The Future Emerges from the Past

The case of Jordan (Mason 2017) highlights the gamble of connecting with the past through genomic testing. Unfortunately for Jordan, his genomic testing identified two variant genes which account for up to 75 per cent of early-onset Alzheimer’s disease cases. Furthermore, his children were identified as having a 50 per cent risk of inheriting the gene which corresponds to the majority of early-onset Alzheimer’s disease cases. Now Jordan is not only burdened with the foreknowledge that he will most likely develop Alzheimer’s disease at a relatively young age but also burdened with the knowledge that his children may share his fate. Jordan was overwhelmed by his attempts to understand the genetic tests and experienced substantial distress. This response highlights the need for industry-wide regulations that adequately prepare individuals for the decision of whether to initiate genomic testing and require the results to be interpreted with genetic counsellors or other suitably skilled doctors. Furthermore, these industry-wide regulations need to be accountable to the same evidence-based standards that regulate the rest of the medical professions.     

Controlling futures? Online Genetic Testing and Neurodegenerative Disease

Online personalized genetic testing services offer accessible and convenient options for satisfying personal curiosity about health and obtaining answers about one’s genetic provenance. They are especially attractive to healthy people who wish to learn about their future risk of disease, as Paul Mason’s (2017) case study of “Jordan” illustrates. In this response, we consider how online genetic testing services are used by people diagnosed with a common neurodegenerative disease, Parkinson’s disease, to gain a sense of certainty regarding the future.     

Identification of Risk Pathways and Functional Modules for Coronary Artery Disease Based on Genome-wide SNP Data

Coronary artery disease(CAD) is a complex human disease, involving multiple genes and their nonlinear interactions, which often act in a modular fashion. Genome-wide single nucleotide polymorphism(SNP) profiling provides an effective technique to unravel these underlying genetic interplays or their functional involvements for CAD. This study aimed to identify the susceptible pathways and modules for CAD based on SNP omics. First, the Wellcome Trust Case Control Consortium(WTCCC) SNP datasets of CAD and control samples were used to assess the jointeffect of multiple genetic variants at the pathway level, using logistic kernel machine regression model. Then, an expanded genetic network was constructed by integrating statistical gene–gene interactions involved in these susceptible pathways with their protein–protein interaction(PPI)knowledge. Finally, risk functional modules were identified by decomposition of the network. Of 276 KEGG pathways analyzed, 6 pathways were found to have a significant effect on CAD. Other than glycerolipid metabolism, glycosaminoglycan biosynthesis, and cardiac muscle contraction pathways, three pathways related to other diseases were also revealed, including Alzheimer's disease, non-alcoholic fatty liver disease, and Huntington's disease. A genetic epistatic network of 95 genes was further constructed using the abovementioned integrative approach. Of 10 functional modules derived from the network, 6 have been annotated to phospholipase C activity and cell adhesion molecule binding, which also have known functional involvement in Alzheimer's disease.These findings indicate an overlap of the underlying molecular mechanisms between CAD and Alzheimer's disease, thus providing new insights into the molecular basis for CAD and its molecular relationships with other diseases.     

Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer’s Disease

Alzheimer’s disease is the most frequent type of dementia and diagnosed late in the progression of the illness when irreversible brain tissue loss has already occurred. For this reason, treatments have been ineffective. It is imperative to find novel therapies ameliorating modifiable risk factors (hypertension, stroke, diabetes, chronic kidney disease, and traumatic brain injury) and effective against early pathogenic mechanisms including alterations in cerebral blood flow leading to poor oxygenation and decreased access to nutrients, impaired glucose metabolism, chronic inflammation, and glutamate excitotoxicity. Angiotensin II receptor blockers (ARBs) fulfill these requirements. ARBs are directly neuroprotective against early injury factors in neuronal, astrocyte, microglia, and cerebrovascular endothelial cell cultures. ARBs protect cerebral blood flow and reduce injury to the blood brain barrier and neurological and cognitive loss in animal models of brain ischemia, traumatic brain injury, and Alzheimer’s disease. These compounds are clinically effective against major risk factors for Alzheimer’s disease: hypertension, stroke, chronic kidney disease, diabetes and metabolic syndrome, and ameliorate age-dependent cognitive loss. Controlled studies on hypertensive patients, open trials, case reports, and database meta-analysis indicate significant therapeutic effects of ARBs in Alzheimer’s disease. ARBs are safe compounds, widely used to treat cardiovascular and metabolic disorders in humans, and although they reduce hypertension, they do not affect blood pressure in normotensive individuals. Overall, there is sufficient evidence to consider long-term controlled clinical studies with ARBs in patients suffering from established risk factors, in patients with early cognitive loss, or in normal individuals when reliable biomarkers of Alzheimer’s disease risk are identified.     

