A review of genome mutation and Alzheimer's disease

Alzheimer's disease (AD) is a complex progressive neurodegenerative disorder of the brain and is the commonest form of dementia. The prevalence of this disease is predicted to increase 3-fold over the next 30 years and to date no reliable and conclusive diagnostic test exists that will identify individuals presymptomatically of susceptibility risk. This review examines the molecular, genetic, dietary and environmental evidence underlying the known pathology of AD and proposes a biologically plausible chromosome instability model to explain some of the features of the disease. Genome damage biomarkers such as aneuploidy of chromosome 17 and 21, oxidative damage to DNA and telomere shortening together with abnormal expression of APP, beta amyloid and tau proteins are discussed in terms of their potential value as risk biomarkers. These biomarkers could then be used in diagnosis and the evaluation of potentially effective preventative measures.     

Brain immune responses cognitive decline and dementia: relationship with phenotype expression and genetic background

Alzheimer's disease (AD) is a progressive degenerative disease of the brain and the most frequent cause of dementia among elderly. The etiology of AD is still obscure, but genetic and environmental factors appear to play differential roles in the disease. Several evidence suggest that inflammation or altered immune responses may play an important role in this disease. The following topics will be discussed: (1) the association of inflammation with brain degenerative processes in AD; (2) the influence of cytokine gene polymorphism upon the risk of developing AD and/or the age at onset of manifestation clinical dementia; (3) the effects of gene allele variations upon the phenotype of immune molecules in the blood and brain of AD patients; (4) the association of genetic variations in some of this molecules with the progression of the disease and cognitive decline.     

Polymorphisms of pro-inflammatory genes and Alzheimer's disease risk: a pharmacogenomic approach

Clinically and pathologically Alzheimer's disease (AD) represents a sequential progressive neurodegenerative disorder. AD is etiologically heterogeneous and accounts for a majority of dementia in western societies. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has lead to the identification of numerous gene polymorphisms that might act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators, although not all the studies were replied. Here, we review several data suggesting that inflammatory genetic variation may contribute to AD susceptibility. All together this information may represent the basis both for future recognition of individuals at risk and for the pharmacogenomic driving of drug responsiveness.     

Genetic basis for Alzheimer's disease and other dementias and prospects of molecular diagnosis

Dementias are diseases of progressive memory loss and intellectual impairment in adults. Alzheimer's disease (AD) amounts to 50-80% of all forms of dementias in middle-aged and elderly individuals. AD includes several clinical and genetic subtypes characterized by the common pattern of specific cerebral hallmarks. Aging and genetic factors are the most important risk factors predisposing to AD. Three gene-bearing mutations for AD have been identified. These included presenilin 1, presenilin 2, and amyloid precursor protein (APP). In addition, the polymorphic isoform of apolyprotein E e4 gene has been found to be a genetic risk factor for some forms of familial and sporadic AD. Other genes for AD are to be identified. The genetic loci or mutations in genes leading to several other neurodegenerative diseases and dementia have been also discovered. These genetic achievements contribute to the development of markers for the presymptomatic diagnosis of dementias and the development of transgenic models in vitro and in vivo for rational therapy of these dramatic diseases.     

Can phages cause Alzheimer’s disease?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with progressive dementia. Multiple processes have been implicated in AD, notably including abnormal beta-amyloid production, tau hyperphosphorylation and neurofibrillary tangles (NFTs), synaptic pathology, oxidative stress, inflammation, protein processing or misfolding, calcium dyshomeostasis, aberrant reentry of neurons into the cell cycle, cholesterol synthesis, and effects of hormones or growth factors. The complexity of the disease, which affects numerous molecules, cells, and systems and impedes attempts to determine which alterations are specifically associated with early pathology. Chlamydia pneumoniae is an obligate intracellular bacterium. Infection with this organism has been suggested to be a risk factor for AD. C. pneumoniae has two phages phiCPAR39 and phage related to phiCPG1. HYPOTHESIS: we propose that these two phages by entering into mitochondria of chlamydia's host cell can work as slow viruses and can initiate AD.     

Genetics of menopause-associated diseases.

Menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is estimated that perhaps 50 million women worldwide will go into menopause annually. Atherosclerotic cardiovascular disease, osteoporotic fractures and Alzheimer's dementia are common chronic disorders after menopause, representing major health problems in most developed countries. Apart from being influenced by environmental factors, these chronic disorders recognize a strong genetic component, and there are now considerable clinic evidences that these disorders are related to low hormonal milieu of postmenopausal women. Here, we review up-to-date available data suggesting that genetic variation may contribute to higher susceptibility to four sporadic chronic syndromes such as osteoporosis (OP), osteoarthritis (OA), Alzheimer's disease (AD) and coronary artery disease (CAD). For these four syndromes candidate genes that today appear as major loci in genetic susceptibility encode for proteins specific of a given system, as the vitamin D receptor (VDR) gene for the skeleton and, therefore, OP or angiotensin converting enzyme (ACE) for the cardiovascular system and, therefore, CAD. The investigation of gene polymorphisms in various pathological conditions typical of postmenopause offer an explanation not only of their genetic inheritance but also of their co-segregation in given individuals. In this view, it may be possible to identify a common set of genes whose variants contribute to a common genetic background for these different disorders. Ideal candidates appear genes of the estrogen response cascade [i.e. estrogen receptor (ERs), enzymes involved in estrogen metabolism or co-activators and co-inhibitors]. All together this information may represent the basis both for future recognition of individuals at risk and for the pharmacogenetic driving of drug responsiveness.     

Vascular abnormalities: the insidious pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) and cerebrovascular dementia (CVD) are two major causes of senile dementia in elderly individuals. Mounting evidence from epidemiological, clinical, and neuropathological studies suggests that there is considerable overlap between AD and CVD with respect to risk factors, prevalence, and pathological changes. Although our lack of understanding on the important contribution of vascular disturbance to pathogenesis of AD has further hindered our understanding of AD, data on the roles of cerebrovascular diseases and systemic vascular diseases in AD need to be carefully analyzed to avoid misinterpretation. Here, we review studies on the cerebral vasculature, cardiac vasculature, and apoE that lead us to contend that vascular abnormalities are likely an important mechanism underlying dementia. Because early and aggressive intervention is available to prevent and treat a number of vascular diseases, therapies that attenuate vascular risk factors could be valuable in preventing and treating AD.     

Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes

Brain glucose metabolism is impaired in Alzheimer's disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin-PI3K-AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM-AD and seven control cases. We found decreases in the levels and activities of several components of the insulin-PI3K-AKT signalling pathway in AD and T2DM cases. The deficiency of insulin-PI3K-AKT signalling was more severe in individuals with both T2DM and AD (T2DM-AD). This decrease in insulin-PI3K-AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin-PI3K-AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin-PI3K-AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin-PI3K-AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease.     

Stress, exercise, and Alzheimer's disease: a neurovascular pathway

Genetic factors are known to play a role in Alzheimer's disease (AD) vulnerability, yet less than 1% of incident AD cases are directly linked to genetic causes, suggesting that environmental variables likely play a role in the majority of cases. Several recent human and animal studies have examined the effects of behavioral factors, specifically psychological stress and exercise, on AD vulnerability. Numerous animal studies have found that, while stress exacerbates neuropathological changes associated with AD, exercise reduces these changes. Some human studies suggest that psychological stress can increase the risk of developing AD, while other studies suggest that exercise can significantly reduce AD risk. Most animal studies investigating the mechanisms responsible for the effects of these behavioral factors have focused on neuronal processes, including the effects of stress hormones and neurotrophic factors on the neuropathological hallmarks of AD, namely amyloid-beta (Aβ) deposition and tau-phosphorylation. However, cumulative evidence indicates that, in humans, AD is associated with the presence of cerebrovascular disease, and cardiovascular risk factors are associated with increased risk of developing AD. There is an extensive literature demonstrating that behavioral factors, particularly stress and exercise, can powerfully modulate the pathophysiology of vascular disease. Thus, the following model proposes that the influence of stress and exercise on AD risk may be partially due to the effects of these behavioral factors on vascular homeostasis and pathology. These effects are likely due to both indirect modification of AD risk through alterations in vascular risk factors, such as hypertension, diabetes, and aortic stiffening, as well as direct influence on the cerebrovasculature, including changes in cerebral blood flow, angiogenesis, and vascular disease. Future studies examining the effects of behavioral factors on AD risk should incorporate measures of both peripheral and cerebral vascular function to further our understanding of the mechanisms by which behavior can modify AD susceptibility. Greater knowledge of the molecular mechanisms behind these behavioral effects would further our understanding of the disease and lead to innovative treatment and preventive approaches.     

