Informed Choice in Direct-to-Consumer Genetic Testing for Alzheimer and Other Diseases: Lessons from Two Cases

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 U.S. 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.     

Autobiologies on YouTube: narratives of direct-to-consumer genetic testing

Despite a growing personal genomics market, little is known about how people engage with the possibilities offered by direct-to-consumer (DTC) genetic testing. In order to help address this gap, this study deploys narrative analysis of YouTube videos posted by individuals who have purchased DTC genetic testing for disease. Genetic testing is said to be contributing to new states of illness, where individuals may become “patients-in-waiting.” In the videos analyzed, we found a new form of storytelling about this ambiguous state of illness, which we refer to as autobiology. Autobiology – the study of, and story about, one's own biology – concerns narratives of sense-making through forms of biological practice, as well as wayfaring narratives which interweave genetic markers and family histories of disease. These autobiologies – part of a broader shift toward public stories about genetics and other healthcare technologies – exhibit playfulness, as well as being bound with consumerist practices.     

Attitudes and knowledge about presymptomatic genetic testing among individuals at high risk for familial,early-onset Alzheimer's disease

The study was conducted in a large Cuban family with early-onset familial Alzheimer's disease (AD). Fifty-six first-degree relatives of familial cases with AD were interviewed concerning their clinical and genetic knowledge about AD and their attitudes toward the possible use of presymptomatic genetic testing of AD. The individuals had only limited knowledge about their personal risk of developing AD. All 56 family members would use presymptomatic testing to know their own risk of AD. Confronted with a hypothetical reproductive choice, 50% would choose not to have children if they themselves had the mutation. A positive prenatal test would lead 48.2% of the participants to have an abortion, and 19.7% would continue the pregnancy regardless of the positive test result.     

Differences between African Americans and Whites in their attitudes toward genetic testing for Alzheimer's disease

The possibility of predictive genetic testing for Alzheimer's disease (AD) has prompted examination of public attitudes toward this controversial new health-care option. This is the first study to examine differences between Whites and African Americans with regard to: (1) interest in pursuing genetic testing for AD, (2) reasons for pursuing testing, (3) anticipated consequences of testing, and (4) beliefs about testing. We surveyed a convenience sample of 452 adults (61% white; 39% African American; 78% female; mean age = 47 years; 33% with family history of AD). Both racial groups indicated general interest in predictive genetic testing for AD, viewed it as having many potential benefits, and believed it should be offered with few restrictions. However, in comparison to whites, African Americans showed less interest in testing (p < 0.01), endorsed fewer reasons for pursuing it (p < 0.01), and anticipated fewer negative consequences from a positive test result (p < 0.001). These preliminary findings show important distinctions between whites and African Americans in their attitudes toward genetic testing for AD. These differences may have implications for how different racial and ethnic groups will respond to genetic testing programs and how such services should be designed. Future research in real-life testing situations with more representative samples will be necessary to confirm these racial and cultural differences in perceptions of genetic testing.     

The relationship between the minor allele content and Alzheimer's disease

Alzheimer's disease (AD) is a chronic neurodegenerative disease. The genetic risk factors of AD remain better understood. Using previously published dataset of common single nucleotide polymorphisms (SNPs), we studied the association between the minor allele content (MAC) in an individual and AD. We found that AD patients have higher average MAC values than matched controls. We identified a risk prediction model that could predict 2.19% of AD cases. We also identified 49 genes whose expression levels correlated with both MAC and AD. By pathway and process enrichment analyses, these genes were found in pathways or processes closely related to AD. Our study suggests that AD may be linked with too many genetic variations over a threshold. The method of correlations with both MAC and traits appears to be effective in high efficiency identification of target genes for complex traits.     