Epigenetic Modulation in Parkinson’s Disease and Potential Treatment Therapies

In the recent past, huge emphasis has been given to the epigenetic alterations of the genes responsible for the cause of neurological disorders. Earlier, the scientists believed somatic changes and modifications in the genetic makeup of DNA to be the main cause of the neurodegenerative diseases. With the increase in understanding of the neural network and associated diseases, it was observed that alterations in the gene expression were not always originated by the change in the genetic sequence. For this reason, extensive research has been conducted to understand the role of epigenetics in the pathophysiology of several neurological disorders including Alzheimer’s disease, Parkinson’s disease and, Huntington’s disease. In a healthy person, the epigenetic modifications play a crucial role in maintaining the homeostasis of a cell by either up-regulating or down-regulating the genes. Therefore, improved understanding of these modifications may provide better insight about the diseases and may serve as potential therapeutic targets for their treatment. The present review describes various epigenetic modifications involved in the pathology of Parkinson’s Disease (PD) backed by multiple researches carried out to study the gene expression regulation related to the epigenetic alterations. Additionally, we will briefly go through the current scenario about the various treatment therapies including small molecules and multiple phytochemicals potent enough to reverse these alterations and the future directions for a better management of PD.

     

The Earlier the Better: Alzheimer’s Prevention,Early Detection,and the Quest for Pharmacological Interventions

Although the risk factors, biomarkers, and medications for Alzheimer’s disease appear to be almost identical in 1993 and 2013, profound changes can de detected throughout this time period. This article maps these recent changes in the conceptualization of Alzheimer’s disease, especially the emerging trend toward prevention. While some preventive practices (e.g., brain training) and the search for early signs and biomarkers (such as APOEε4) have existed for a long time, the recent broadening of scope to include cardiovascular risk factors and their prevention, paired with pre-symptomatic detection of disease-specific biomarkers, has considerably impacted the conventional understanding of this syndrome and the possibilities for pharmacological and non-pharmacological interventions. The rationale for emphasizing multiple logics when explaining these changes is to avoid simplified argumentative pathways that exist among some scientists.     

Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data

High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.     

Review: Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease

Background

In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hypertension, hyperlipidemia and environmental exposures have been identified as risk factors for Alzheimer disease. In this article, we provide physicians with practical guidance on risk assessment and primary prevention of Alzheimer disease based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.

Methods

We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that met the following criteria: dementia (all-cause, Alzheimer disease or vascular dementia) as the outcome; longitudinal cohort study; study population broadly reflective of Canadian demographics; and genetic risk factors and general risk factors (e.g., hypertension, education, occupation and chemical exposure) identified. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.

Results

Of 3424 articles on potentially modifiable risk factors for dementia, 1719 met our inclusion criteria; 60 were deemed to be of good or fair quality. Of 1721 articles on genetic risk factors, 62 that met our inclusion criteria were deemed to be of good or fair quality. On the basis of evidence from these articles, we made recommendations for the risk assessment and primary prevention of Alzheimer disease. For the primary prevention of Alzheimer''s disease, there is good evidence for controlling vascular risk factors, especially hypertension (grade A), and weak or insufficient evidence for manipulation of lifestyle factors and prescribing of medications (grade C). There is good evidence to avoid estrogens and high-dose (> 400 IU/d) of vitamin E for this purpose (grade E). Genetic counselling and testing may be offered to at-risk individuals with an apparent autosomal dominant inheritance (grade B). Screening for the apolipoprotein E genotype in asymptomatic individuals in the general population is not recommended (grade E).