Dementia with Lewy Bodies. A Distinct Non‐Alzheimer Dementia Syndrome?

Lewy body formation is central to the pathological phenotype of a spectrum of disorders. The most familiar of these is the extrapyramidal syndrome of idiopathic Lewy-body Parkinson's disease (PD). Studies of dementia in the elderly suggest that another manifestation of Lewy body pathology is equally or more common than Parkinson's disease. This syndrome of Dementia with Lewy bodies (DLB) has been given a number of diagnostic labels and is characterised by dementia, relatively mild parkinsonism, visual hallucinations, and fluctuations in conscious level. Although many of these features can arise in Parkinson's disease, the patients with DLB tend to have early neuropsychiatric features which predominate the clinical picture, and the diagnosis of the syndrome in practice is more concerned with the differential diagnosis of Alzheimer's disease (AD). Distinction from AD has clinical importance because of potentially differing therapeutic implications. Diagnostic guidelines for the clinical diagnosis and pathological evaluation of DLB are reviewed. Research into the disorder has centered around characterising the clinical, neuropsychological, pathological, neurochemical and genetic relationships with Alzheimer's disease on the one hand, and Parkinson's disease on the other. Many cases of DLB have prominent pathological features of AD and there are some shared genetic risk factors. Differences from the pathology of PD are predominantly quantitative rather than qualitative and evidence is discussed which suggests that DLB represents a clinicopathological syndrome within the spectrum of Lewy body disorders. The possibility that the syndrome represents a chance association of PD and AD is not supported by published studies.     

ApoE genotype accounts for the vast majority of AD risk and AD pathology

In this review, evidence is provided that apolipoprotein E (apoE) genotype accounts for the majority of Alzheimer's disease (AD) risk and pathology. The three major human isoforms, apoE2, apoE3, and apoE4, are encoded by different alleles (2, 3, 4) and regulate lipid metabolism and redistribution. ApoE isoforms differ in their effects on AD risk and pathology. Clinical and epidemiological data have indicated that the 4 allele may account for 50% of AD in the United States. Further, the rarity of AD among carriers of the 2 allele suggests that allelic variations in the gene encoding this protein may account for over 95% of AD cases. ApoE4 disrupts memory function in rodents. Further studies have indicated that fragments of apoE may contribute to both plaque and tangle formation. Thus, the epidemiologic and basic science evidence suggest that apoE genotype accounts for the vast majority of AD risk and pathology.     

Epidemiology and risk factors of Alzheimer's disease

Alzheimer's disease or dementia of the Alzheimer's type (AD/DAT) is one of the most common dementia conditions and it amounts to over 40-90% of dementia cases among elderly and old patients. Epidemiological studies in this area make a great contribution to the study of the etiology and risk factors of AD/DAT). The collaborative reanalysis of AD/DAT prevalence and incidence in EEC countries ("EURODERM" programme) shows that the overall European age-specific prevalence of AD does not differ greatly. There was an exponential increase in age-specific AD/DAT prevalence was found with age, as evidenced by the studies made in Russia. Sex-specific prevalence and incidence of AD/DAT are unclear since the fact that the condition more often occurs in elderly women than in men of the same age has not been confirmed. The data on risk factors obtained in cohort and case-control studies of AD/DAT have been analyzed. Progress in molecular genetics has identified 3 genes that are responsible for the occurrence of familial forms of the disease. The gene of apolipoprotein E on chromosome 19 is recognized to be the major genetic risk factor of late AD/DAT. The role of gene mutations in the trigger mechanisms of sporadic BA/DAT is also discussed. The environmental risk factors of AD/DAT include brain injury, viral infections, neutroxic chemicals, various immunological and hormonal disorders. The protective role of such factors as long-term use of nonsteroid antiinflammatory agents and estrogens is discussed. The involvement of nicotine dependence in the pathogenesis and the role of smoking as a possible protective factor are the subject of discussion. Such factors as education levels, occupation, stresses are widely discussed, although their role is considered to be controversial. The Russian study revealed the influence of chronic stress on AD development. The authors consider that chronic stress may play an important role in AD/DAT progression.     