Trained immunity in viral infections,Alzheimer's disease and multiple sclerosis: A convergence in type I interferon signalling and IFNβ-1a

Type I interferon (IFN-I) signalling represents a major target for modulation in a virus' bid for latency. IFN-I perturbations are also present in such as Alzheimer's disease (AD) and multiple sclerosis (MS), where viral infections are known to increase symptomatic burden. IFN-I modulation such as via IFNβ-1a, an established MS treatment, has been researched to a limited extent to both AD and COVID-19. In this mini review, we present emerging research on trained immunity as a pathogenetic basis for Alzheimer's disease and the emerging context for IFNβ-1a repositioning, via mechanisms shared with multiple sclerosis and induced by viral infections.     

Evaluating online direct-to-consumer marketing of genetic tests: informed choices or buyers beware?

Commercialization of genetic technologies is expanding the horizons for the marketing and sales of genetic tests direct-to-consumers (DTCs). This study assesses the information provision and access requirements that are in place for genetic tests that are being advertised DTC over the Internet. Sets of key words specific to DTC genetic testing were entered into popular Internet search engines to generate a list of 24 companies engaging in DTC advertising. Company requirements for physician mediation, genetic counseling arrangements, and information provision were coded to develop categories for quantitative analysis within each variable. Results showed that companies offering risk assessment and diagnostic testing were most likely to require that testing be mediated by a clinician, and to recommend physician-arranged counseling. Companies offering enhancement testing were less likely to require physician mediation of services and more likely to provide long-distance genetic counseling. DTC advertisements often provided information on disease etiology; this was most common in the case of multifactorial diseases. The majority of companies cited outside sources to support the validity of claims about clinical utility of the tests being advertised; companies offering risk assessment tests most frequently cited all information sources. DTC advertising for genetic tests that lack independent professional oversight raises troubling questions about appropriate use and interpretation of these tests by consumers and carries implications for the standards of patient care. These implications are discussed in the context of a public healthcare system.     

CD33 in Alzheimer's Disease

The amyloid-beta peptide (Aβ) cascade hypothesis posits that Aβ accumulation is the fundamental initiator of Alzheimer's disease (AD), and mounting evidence suggests that impaired Aβ clearance rather than its overproduction is the major pathogenic event for AD. Recent genetic studies have identified cluster of differentiation 33 (CD33) as a strong genetic locus linked to AD. As a type I transmembrane protein, CD33 belongs to the sialic acid-binding immunoglobulin-like lectins, mediating the cell–cell interaction and inhibiting normal functions of immune cells. In the brain, CD33 is mainly expressed on microglial cells. The level of CD33 was found to be increased in the AD brain, which positively correlated with amyloid plaque burden and disease severity. More importantly, CD33 led to the impairment of microglia-mediated clearance of Aβ, which resulted in the formation of amyloid plaques in the brain. In this article, we review the recent epidemiological findings of CD33 that related with AD and discuss the levels and pathogenic roles of CD33 in this disease. Based on the contributing effects of CD33 in AD pathogenesis, targeting CD33 may provide new opportunities for AD therapeutic strategies.     

Is Alzheimer's disease a systemic disease?

Although Alzheimer's disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease-modifying therapies.     

Applications and Challenges of Machine Learning Methods in Alzheimer's Disease Multi-Source Data Analysis

BackgroundRecent development in neuroimaging and genetic testing technologies have made it possible to measure pathological features associated with Alzheimer''s disease (AD) in vivo. Mining potential molecular markers of AD from high-dimensional, multi-modal neuroimaging and omics data will provide a new basis for early diagnosis and intervention in AD. In order to discover the real pathogenic mutation and even understand the pathogenic mechanism of AD, lots of machine learning methods have been designed and successfully applied to the analysis and processing of large-scale AD biomedical data.ObjectiveTo introduce and summarize the applications and challenges of machine learning methods in Alzheimer''s disease multi-source data analysis.MethodsThe literature selected in the review is obtained from Google Scholar, PubMed, and Web of Science. The keywords of literature retrieval include Alzheimer''s disease, bioinformatics, image genetics, genome-wide association research, molecular interaction network, multi-omics data integration, and so on.ConclusionThis study comprehensively introduces machine learning-based processing techniques for AD neuroimaging data and then shows the progress of computational analysis methods in omics data, such as the genome, proteome, and so on. Subsequently, machine learning methods for AD imaging analysis are also summarized. Finally, we elaborate on the current emerging technology of multi-modal neuroimaging, multi-omics data joint analysis, and present some outstanding issues and future research directions.     

