Evaluating the Link Between Cardiovascular Risk and Alzheimer’s Disease: A Comprehensive Case-Control Study in Castilla y León, Spain

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.

A dvances in our understanding of vascular cognitive impairment (VCI) have springboarded from further elucidation of the role of vascular risk factors, surgical procedures, medications, and neuroimaging studies that are related to this condition. The main focus of this VCI review will highlight the relation of diabetes mellitus and hippocampal dysfunction in VCI; coronary artery bypass surgery and cognitive decline; the role of cerebral amyloid angiopathy (CAA) in vascular dysfunction; and a discussion of other cardiovascular risk factors, treatment, and neuroimaging findings related to disease progression; and histopathologic and genetic correlates.

BackgroundIncreasing evidence suggests that sex influences several aspects of Alzheimer’s disease (AD). Cardiovascular risk factors are associated with AD, and men and women differ in the prevalence of these risk factors. We aimed at determining whether (1) sex and cardiovascular risk factors have an effect on CSF biomarkers; (2) sex modifies the association between cardiovascular risk factors and CSF biomarkers in middle aged cognitively unimpaired individuals of the ALFA+ study.MethodWe measured CSF Ab42, Ab40, p‐tau, t‐tau, neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, S100, IL6, sVCAM1, sICAM1, MCP1 and α‐synuclein in 381 participants of the ALFA+ study (34.4% Ab‐positive, 65.6% Ab‐negative; Ab42/40 cutoff = 0.071). Biomarker measurements were performed using MSD, Roche NeuroToolKit and Elecsys® immunoassays. The following cardiovascular risk variables were studied: hypertension, smoking, dyslipidaemia, physical activity, LDL and HDL cholesterol, glucose, Hb1Ac, triglycerides, BMI and systolic and diastolic blood pressure. ANCOVA was performed to test the effect of sex on each biomarker and potential interaction effects between sex and cardiovascular variables.ResultWe found that CSF NfL, GFAP, IL6, sVCAM1 and MCP1 were higher in men, while CSF neurogranin and YKL40 were higher in women. These differences were still significant after adjusting for Ab pathology. Regarding cardiovascular variables, men had higher diastolic blood pressure, glucose and triglycerides, while women had higher total, LDL and HDL cholesterol. After adjusting for these cardiovascular variables, sex differences in CSF NfL were still significant, suggesting that they were not confounded by cardiovascular factors (Table 1). In the whole cohort, we observed that sex modifies the association with physical activity levels and CSF NfL (interaction ‘sex x physical activity’: p=0.019). After stratifying by Ab status, we observed that higher physical activity was associated with lower CSF NfL only in Ab positive men (Figure 1).ConclusionSex affects CSF biomarkers and modifies their association with cardiovascular risk factors. Specifically, physical activity is associated with lower NfL in middle aged men in the preclinical stage of the Alzheimer’s continuum, but not in women. Our results suggest that the impact of cardiovascular risk factors on neurodegeneration differs between men and women.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is largely associated with cognitive disability, amnesia, and abnormal behavior, which accounts for about two third of people with dementia worldwide. A growing body of research demonstrates that AD is connected to several factors, such as aberrant accumulation of amyloid-beta (Aβ), increase in the hyperphosphorylation of Tau protein, and the formation of neurofibrillary tangles, mitochondrial dysfunction, and inordinate production of reactive oxygen species (ROS). Despite remarkable efforts to realize the etiology and pathophysiology of AD, until now, scientists have not developed and introduced medications that can permanently cease the progression of AD. Thus, nowadays, research on the role of natural products in the treatment and prevention of AD has attracted great attention. Kaempferol (KMP), one of the prominent members of flavonols, exerts its ameliorative actions via attenuating oxidative stress and inflammation, reducing Aβ-induced neurotoxicity, and regulating the cholinergic system. Therefore, in this review article, we outlined the possible effects of KMP in the prevention and treatment of AD. PRACTICAL APPLICATIONS: Kaempferol (KMP) exerts its ameliorative actions against AD via attenuating oxidative stress and inflammation, reducing Aβ-induced neurotoxicity, and regulating the cholinergic system. The beneficial effects of KMP were addressed in both in vitro and in vivo studies; however, conducting further research can warrant its long-term effects as a safe agent. Therefore, after confirming its favorable functions in the prevention and treatment of AD, it could be used as a safe and effective agent.