The genetics of Alzheimer''s disease

Alzheimer's disease (AD) is the major cause of dementia in the U.K. The clinical diagnosis of the specific disease resulting in dementia is unreliable and thus a definitive diagnosis of AD is best made in conjunction with post-mortem findings of amyloid plaques and neurofibrillary tangles. Alzheimer's disease is neuropathologically indistinguishable in the young and old, but has been divided arbitrarily into early- and late-onset disease using age cut-offs of 60 or 65 years. Twin and family studies suggest that genetic factors play a major role in its aetiology. This review considers the three loci which have been shown to be associated with early-onset AD: amyloid precursor protein, presenilin (PS)-l and PS-2. Mutations in these genes seem to be associated with overproduction of the 42-amino acid form of β-bamyloid, suggesting that this may be a central pathological process in AD. The impact of the different apo E alleles on the risks for late- and early-onset AD is discussed and compared with other dementing conditions. Recent analyses suggest that there are likely to be other genes besides apo E which impact on late-onset AD risk. The possible roles in AD of the mitochondria) mutation at position 4336, the PS intron 8 polymorphism, and variants in the alpha I-antichymotrypsin and VLDL-receptor genes, are considered.     

Association of interleukin-1 gene polymorphisms with dementia in a community-based sample: the Honolulu-Asia Aging Study

The interleukin-1 (IL-1) pro-inflammatory cytokine family participates in inflammatory processes and vessel damage involved in neurodegeneration. Recent studies suggest that Alzheimer's disease (AD) and vascular dementia (VaD) may share genetic risk factors. In this study, the frequency of polymorphisms in the genes coding for interleukin (IL)-1alpha, IL-1beta and the IL-1 receptor antagonist (RN) and their genotype associations with late-onset AD and VaD were determined in a Japanese-American cohort of men (n=931) participating in the Honolulu-Asia Aging Study (HAAS). A significant association was found between the IL-1beta (-511) and IL-1RN (+2018) polymorphisms and AD, suggesting that these variants confer an increased risk. Possessing the IL-1beta (-511) T/T genotype was also associated with VaD. There was no difference in the IL-1beta (+3953) frequency among the groups. Our results support the hypothesis that certain genetic variations contained within the IL-1 gene family contribute to the pathogenesis of dementia.     

Blood pressure and the risk for dementia—A double edged sword

Alzheimer's disease (AD) and vascular dementia (VaD) are important causes of cognitive decline in the elderly. As a result of the aging population, the incidence of dementia is expected to increase substantially over the coming decades. Many studies have identified that vascular risk factors are implicated in the pathogenesis of both AD and VaD. Longitudinal studies have suggested that high blood pressure in midlife is associated with a higher incidence of both AD and VaD in later life. The association appears weaker for hypertension in later life. Some studies also suggest that hypotension; especially low diastolic blood pressure in late-life is also associated with an increased risk of AD. Long-standing hypertension may lead to severe atherosclerosis and impaired cerebrovascular autoregulation. A decline in blood pressure in later life may contribute to diminished cerebral perfusion. The subsequent ischaemic state may lead to increased cerebral β-amyloid accumulation.     

Twin studies of Alzheimer's disease: An approach to etiology and prevention

Epidemiologic studies of environmental factors associated with risk of Alzheimer's disease (AD) have produced inconsistent and disappointing results. By contrast, family/genetic studies and case control investigations suggest that genetic causes of AD are important. The investigation of such genetic causes remains an important aim in all forms of AD including typical, late-onset disease where linkage work is impractical. But the public health burden of AD creates an especially urgent need to identify environment risk factors, if these exist, since they will more likely be susceptible to intervention. Such environmental factors may interact with genetic susceptibility to accelerate or retard disease expression, and environmental interventions that delay onset may constitute an important strategy for prevention. All these issues may be addressed by twin studies of AD, but the few such studies to date have been limited by small samples and other methodologic difficulties. This paper reviews the rationale for twin studies of AD, and describes briefly the work in this area to date. It also discusses a number of suggestions for methodologic improvements. We conclude that the time is ripe for twin studies of AD, and that such work holds considerable potential for the investigation of etiology and, possibly, for the identification of strategies for prevention.     

Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism

Alzheimer's Disease (AD) is a devastating disease that affects millions of elderly persons. Despite years of intense investigations, genetic risk factors that affect the majority of AD cases have yet to be determined. Recent studies suggest that cholesterol metabolism has integral part in AD pathogenesis, suggesting that genes that regulate lipid metabolism may also play roles in AD. This review will first describe emerging evidence that links cholesterol to the mechanisms thought to underlie AD. Based on this rationale, candidate genes located in regions implicated in AD that have roles in lipid metabolism will then be discussed.     