Genetic background modifies CNS‐mediated sensorimotor decline in the AD‐BXD mouse model of genetic diversity in Alzheimer's disease

Many patients with Alzheimer's dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual's ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer's disease, the AD‐BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD‐BXDs and the relationship to cognitive decline in these mice. We found that age‐ and AD‐related declines in coordination, balance and vestibular function vary significantly across the panel, indicating genetic background strongly influences the expressivity of the familial AD mutations used in the AD‐BXD panel and their impact on motor function. Although young males and females perform comparably regardless of genotype on narrow beam and inclined screen tasks, there were significant sex differences in aging‐ and AD‐related decline, with females exhibiting worse decline than males of the same age and transgene status. Finally, we found that AD motor decline is not correlated with cognitive decline, suggesting that sensorimotor deficits in AD may occur through distinct mechanisms. Overall, our results suggest that AD‐related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease.     

Chronic stress and Alzheimer's disease: the interplay between the hypothalamic–pituitary–adrenal axis,genetics and microglia

Chronic psychosocial stress is increasingly being recognised as a risk factor for sporadic Alzheimer's disease (AD). The hypothalamic–pituitary–adrenal axis (HPA axis) is the major stress response pathway in the body and tightly regulates the production of cortisol, a glucocorticoid hormone. Dysregulation of the HPA axis and increased levels of cortisol are commonly found in AD patients and make a major contribution to the disease process. The underlying mechanisms remain poorly understood. In addition, within the general population there are interindividual differences in sensitivities to glucocorticoid and stress responses, which are thought to be due to a combination of genetic and environmental factors. These differences could ultimately impact an individuals’ risk of AD. The purpose of this review is first to summarise the literature describing environmental and genetic factors that can impact an individual's HPA axis reactivity and function and ultimately AD risk. Secondly, we propose a mechanism by which genetic factors that influence HPA axis reactivity may also impact inflammation, a key driver of neurodegeneration. We hypothesize that these factors can mediate glucocorticoid priming of the immune cells of the brain, microglia, to become pro-inflammatory and promote a neurotoxic environment resulting in neurodegeneration. Understanding the underlying molecular mechanisms and identifying these genetic factors has implications for evaluating stress-related risk/progression to neurodegeneration, informing the success of interventions based on stress management and potential risks associated with the common use of glucocorticoids.     

Neural network on interval-censored data with application to the prediction of Alzheimer's disease

Alzheimer's disease (AD) is a progressive and polygenic disorder that affects millions of individuals each year. Given that there have been few effective treatments yet for AD, it is highly desirable to develop an accurate model to predict the full disease progression profile based on an individual's genetic characteristics for early prevention and clinical management. This work uses data composed of all four phases of the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, including 1740 individuals with 8 million genetic variants. We tackle several challenges in this data, characterized by large-scale genetic data, interval-censored outcome due to intermittent assessments, and left truncation in one study phase (ADNIGO). Specifically, we first develop a semiparametric transformation model on interval-censored and left-truncated data and estimate parameters through a sieve approach. Then we propose a computationally efficient generalized score test to identify variants associated with AD progression. Next, we implement a novel neural network on interval-censored data (NN-IC) to construct a prediction model using top variants identified from the genome-wide test. Comprehensive simulation studies show that the NN-IC outperforms several existing methods in terms of prediction accuracy. Finally, we apply the NN-IC to the full ADNI data and successfully identify subgroups with differential progression risk profiles. Data used in the preparation of this article were obtained from the ADNI database.     

