: Chronic hypertension is associated with an increased risk of both vascular dementia and Alzheimer’s disease (AD). In this context, the role of anti-hypertensive therapy for the prevention and delay of cognitive decline and dementia is of central importance. Most longitudinal studies have shown a significant inverse association between anti-hypertensive therapies and dementia incidence and for some of these, particularly in AD. Seven randomized, double blind placebo-controlled trials have evaluated the benefit of antihypertensive treatments on cognition. Three of them found positive results in term of prevention of dementia (SYST-EUR) or cognitive decline (PROGRESS, HOPE). Others disclosed non-significant results (MRC, SHEP, SCOPE, HYVET-COG). This discrepancy emphasizes the difficulty to perform such trials: the follow-up has to be long enough to disclose a benefit, a large number of patients is needed for these studies, and because of ethical reasons some anti-hypertensive treatments are often prescribed in the placebo group. Results of the two more recent meta-analyses are inconsistent, possibly due methodological issues. Antihypertensive treatments could be beneficial to cognitive function by lowering blood pressure and/or by specific neuroprotective effect. Three main antihypertensive subclasses have been associated with a beneficial effect on cognitive function beyond blood pressure reduction (calcium channel blockers, angiotensin converting enzyme inhibitor, angiotensin-AT1-receptor-blockers). Further long-term randomized trials, designed especially to assess a link between antihypertensive therapy and cognitive decline or dementia are therefore needed with cognition as the primary outcome. A low blood pressure threshold that could be deleterious for cognitive function should also be determined.

Pages 915-924
Review
Laura Middleton, Kristine Yaffe
Targets for the Prevention of Dementia
Abstract: The prevalence of dementia is expected to increase dramatically over the upcoming decades due to the aging population. Since treatment is still short of a cure, preventative strategies are of the utmost importance. Stimulating activity (cognitive, physical, and social), vascular risk factors, and diet may play important roles in preventative strategies. Dementia risk may be modified by participation in stimulating activities. One study suggested that the cognitive, physical, and social components of activity were of equal importance to cognitive outcomes. However, while exercise interventions appear to benefit global cognition, the benefits from cognitive training appear to be domain specific. People with vascular risk factors (hypertension, diabetes, dyslipidemia, and obesity) appear to be at higher risk for dementia than those without in observational studies. Controlled trials suggest that vascular risk management via some pharmaceutical interventions may benefit cognition, though results are inconsistent. Finally, people who adhere to a Mediterranean diet or who have high intake of antioxidants and omega-3 fatty acids have reduced likelihood of dementia in observational studies. However, supplementation in controlled trials has not generally been successful at improving cognitive outcomes. A single supplement may be insufficient to prevent dementia; it may be that the overall diet is more important. Future large randomized controlled studies should examine whether interventions can reduce the risk of dementia and whether combining cognitive, physical, and social activity, vascular risk reduction, and dietary interventions might have additive or multiplicative effects.

Pages 925-933
Review
Bernadette McGuinness and Peter Passmore
Can Statins Prevent or Help Treat Alzheimer’s Disease?
Abstract: Evidence accumulating from biological and epidemiological studies suggests that high levels of serum cholesterol may promote the pathological processes that lead to Alzheimer's disease (AD). Lowering cholesterol in experimental animal models slows the expression of Alzheimer's pathology. These findings raise the possibility that treating humans with cholesterol lowering medications might reduce the risk of developing AD or help treat it. The statins (lovastatin, pravastatin, simvastatin, and others) are powerful cholesterol lowering agents of proven benefit in vascular disease. Several clinical studies comparing the occurrence of AD between users and non-users of statins suggested that risk of AD was substantially reduced among the users. However, because these studies were not randomized trials, they provided insufficient evidence to recommend statin therapy. Cochrane reviews are based on the best available information about healthcare interventions and they focus primarily on randomized controlled trials (RCTs). On the issue of prevention, two randomized trials have been carried out and neither showed any reduction in occurrence of AD in patients treated with statins compared to those given placebo. Statins cannot therefore be recommended for the prevention of AD. Regarding treatment of AD, the large RCTs which have assessed this outcome have not published their results. Initial analysis from the studies available indicate statins have no benefit on the outcome measure ADAS-Cog but have a significant beneficial effect on MMSE as an outcome. We need to await full results from the RCTs before we can be certain. In addition statins were not detrimental to cognition in either systematic review.

Pages 935-942
Review
M. Hassan Murad, Victor M. Montori
Evidence-Based Medicine: Application in Alzheimer’s Disease Research
Abstract: The two fundamental principles of evidence-based medicine indicate that a hierarchy of evidence exists and that evidence alone is never sufficient to make clinical decisions. Incorporation of factors other than evidence such as patients’ values and preferences, clinical context, and resource allocation are essential factors for decision making. The knowledge of these principles orients the use of clinical care research by evidence users such as patients, clinicians, and policy makers; and also helps researchers create research protocols and agendas that produce evidence that fulfills the needs of these users. Examples of research in Alzheimer’s disease are presented to illustrate how evidence is produced, appraised and utilized.

Pages 943-948
Meeting Report from the Alzheimer Research Forum
The 7th Leonard Berg Symposium, Part 1

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