The role of cerebral ischemia in Alzheimer's disease

The Alzheimer type of dementia and stroke are known to increase at comparable rates with age. Recent advances suggest that vascular risk factors linked to cerebrovascular disease and stroke in the elderly significantly increase the risk of developing Alzheimer's disease (AD). These include atherosclerosis, atrial fibrillation, coronary artery disease, hypertension, and diabetes mellitus. Moreover, review of various autopsy series shows that 60-90% of AD cases exhibit variable cerebrovascular pathology. Although some vascular lesions such as cerebral amyloid angiopathy, endothelial degeneration, and periventricular white matter lesions are evident in most cases of AD, a third will exhibit cerebral infarction. Despite the interpretation of pathological evidence, longitudinal clinical studies suggest that the co-existence of stroke and AD occurs more than by chance alone. Strokes known to occur in patients with Alzheimer syndrome and most frequently in the oldest old substantially worsen cognitive decline and outcome, implicating some interaction between the disorders. Nevertheless, the nature of a true relationship between the two disorders seems little explored. What predisposes to strokes in underlying cognitive decline or AD? Is it possible that cerebral ischemia is a causal factor for AD? I examined several vascular factors and the vascular pathophysiology implicated in stroke and AD, and propose that cerebral ischemia or oligemia may promote Alzheimer type of changes in the aging brain. Irrespective of the ultimate pathogenetic mechanism, these approaches implicate that management of peripheral vascular disease is important in the treatment or prevention of Alzheimer's disease or mixed dementia.     

The future of Alzheimer's disease: the next 10 years

Alzheimer's disease (AD) is a fast growing world-wide epidemic. AD is a genetically complex, slowly progressive, and irreversible neurodegenerative disease of the brain. During decades of asymptomatic progression multiple interactive systems, pathways and molecular mechanisms (e.g. protein processing, aberrant signaling, inflammation and immune system, lipid transport, endocytosis, apoptosis, oxidative damage and response to stress, tau pathology, neuron and synapse loss, energy metabolism), contribute to the development of the early clinical prodromal stage with episodic memory deficits and to further decline and loss of general cognitive functioning during the final syndromal dementia stage. The non-mendelian genetically complex "sporadic" AD type is the most common form of dementia affecting people usually over the age of 65. Despite considerable progress of AD research in recent years and evolving paradigm shifts in both pathophysiological concepts as well as in diagnostic criteria fundamental challenges have not yet been resolved. The strong age-related incidence, the recent failure and complete lack of disease-modifying or preventive therapy that may delay onset or substantially affect the pathophysiology of AD, result in an enormous burden posed both on individuals, their families and care givers, and the societies at large, and these call for urgent concerted worldwide measures. Based on the meeting of the German Task Force on Alzheimer's Disease (GTF-AD) in Paris on July 19th 2011, the present position paper provides an overview on the current state and future developments in epidemiology, pathophysiology, disease conceptualization, diagnostic criteria and their use in research and clinical practice, as well as preventive and symptomatic therapeutic approaches. Particular emphasis is placed on a discussion of the different approaches to diagnostics and therapy taken by preventive/public health medicine, methodologically advanced academic research propagating the use of sophisticated biomarkers, and everyday clinical practice focusing on patient-centered care. During the next 10 years, major advances both in early detection as well as in therapy and comprehensive AD care seem mandatory. These still unmet needs call for ever more concerted and focused efforts in research across the world to combat the erupting and as yet uncontrolled epidemic of AD.     

Brain matrix metalloproteinase 1 levels are elevated in Alzheimer's disease

Several lines of evidence indicate that there may be an inflammatory component to the pathology of Alzheimer's disease (AD), the major form of degenerative dementia in the elderly. Activity of inflammatory cells, and the elaboration of toxic molecules by such cells may be a significant factor in disease progression. In peripheral inflammatory states, the increased activity of matrix metalloproteinase (MMP) enzymes are a major cause of tissue breakdown and secondary damage in diseases such as rheumatoid arthritis. The activity of such enzymes in the normal or diseased central nervous system is, however, not well characterized. We have therefore determined the levels of MMP 1 (collagenase) in the normal human brain and in AD. MMP1 levels were relatively low though were significantly elevated by approximately 50% in AD in all cortical areas examined. Given the activity towards collagen of MMP1, it is possible that enhanced MMP1 activity in AD, may contribute to the blood-brain barrier dysfunction seen in AD.