Interpretation

Despite the personal and societal burden of dementia, our understanding of genetic predisposition to dementias and the contribution of other risk factors remains limited. More importantly, there are few data to explain the overall risks and benefits of prevention strategies or their impact of risk modification.

Articles to date in this series

• Chertkow H. Diagnosis and treatment of dementia: Introduction. Introducing a series based on the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. CMAJ 2008;178:316-21.

     

The Science of Vascular Contributions to Cognitive Impairment and Dementia (VCID): A Framework for Advancing Research Priorities in the Cerebrovascular Biology of Cognitive Decline

The World Health Organization reports that 47.5 million people are affected by dementia worldwide. With aging populations and 7.7 million new cases each year, the burden of illness due to dementia approaches crisis proportions. Despite significant advances in our understanding of the biology of Alzheimer’s disease (AD), the leading dementia diagnosis, the actual causes of dementia in affected individuals are unknown except for rare fully penetrant genetic forms. Evidence from epidemiology and pathology studies indicates that damage to the vascular system is associated with an increased risk of many types of dementia. Both Alzheimer’s pathology and cerebrovascular disease increase with age. How AD affects small blood vessel function and how vascular dysfunction contributes to the molecular pathology of Alzheimer’s are areas of intense research. The science of vascular contributions to cognitive impairment and dementia (VCID) integrates diverse aspects of biology and incorporates the roles of multiple cell types that support the function of neural tissue. Because of the proven ability to prevent and treat cardiovascular disease and hypertension with population benefits for heart and stroke outcomes, it is proposed that understanding and targeting the biological mechanisms of VCID can have a similarly positive impact on public health.     

Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography

Late-onset Alzheimer’s disease (LOAD) is known to have a complex, oligogenic etiology, with considerable genetic heterogeneity. We investigated the influence of genetic interactions between genes in the Alzheimer’s disease (AD) pathway on amyloid-beta (Aβ) deposition as measured by PiB or AV-45 ligand positron emission tomography (PET) to aid in understanding LOAD’s genetic etiology. Subsets of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts were used for discovery and for two independent validation analyses. A significant interaction between RYR3 and CACNA1C was confirmed in all three of the independent ADNI datasets. Both genes encode calcium channels expressed in the brain. The results shown here support previous animal studies implicating interactions between these calcium channels in amyloidogenesis and suggest that the pathological cascade of this disease may be modified by interactions in the amyloid–calcium axis. Future work focusing on the mechanisms of such relationships may inform targets for clinical intervention.     

Caloric restriction: beneficial effects on brain aging and Alzheimer’s disease

Dietary interventions such as caloric restriction (CR) extend lifespan and health span. Recent data from animal and human studies indicate that CR slows down the aging process, benefits general health, and improves memory performance. Caloric restriction also retards and slows down the progression of different age-related diseases, such as Alzheimer’s disease. However, the specific molecular basis of these effects remains unclear. A better understanding of the pathways underlying these effects could pave the way to novel preventive or therapeutic strategies. In this review, we will discuss the mechanisms and effects of CR on aging and Alzheimer’s disease. A potential alternative to CR as a lifestyle modification is the use of CR mimetics. These compounds mimic the biochemical and functional effects of CR without the need to reduce energy intake. We discuss the effect of two of the most investigated mimetics, resveratrol and rapamycin, on aging and their potential as Alzheimer’s disease therapeutics. However, additional research will be needed to determine the safety, efficacy, and usability of CR and its mimetics before a general recommendation can be proposed to implement them.     

The DRD2 <Emphasis Type="Italic">Taq1A A1</Emphasis> Allele May Magnify the Risk of Alzheimer’s in Aging African-Americans

Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer’s; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer’s disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer’s in aging African-Americans. Research linking this high risk for Alzheimer’s in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.     