Dementia is a syndrome characterized by failure of recent memory and other cognitive functions that is usually insidious in onset but steadily progresses with age. Alzheimer’s disease (AD) is the most common form of senile dementia. It is neuropathologically characterized by extracellular and perivascular aggregation of amyloid β (Aβ) peptide, by the generation of intracellular neurofibrillary tangles due to a hyperphosphorylation of tau protein and by an increased rate of neuronal degeneration. The degenerative process starts 20-30 years before the clinical onset of the disease. Clinical diagnosis of AD is difficult but possible, but can only be confirmed by biopsy or autopsy. At present, no biological marker exists for early diagnosis of AD during life. Therefore, identification of biomarkers for AD would be of great value for clinical diagnosis of incipient AD. Recent studies have proven the involvement of inflammatory processes in the neurodegenerative events in AD. Inflammation may not be the first event in the progression of the disease, but it involves activation of glia cells including microglia and astrocytes and subsequent release of proinflammatory mediators. Cytokines released such as IL-1, TNF-α and IL-6 are the main proinflammatory cytokines that can modulate inflammatory responses as well as glial proliferation and activation. Oxidative stress triggered by inflammatory processes causes changes in proteins such as tyrosine nitration or lipid peroxidation. Aβ deposits, tau hyperphosphorylation, inflammation and oxidative stress may finally lead to changes in synaptic connectivity and efficacy including perturbation of long-term potentiation (LTP), important in the formation of memory. Proteomic technology used in these studies is a recent technology which is a two step process: separation of proteins and their subsequent analysis by mass spectrometry. Moreover, this technology can provide new information concerning the expression level, post-translational modification of specific proteins as well as their conformational changes during disease progression. In our study, this technology was modified and improved, e.g by the miniaturization of the complete process. Proteomic technology was also used in parallel with other methods such as chromatography in order to increase the sensitivity of detection by mass spectrometry. This study aimed: 1) To establish that cytokine treatment of human microglia cells is an efficient method to study certain aspects of AD pathogenesis. For this analysis, a map of protein expression in normal and in treated microglia cells was made. 2) To map protein expression in APP/PS2 transgenic mice, a model for human AD, in order to compare human AD brain with murine models. 3) To identify highly nitrated proteins in brains of transgenic animals. Several proteins were found to be modified after injury. 4) To provide evidence for instability of synapses in AD brains. To start with this study, the technologies used to map mouse brain cytosolic proteins were improved. 5) To isolate synaptosomal membranes from the whole brain and to analyse it by massspectrometry. For mapping synaptic membrane protein expression in controls or transgenic mouse models, the technology was miniaturizated and optimized. This study is still in progress.

Battle against Alzheimer's Disease: The Scope and Potential Value of Magnetic Resonance Imaging Biomarkers

Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. Traditionally thought of as an untreatable degenerative condition, recent advances in drug therapy have challenged this view. The disease is characterised by an insidious decline in cognitive and non-cognitive function. Classically, short and long-term memory is impaired while language skills, concentration and attention are often affected. This results in impaired ability to learn and retain new skills as well as the loss of existing ones. Non-cognitive function is the global term used to describe problems such as depression, agitation, personality changes, delusions and hallucinations. These factors have a significant impact on patient behaviour and a very real impact on the quality of life for both patients and caregivers. Diagnosis of AD is clinically based, and using the NINCDS-ADRDA criteria (Table 1) [1], a diagnosis of probable or possible AD can be made. Definitive diagnosis relies on pathological confirmation, which in the majority of cases is rarely completed. With the development of AD specific treatments, definition of AD from other types of dementia is very important. Table 1 NINCDS-ADRDA Criteria for clinical diagnosis of Alzheimer’s disease. Pathogenesis The pathogenesis of AD has not yet been elucidated. It is widely accepted that a combination of genetic susceptibility factors and environmental triggers are responsible for late onset sporadic AD, the most common form of the disease. An understanding of the disease mechanism remains elusive, and is the key to developing a disease modifying agent. Currently, it is proposed that beta amyloid protein, abnormal tau protein or possibly both play key factors in the development of disease. It has been widely postulated that oxidative damage and a slow inflammatory process are two possible mechanisms involved. As yet, no product with proven disease modifying properties is available, and current treatments offer symptomatic benefit only. The development of acetylcholinesterase (AChe) inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD [2] and the resultant cholinergic deficit contributes to the cognitive impairment of these patients [3]. Although many believe this ‘cholinergic hypothesis’ to be important, others feel it represents a less significant component of the disease process [4]. Many other neurotransmitters are affected in AD, and the relative importance of each in relation to clinical findings has not been fully elucidated. Initial work focused on the use of acetylcholine precursors, using a similar rationale to dopamine therapy in Parkinson’s disease. A series of small trials using precursors such as choline and phosphatidylcholine showed no reliable improvement in cognitive function, with only 10 out of 43 trials reporting any positive effect [5]. There has been renewed interest in muscarinic agonists drugs, which when first introduced, had major problems with adverse cholinergic effects. Better understanding of the molecular pathology of muscarinic receptors and their subtypes has led to the development of more specific agonists. Drugs such as xanomeline, milameline, and civimeline have reached clinical trials, and the improvements seen in cognitive function are reviewed by Avery et al. [6]. There are also claims that these drugs have disease modifying properties, with effects on APP processing and tau phosphorylation. Muscarinic agonists remain in trial, but have yet to fulfil their potential in AD treatment. The only group of drugs currently licensed for AD treatment is the AChe inhibitors, which act through inhibition of the enzyme acetylcholinesterase (AChe), responsible for the breakdown of ACh in the neural synapse. A meta-analysis of the early AChe inhibitor treatments was encouraging [7] and these proceeded to larger placebo controlled double-blind trials.