Susceptibility genes and the question of embodied identity

Drawing on an assumption of the co-construction of the material and the social, late-onset Alzheimer's disease (AD) is used as an illustrative example to assess claims for an emergent figure of the "individual genetically at risk." Current medical understanding of the genetics of AD is discussed, followed by a summary of media and AD society materials that reveal an absence of gene hype in connection with this disease. Excerpts from interviews with first-degree relatives of patients diagnosed with AD follow. Interviewees hold complex theories of causation. After genetic testing they exhibit few if any subjective changes in embodied identity or lifestyle. Family history is regarded by interviewees as a better indicator of future disease than is genetic testing. We argue that, even when molecular genetics are better understood, predictions about complex disease based on genotyping will be fraught with uncertainty, making problematic the concept of individuals as genetically at risk when applied to late-onset complex disease.     

SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease

Alzheimer''s Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau₁₈₁) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau₁₈₁ levels in two independent CSF series . We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series . Our analyses suggest that genetic variants associated with CSF ptau₁₈₁ levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ₄₂ levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ₄₂ levels. Finally, we believe genome-wide association studies of CSF tau/ptau₁₈₁ levels should identify novel genetic variants which will likely influence rate of progression of AD.     

Genetic factors and a polygenic model of Alzheimer's disease

Genetic factors are responsible, to a certain degree, for many, if not all, Alzheimer's disease (AD) cases. A certain proportion of early-onset (below 65 years of age) AD cases follows an autosomal dominant mode of inheritance. Three genes were identified whose mutations account for 50-70% of early-onset monogenic AD cases in AD pedigrees. These are the genes of the amyloid precursor protein (APP) and two presenilins (PS I and PS II). The polymorphic variant of apolipoprotein E, APOE epsilon 4, is a genetic causative factor in familial and sporadic cases of various early- and late-onset AD forms (it is found, in general, in 20-50% of all AD cases). The action of the epsilon 4 allele is codominant, with the AD risk increased in homozygotes (epsilon 4/epsilon 4 > epsilon 4 > epsilon 3 or epsilon 2). In contrast to the mutations in the PS I and APP genes, the APOE epsilon 4 allele is not a necessary and sufficient condition for AD development. Mutations in these genes have not been found in a proportion of familial early-onset AD cases and are not causative factors in the majority of late-onset familial and sporadic forms. The genes determining AD are evolutionarily conservative and are expressed in all human tissues as early as at initial ontogenetic stages. This raises the question as to why AD is a progressive disorder affecting certain cerebral regions only at middle or old age. A hypothesis and model are suggested to explain the interaction between evolutionary, ontogenetic, and epigenetic factors of the development of the central nervous system and the products of genes whose mutations result in AD. Findings of different mutant genes indicate that AD is a set of genetic disorders (ADs) with a common pathological manifestation.     

Genetic tests: between risks and opportunities. The case of neurodegenerative diseases