DNA sampling and banking in clinical genetics and genetic research

Health-related direct-to-consumer (DTC) genetic testing has been a controversial practice. Especially problematic is predictive testing for Alzheimer disease (AD), since the disease is incurable, prevention is inconclusive, and testing does not definitively predict an individual's future disease status. In this paper, I examine two contrasting cases of subjects who learn through genetic testing that they have an elevated risk of developing AD later in life. In these cases, the subject's emotional response to the result is related to how well prepared she was for the real-life personal implications of possible test results. Analysis leads to the conclusion that when groups of health-related genetic tests are offered as packages by DTC companies, informed consumer choice is rendered impossible. Moreover, I argue, this marketing approach contravenes US Federal Trade Commission policies for non-deceptive commercial communications. I conclude by suggesting ways to improve the prospects for informed consumer choice in DTC testing.     

Nrf2—a therapeutic target for the treatment of neurodegenerative diseases

The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Aging is the primary risk factor for developing neurodegenerative diseases. In addition to age, genetic and environmental risk factors have also been associated with disease development. The primary reactive insults associated with the aging process are a result of oxidative stress (OS) and nitrosative stress (NS). Markers of increased oxidative stress, protein and DNA modification, inflammation, and dysfunctional proteostasis have all been implicated in contributing to the progression of neurodegeneration. The ability of the cell to combat OS/NS and maintain a clearance mechanism for misfolded aggregating proteins determines whether or not it will survive. A critical pathway in this regard is the Nrf2 (nuclear factor erythroid 2-related factor 2)- antioxidant response element (ARE) pathway. Nrf2 activation has been shown to mitigate a number of pathologic mechanisms associated with Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis. This review will focus on the role of Nrf2 in these diseases and the potential for Nrf2 activation to attenuate disease progression.     

Online-Datenbanken und systematische Metaanalysen komplex-genetischer Erkrankungen

Susceptibility to genetically complex disorders is determined by an unknown number of genetic determinants, and decades of intensive research have yielded hundreds of such potential susceptibility loci for Alzheimer’s disease (AD), Parkinson’s disease (PD), schizophrenia (SZ), and multiple sclerosis (MS). The results of genome-wide association studies are now adding to an already vast and complicated body of data. To facilitate the evaluation and interpretation of these findings, we have recently created online databases for genetic association studies in AD, PD, SZ, and MS. In addition to providing detailed summaries for each eligible study, the databases present the results of allele-based meta-analyses for all polymorphisms with sufficient genotype data. In this review, we discuss the background and implications of the database approach developed by our group, using current findings from the AD (AlzGene) and PD (PDGene) databases as examples.     

Molecular and cellular mechanisms of sporadic Alzheimer’s disease: Studies on rodent models <Emphasis Type="Italic">in vivo</Emphasis>

In this review, recent data are presented on molecular and cellular mechanisms of pathogenesis of the most widespread (about 95%) sporadic forms of Alzheimer’s disease obtained on in vivo rodent models. Although none of the available models can fully reproduce the human disease, several key molecular mechanisms (such as dysfunction of neurotransmitter systems, especially of the acetylcholinergic system, β-amyloid toxicity, oxidative stress, neuroinflammation, mitochondrial dysfunction, disturbances in neurotrophic systems) are confirmed with different models. Injection models, olfactory bulbectomy, and senescence accelerated OXYS rats are reviewed in detail. These three approaches to in vivo modeling of sporadic Alzheimer’s disease have demonstrated a considerable similarity in molecular and cellular mechanisms of pathology development. Studies on these models provide complementary data, and each model possesses its specific advantages. A general analysis of the data reported for the three models provides a multifaceted and the currently most complete molecular picture of sporadic Alzheimer’s disease. This is highly relevant also from the practical viewpoint because it creates a basis for elaboration and preclinical studies of means for treatment of this disease.     