Objectives: Alzheimer’s disease (AD) is a serious neurodegenerative disease. Although many therapeutic strategies have been studied, their clinical applications are immature. Moreover, these methods can only alleviate symptoms rather than cure it, posing a challenge to brain health in older adults worldwide. Curcumin (CUR) is a very promising natural compound for nerve protection and treatment. It can prevent and treat AD, and on the other hand, its fluorescence properties can be used in the diagnosis of AD. However, CUR is characterized by very low water solubility, fluid instability, rapid metabolism, low bioavailability and difficulty in penetrating the biological barriers, which limit its application. Nanocarriers are a potential material to improve the biocompatibility of CUR and its ability to cross biological barriers. Therefore, delivering CUR by nanocarriers is an effective method to achieve better efficacy. Methods: In this review, the preventive, therapeutic and diagnostic effects of CUR nanoformulations on AD, as well as various patents, clinical trials and experimental research progress in this field are discussed. The aim is to provide detailed reference and practical suggestions for future research. Results: CUR has a variety of pharmacological activities in the prevention and treatment of AD, and its nanoformulation can effectively improve solubility, bioavailability and the ability to penetrate the blood-brain barrier. Significant benefits have been observed in the current study. Discussion: CUR formulations have a good prospect in the prevention, diagnosis and treatment of AD, but the safety and principle of its administration need more detailed study in the future.

Alzheimer’s disease (AD) is a progressive degenerative neurological illness with insidious onset. Due to the complexity of the pathogenesis of AD and different pathological changes, the clinical phenotypes of dementia are diverse, and these pathological changes also interact with each other. Therefore, it is of great significance to search for biomarkers that can diagnose these pathological changes to improve the ability to monitor the course of disease and treat the disease. The pathological mechanism hypothesis with high recognition of AD mainly includes the accumulation of β-amyloid (Aβ) around neurons and hyperphosphorylation of tau protein, which results in the development of neuronal fiber tangles (NFTs) and mitochondrial dysfunction. AD is an irreversible disease; currently, there is no clinical cure or delay in the disease process of drugs, and there is a lack of effective early clinical diagnosis methods. AD patients, often in the dementia stages and moderate cognitive impairment, will seek medical treatment. Biomarkers can help diagnose the presence or absence of specific diseases and their pathological processes, so early screening and diagnosis are crucial for the prevention and therapy of AD in clinical practice. β-amyloid deposition (A), tau pathology (T), and neurodegeneration/neuronal damage (N), also known as the AT (N) biomarkers system, are widely validated core humoral markers for the diagnosis of AD. In this paper, the pathogenesis of AD related to AT (N) and the current research status of cerebrospinal fluid (CSF) and blood related biomarkers were reviewed. At the same time, the limitations of humoral markers in the diagnosis of AD were also discussed, and the future development of humoral markers for AD was prospected. In addition, the contents related to mitochondrial dysfunction, prion virology and intestinal microbiome related to AD are also described, so as to understand the pathogenesis of AD in many aspects and dimensions, so as to evaluate the pathological changes related to AD more comprehensively and accurately.