Commercial genetic testing challenges traditional medical practice and the doctor–patient relationship. Neurodegenerative diseases may serve as the practical and ethical testing ground for the application of genomics to medicine.In the age of the Internet, a wealth of information lies at your fingertips—even your genetic ancestry and your fate in terms of health and sickness. A Google search for ‘genetic testing'' immediately comes up with a list of companies offering quick, direct-to-consumer genetic tests (DCGT) for relatively little money. “Claim your kit, spit into the tube and send it to the lab,” states the website of 23andMe—the company whose Personal Genome Service was named the ‘2008 Invention of the Year'' by Time magazine. Six to eight weeks after sending in a sample, customers can log on to the company website and learn about their genetic origins and ancestry if they opted for the ‘Fill in Your Family Tree'' option, or can explore their genetic profile under the “Health Edition” and what it says about personal disease risks and drug responses.The availability of next-generation high-throughput DNA sequencers has enabled companies to sequence the genes of a large number of customers at a low costs and with few personnel23andMe is one of several companies that offer predictive genetic tests covering a range of multifactorial and monogenic disorders (STOA, 2008). This is clearly a revolutionary approach to personalized medicine; it not only allows individuals to learn about genetic risk factors for a variety of diseases, but also does so outside the established medical system. Before the advent of DCGTs, genetic tests were only carried out at specialized medical institutions under controlled conditions, and only on referral from a physician. The decreasing price of DNA sequencing, new technologies for high-throughput sequencing and the growth of the Internet have all helped to reduce the technical, financial and access barriers to genetic testing. It is therefore not surprising that private enterprises moved into this fast-developing market.The availability of next-generation high-throughput DNA sequencers enables companies to sequence the genes of a large number of customers at a low cost and with few personnel. They can therefore offer this service at attractive prices, in the range of a few hundred dollars. The Internet conversely enables accessibility: a few mouse clicks are enough, while completely bypassing the usual checks and balances of organized healthcare. This means that expert advice is often lacking for patients about results that predict inherited risks for diabetes, cancer, neurological disorders and drug response (STOA, 2008).The simple, affordable and rapid service offered by these companies raises concerns about the clinical validity and utility of the tests, as well as the information and support that they offer to properly interpret the results. In June this year, the US Food and Drug Administration (FDA) contacted five companies that sell genetic tests directly to consumers and asked them to prove the validity of their products (Pollack, 2010). The FDA argues that genetic tests are diagnostic tools that must obtain regulatory approval before they can be marketed, but it did not order the companies to stop selling their tests. 23andMe—one of the five companies that were contacted—replied: “We are sensitive to the FDA''s concerns, but we believe that people have the right to know as much about their genes and their bodies as they choose” (Pollack, 2010). Last year, researchers from the J. Craig Venter Institute (San Diego, CA, USA) and the Scripps Translational Science Institute (La Jolla, CA, USA) reported inconsistencies between results obtained from two DCGT companies in an opinion article in Nature and made recommendations for improving predictions (Ng et al, 2009).A balance must be struck between consumer choice, consumer benefit and consumer protection. On one side is the individual''s right to have access to information about his or her health condition and health risks, so as to be able to take preventive measures. On the other side, serious questions have emerged about the lack of proper counselling in a professional setting. Are customers able to correctly understand, interpret and manage the information gained from a genetic test? Are they prepared to deal with the health risk information such a test provides? Are the scientific community and society as a whole ready to change the focus in medicine from morphological and physiological factors to molecular and genetic information?A balance must be struck between consumer choice, benefit and protectionThese concerns become more complicated when companies offer genetic tests for neurodegenerative disorders for which there are no preventive measures or treatments, such as Alzheimer, Parkinson or Huntington diseases. Most of these diseases are severe, debilitating and can lead to stigmatization and possible discrimination for patients. Brain disorders that cause progressive mental decline affect not only the health of the individual, but also their identity, self-consciousness and role within the family and society. As Judit Sándor, Director of the Centre for Ethics and Law in Biomedicine at the Central European University (Budapest, Hungary) put it: “The stigmatization of hereditary diseases in society may lead to ethical and legal consequences that are difficult to grasp. The stigma associated with neurodegenerative diseases would be even harder to bear if the disease is proven to be hereditary by some form of genetic testing.”In this context, 60 