Alzheimer’s Disease is an Important Risk Factor of Fractures: a Meta-analysis of Cohort Studies

The risk of fracture in individuals with Alzheimer’s disease had not been fully quantified. A systematic review and meta-analysis of cohort studies was performed to estimate the impact of Alzheimer’s disease on risk of fractures. Pubmed and Embase were searched for eligible cohort studies assessing the association between Alzheimer’s disease and risk of fractures. The overall relative risks (RRs) with 95% CIs were calculated using a random-effects model to evaluate the association. Six cohort studies with a total of 137,986 participants were included into the meta-analysis. Meta-analysis of a total of six studies showed that Alzheimer’s disease was significantly associated with two-fold increased risk of fractures (RR?=?2.18, 95 % CI 1.64–2.90, P?<?0.001; I ²?=?91.4 %). Meta-regression analysis showed that type of fractures was a source of heterogeneity (P?=?0.003). Meta-analysis of five studies on hip fracture showed that Alzheimer’s disease was significantly associated with 2.5-fold increased risk of hip fracture (RR?=?2.52, 95 % CI 2.26–2.81, P?<?0.001; I ²?=?25.2 %). There was no risk of publication bias observed in the funnel plot. There is strong evidence that Alzheimer’s disease is a risk factor of hip fracture.     

The Endo-lysosomal System in Parkinson’s Disease: Expanding the Horizon

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, and its prevalence is increasing with age. A wealth of genetic evidence indicates that the endo-lysosomal system is a major pathway driving PD pathogenesis with a growing number of genes encoding endo-lysosomal proteins identified as risk factors for PD, making it a promising target for therapeutic intervention. However, detailed knowledge and understanding of the molecular mechanisms linking these genes to the disease are available for only a handful of them (e.g. LRRK2, GBA1, VPS35). Taking on the challenge of studying poorly characterized genes and proteins can be daunting, due to the limited availability of tools and knowledge from previous literature. This review aims at providing a valuable source of molecular and cellular insights into the biology of lesser-studied PD-linked endo-lysosomal genes, to help and encourage researchers in filling the knowledge gap around these less popular genetic players. Specific endo-lysosomal pathways discussed range from endocytosis, sorting, and vesicular trafficking to the regulation of membrane lipids of these membrane-bound organelles and the specific enzymatic activities they contain. We also provide perspectives on future challenges that the community needs to tackle and propose approaches to move forward in our understanding of these poorly studied endo-lysosomal genes. This will help harness their potential in designing innovative and efficient treatments to ultimately re-establish neuronal homeostasis in PD but also other diseases involving endo-lysosomal dysfunction.     

Sporadic Alzheimer’s Disease Begins as Episodes of Brain Ischemia and Ischemically Dysregulated Alzheimer’s Disease Genes

The study of sporadic Alzheimer’s disease etiology, now more than ever, needs an infusion of new concepts. Despite ongoing interest in Alzheimer’s disease, the basis of this entity is not yet clear. At present, the best-established and accepted “culprit” in Alzheimer’s disease pathology by most scientists is the amyloid, as the main molecular factor responsible for neurodegeneration in this disease. Abnormal upregulation of amyloid production or a disturbed clearance mechanism may lead to pathological accumulation of amyloid in brain according to the “amyloid hypothesis.” We will critically review these observations and highlight inconsistencies between the predictions of the “amyloid hypothesis” and the published data. There is still controversy over the role of amyloid in the pathological process. A question arises whether amyloid is responsible for the neurodegeneration or if it accumulates because of the neurodegeneration. Recent evidence suggests that the pathophysiology and neuropathology of Alzheimer’s disease comprises more than amyloid accumulation, tau protein pathology and finally brain atrophy with dementia. Nowadays, a handful of researchers share a newly emerged view that the ischemic episodes of brain best describe the pathogenic cascade, which eventually leads to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible dementia of Alzheimer type. The most persuasive evidences come from investigations of ischemically damaged brains of patients and from experimental ischemic brain studies that mimic Alzheimer-type dementia. This review attempts to depict what we know and do not know about the triggering factor of the Alzheimer’s disease, focusing on the possibility that the initial pathological trigger involves ischemic episodes and ischemia-induced gene dysregulation. The resulting brain ischemia dysregulates additionally expression of amyloid precursor protein and amyloid-processing enzyme genes that, in addition, ultimately compromise brain functions, leading over time to the complex alterations that characterize advanced sporadic Alzheimer’s disease. The identification of the genes involved in Alzheimer’s disease induced by ischemia will enable to further define the events leading to sporadic Alzheimer’s disease-related abnormalities. Additionally, knowledge gained from the above investigations should facilitate the elaboration of the effective treatment and/or prevention of Alzheimer’s disease.