In 1906, Alois Alzheimer first documented the case of Auguste Deter, a patient with a combination of cognitive deficits, psychiatric symptoms, and microscopic brain lesions. This histopathological and clinical constellation was then designated by Emil Kraepelin as Alzheimer's disease (AD) [1]. Nowadays, AD became the most common progressive neurodegenerative disease and the most common form of dementia among the elderly [2, 3]. In the clinic, the late-onset AD (LOAD) accounts for 95% of all AD cases and is currently considered as a genetic complex disorder that is probably caused by a combination of multiple risk alleles and environmental factors [4]. To date, APOE is the only unequivocally established susceptibility gene for LOAD [5]. However, it has been estimated that the variations of APOE account for less than 50% of LOAD risk, suggesting that there are additional genetic risk factors which remain to be uncovered. Recent advances in genetic approaches led to the identification of numerous risk genes for AD, which has greatly extended our knowledge on the genetic components of this disease [6]. In this special issue, the paper entitled “Clinical Genetics of Alzheimer's Disease” by Z. Zou et al. outlined these novel susceptibility genes, such as CLU, CR1, CD33, PICALM, BIN1, TREM2, and PLD3. More importantly, they summarized the recent evidence regarding the functions of these genes as well as their association with phenotypes and pathogenesis of AD. This allowed readers to get a good understanding on the research advances in the genetic basis and pathological mechanisms of this devastating disease. Regarding the neuropathology, AD is mainly characterized by the formation of extracellular neuritic plaques containing the amyloid-β peptide (Aβ) and intraneuronal accumulation of neurofibrillary tangles constituted by hyperphosphorylated tau protein. In 2002, John Hardy proposed “amyloid hypothesis,” which emphasized Aβ accumulation as the initial pathological events in the progression of AD [7]. Therefore, therapeutic strategies against Aβ, especially Aβ-induced neurotoxicity, have attracted a lot of attention in recent years. In the current issue, by employing primary neuron culture, C.-F. Lau et al. provided the first evidence that testosterone could protect against Aβ-induced synaptic dysfunction and degeneration in “Protective Effects of Testosterone on Presynaptic Terminals against Oligomeric β-Amyloid Peptide in Primary Culture of Hippocampal Neurons.” These exciting findings emphasized testosterone as a potential endogenous target of drug development, which might open up a new avenue for the prevention and treatment of AD. Additionally, in this issue, another original paper entitled “Inhibitory Effects of Edaravone in β-Amyloid-Induced Neurotoxicity in Rats” by F. He et al. provided preclinical evidence concerning the beneficial effects of edaravone, a free radical scavenger mainly used for stoke treatment, in an AD model induced by Aβ injection. For the first time, they showed that edaravone could attenuate Aβ-induced increase of voltage-gated calcium channel currents and cholinergic neurons losses, which subsequently improved learning and memory performance. Their interesting finding implied that edaravone might have a practical clinical use for AD prevention and treatment, emphasizing the notion that many therapeutic agents possessed pleiotropic actions in addition to their main applications. In addition to its own neurotoxicity, Aβ as the central pathological factor also initiates a series of secondary events in AD progression, such as neuroinflammation. Activation of microglia, the main immune cell in the brain, is considered as a central event in Aβ-induced neuroinflammation. Actually, several lines of evidence suggested a “double-edged sword” function of microglia during the progression of AD [8]. On one hand, long-term Aβ stimulation results in the dysfunction of microglia in the brain, which is characterized by the overproduction of proinflammatory cytokines, subsequently leading to the bystander neuronal and synaptic damage. On the other hand, activated microglia participates in the phagocytosis of Aβ through its phagocytic activity and thus prevents the deposition of Aβ and the formation of amyloid plaques. In this special issue, a review article entitled “Microglia in Alzheimer's Disease” by Y. Li et al. summarized the recent advances concerning microglia during AD progression. Meanwhile, they also introduced the recent basic and clinic efforts regarding how to prevent and treat this disease via precise modulation of microglial functions. Their contributions will greatly help the readers to get a better understanding on the role of microglia and neuroinflammation in the mechanisms and therapeutics of AD. In summary, the articles in this issue cover the recent progress in the genetic basis and molecular mechanisms underlying AD pathogenesis, accompanied with the development of diagnostic approaches and therapeutic strategies for this disease. We hope that the reader will extend their knowledge about the basic and clinical aspects of AD through this collection of articles. Teng Jiang Raymond Chuen-Chung Chang Hanna Rosenmann Jin-Tai Yu

There is growing clinical and neuropathologic evidence suggesting that cognitive decline in early Alzheimer's disease (AD) is aggravated by a synergistic relationship between AD and cerebrovascular disease associated with cardiovascular risk factors such as diabetes and hypertension. Here we used the stereologic "Space Balls" method to investigate the relationships between AD pathology and cardiovascular risk factors in postmortem human brains of patients with hypertension and diabetes in two groups - one consisting of cases with AD diagnosis and one of cases without. Hippocampal CA1 and CA3 microvasculature length density estimates were generated to characterize quantitatively the contribution of cardiovascular risk factors to the severity of neuropathologic changes. Our main finding is that the mean and variance of length density values in the AD group were significantly increased from the non-AD group, regardless of the absence or presence of a cardiovascular risk factor. An additional finding is that in the AD group without a risk factor, dementia severity correlated with amount of length density change in the CA1 field-this correlation did not exist in the AD groups with risk factors. Our findings suggest a role for cardiovascular risk factors in quantifiable change of hippocampal CA1 field microvasculature, as well as suggest a possible role of cardiovascular risk factors in altering microvasculature pathology in the presence of AD.