experts from a range of disciplines—scientists, clinicians, philosophers, sociologists, jurists, journalists and patients—from Europe, Canada and the USA met at the 2010 workshop ‘Brains In Dialogue On Genetic Testing'' in Trieste, Italy. The meeting was organized by the International School for Advanced Studies, as part of the European project ‘Brains in Dialogue'', which aims to foster dialogue among key stakeholders in neuroscience (www.neuromedia.eu). The use of predictive genetic testing for neurodegenerative diseases was the main focus of the meeting and represents an interesting model for discussing the risks and benefits of DCGTs.Very few neurodegenerative disorders have a typical Mendelian inheritance. The most (in)famous is Huntington disease, which typically becomes noticeable in middle age. Symptoms include progressive choreiform movements, cognitive impairment, mood disorders and behavioural changes. Huntington disease is caused by an increase in the number of CAG repeats in the gene Huntingtin, which can be tested for easily and reliably (Myers, 2004) in order to confirm a diagnosis or predict the disease, in at-risk groups or prenatally. The results have psychological and ethical implications that affect individuals and their families. According to the STOA report on DCGTs, only one company offers a test for Huntington disease.Most neurodegenerative disorders have a more complex set of genetic and environmental risk factors that make it difficult—if not impossible—to predict the risk of disease at a certain age. A small percentage of cases of Alzheimer and Parkinson diseases—usually early-onset—carry specific mutations with a Mendelian inheritance, but genetic factors are also involved in the most common late-onset forms of these diseases (Avramopoulos, 2009; Klein & Schlossmacher, 2006). Nicholas Wood of University College London, UK, commented that: “[t]here has been a revolution in our molecular genetic understanding of Parkinson''s disease. Twenty years ago Parkinson''s disease perhaps was considered the archetype of non-genetic disease. It is now clear that a growing list of genes is primarily responsible for Mendelian forms of Parkinson''s disease. It is also clear from recent studies that, due to reduced penetrance, some of these ‘Mendelian genes'' play a role in the so-called sporadic disease.” Nevertheless, a genetic test based on susceptibility genes would not enable a clear diagnosis—as in the case of Huntington disease—but only an estimate of the individual''s risk of developing the disease later in life, with varying reliability.For Alzheimer disease, genetic testing is usually only recommended for individuals with a family history of early-onset or with immediate relatives who already have the disease. The most common form of late-onset Alzheimer disease has a complex inheritance pattern. The medical establishment does not therefore recommend genetic testing for it, although a polymorphism in the Apolipoprotein E (APOE) gene has been unequivocally associated with Alzheimer disease (Avramopoulos, 2009). The identification of such risk factors through epidemiological studies provides valuable information about the molecular basis of the disease, but the management of this information at the individual level seems difficult for clinicians and patients. Agnes Allansdottir of the University of Siena, Italy, explained these difficulties stating that “research on decision-making processes demonstrates that we humans have severe problems dealing with probabilities.”Sándor expressed concerns that these difficulties could lead to additional discrimination. “Most people know what to do if they have high blood pressure, for instance. However, information coming from a genetic test is much more complex—their reading and interpretation require special expertise,” she said. She pointed out that some groups might be unable to access that expertise, while others might be unable to understand the information. “As a consequence, they will suffer an additional form of discrimination that is the ‘discrimination in the accessibility'' of sensitive and complex medical data, and that affects […] the right to privacy, as well.”…“research on decision-making processes demonstrates that we humans have severe problems dealing with probabilities”It is certainly possible that individuals who do not understand what probabilistic estimates of risk mean will be upset to find out they have a higher risk of developing a certain disorder, even though in absolute terms this risk is marginal. Avoiding this situation is what genetic counselling tries to achieve: to inform patients and help them to interpret the results of genetic tests. For the same reason, genetic testing for most common forms of late-onset Alzheimer or Parkinson disease—both of which are multifactorial—is not recommended, precisely because of the limited predictive value of these tests and the lack of proven preventive measures. However, various companies including deCODEme offer to identify your APOE variant and calculate “your risk of developing late-onset Alzheimer''s Disease” as part of their service.Research has demonstrated that genetic testing may be a useful coping strategy for some at-risk individuals (Gooding et al, 2006), a conclusion that was also reached by the Risk Evaluation and Education for Alzheimer''s Disease (REVEAL) study (Green et al, 2009). Some results showed that knowledge of their APOE genotype and numerical lifetime risk influenced the health-related behaviour of asymptomatic adult children of Alzheimer disease patients. The discovery of increased