The purpose of this study was to conduct a systematic review of the literature of cardiovascular factors pertaining to incident Alzheimer disease (AD). A systematic literature review was conducted of all studies of cardiovascular risk factors for incident AD listed in PubMed in English from 2000 to 2007. Risk factors included hypertension, diabetes, exercise, alcohol intake, smoking, B complex vitamins, homocysteine, stroke, atrial fibrillation, apolipoprotein E (APOE), lipids, and diet. Inclusion criteria consisted of diagnoses of incident AD and longitudinal studies with cohorts of 500 or more. Individual clinically defined risk factors such as hypertension and diabetes were not significantly associated with increased risk for AD. The strength of the association for hypertension could be considerably strengthened by changing criteria such as midlife measurements or using higher cutoffs for systolic blood pressure. APOE epsilon4 was the most consistent risk factor. Interactions between risk factors modify risk particularly for hypertension and diabetes. Interactions modifying risk were also found for exercise and physical function, APOE epsilon4, diabetes, and cholesterol. In this review, the evidence that single clinically defined cardiovascular risk factors are significantly associated with incident AD is inconsistent at best. The strength of the association of cardiovascular risk factors and AD can be influenced greatly by changing the parameters of measurement of risk factors and by identifying interactions between the factors.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. No effective therapies for AD are yet available, and potentially preventive lifestyle factors, including diet and physical activity, have become a focus of AD research. One such factor is moderate wine consumption, which has been claimed to be neuroprotective, and some studies have suggested a potential role for grapes and wine in retarding cognitive decline and other effects of aging. Polyphenols contained in grapes have been investigated as a preventive measure or potential therapy for dementia. The best-studied fruit polyphenol, the stilbenoid resveratrol (trans-3,5,4’-trihydroxystilbene), is known for its anti-oxidant and anti-inflammatory properties. The present short review evaluates the evidence regarding the role of red wine and resveratrol in the prevention and treatment of AD. Some research findings have suggested that resveratrol may be useful in the treatment of neurodegenerative diseases, including AD, due to its ability to reduce cognitive decline and to inhibit amyloid β aggregation in animal models of dementia. Studies in rodents have demonstrated neuroprotective effects of resveratrol on central features of AD, including decreased amyloid deposition and tau-hyperphosphorylation, enhanced hippocampal neurogenesis, and improved memory functions. The mechanisms through which resveratrol exerts neuroprotective efficacy in animals remain to be established. The potential of resveratrol to act as a nutraceutical targeting neuropathological changes in AD and exerting neuroprotective efficacy may be related to its anti-oxidant activities and its ability to antagonize amyloid aggregation, suppress neuroinflammation, decrease mitochondrial dysfunction, and modulate signaling pathways. In contrast to the neuroprotective activity of resveratrol in various in-vitro and in-vivo models, evidence of the ability of resveratrol to prevent age-associated neurodegeneration in humans and to improve cognitive deficits in AD is lacking. Thus, whether resveratrol has any beneficial effects in humans remains to be established. Pterostilbene (trans-3,5-dimethoxy-4’-hydroxystilbene), an analog of resveratrol, appears to be more effective than resveratrol in ameliorating brain alterations associated with aging and may be a more promising compound for future research. Moderate red wine intake is unable to provide resveratrol in amounts required for clinically relevant effects in AD. Were resveratrol proven to be effective in combatting AD, supplements or a drug should be substituted for wine as a source. Moreover, the toxic effects of alcohol should be considered, since recent evidence suggests that no level of alcohol consumption has beneficial health effects. In particular, long-term alcohol consumption, even in moderate quantities, is associated with multiple markers of abnormal brain structure, including hippocampal atrophy. Moderate drinking to promote brain health is not justified, and any claims regarding the potential efficacy of red wine in the prevention of AD are unsubstantiated and irresponsible.

Smoking cessation and Alzheimer’s disease: facts, fallacies and promise