risk of disease through an education-and-disclosure protocol was associated with a stronger motivation to engage in behaviours that reduce risk, such as changes in medications or vitamin intake, even if their effectiveness is still unclear (Chao et al, 2008). Genotype disclosure did not result in short-term psychological problems, despite the frightening nature of the disease and the lack of therapies for it (Green et al, 2009). These studies highlight the importance of education and counselling in understanding risk and evaluating the means of counteracting it.Yet the ease with which DCGT companies offer tests over the Internet creates a new kind of autonomy for patients. “Genetic information serves often as a key to future decisions. Based on the information, they may rearrange the priorities in their life or change their lifestyle in order to fight against the manifestation of the disease, to decrease its symptoms or simply delay its progress,” Sándor said. “For many people, nothing else is worse than the lack of certainty and thus knowledge, in itself, can be a value.”To know or not to know: that is the question—particularly for neurodegenerative diseases. In addition to the opinions of the experts at the meeting, the public round table, ‘Health and DNA: my life, my genes'', showed that the choice whether to take a test should be a personal decision; certainly nobody should be forced in one direction or another. During the discussion, different opinions and experiences regarding the use of genetic testing were presented by members of the panel and the public. Verena Schmocker, a Swiss woman affected by Parkinson disease, explained why she refused to be tested, despite a strong family history of early-onset Parkinson disease. “I knew already that the disease was in my family, but I didn''t want to take any genetic test. I chose to live my life day by day and live what is there for me to live.” Another woman in the audience explained that she wanted to know her destiny: “[w]hen 15 years ago I was diagnosed with Huntington''s disease I woke up from a nightmare of doubts. I started organizing my life, I got married and got prepared for the future.”In many ways, Huntington disease is an unrepresentative example—not only because it is an untreatable, debilitating Mendelian disease, but also because patients typically receive mandatory and sophisticated patient counselling. Most importantly, as Marina Frontali from the National Research Council (Rome, Italy) highlighted, counselling should enable and respect autonomous decisions by the person at risk, even in light of third-party pressure to take the test, not just by employers or insurance companies, but also by family members. The counselling service for Huntington disease—through a tight collaboration between laypeople and professionals—is a valuable example of the management of genetic testing.…the ease with which DCGT companies offer tests over the Internet creates a new kind of autonomy for patientsThe Eurobarometer 2005 survey showed that EU citizens are generally supportive of the use of genetic data for diagnosis and research, and 64% of the respondents said that they would take a genetic test to detect potential diseases (EC, 2006). In reality, however, attitudes vary between countries: in most cases, people would be willing to take a test only in exceptional circumstances or only if it was highly regulated and controlled. Interestingly, those countries in which people expressed more concern and negative attitudes towards testing were those with higher levels of education and scientific literacy, where the mass media is more attentive to science and technology and where the public and political debate is more advanced. It shows, again, that increasing scientific literacy is not enough to overcome people''s fears and objections to genetic testing; the more they understand the issues, the less likely people are to be enthusiastic about new technologies.These concerns notwithstanding, the number of tests that are available is growing, and genetic testing—whether as part of the healthcare system or through DCGT companies—is becoming a model for preventive medicine and discussions about the impact of genetics on public health (Brand et al, 2008). The advances brought about by genomics will lead to more targeted health promotion messages and disease prevention programmes specifically directed at susceptible individuals and families, or at subgroups of the population, based on their genomic risk profile.The controversial nature of the political discourse concerning science and health often raises controversy, and the integration of genomics into public healthcare, research and policy might therefore be challenging. According to Brand et al (2008), the question is not whether the use of genomics in public health is dangerous, but whether excluding genomic information from public health interventions and withholding the potential of evidence-based prevention might do more harm. The next decade will provide a window of opportunity in which to prepare and educate clinicians, public health professionals, policy-makers and the public for the integration of genomics into healthcare. Brand et al (2008) argue that there is an ethical obligation to meet this challenge and make the best use of the opportunities provided by scientific progress.This, inevitably, requires a legal and regulatory framework to ensure that the benefits are made widely available to the population and, in particular, to protect consumers—today, DCGT by private companies remains a largely unregulated market. In 2008, the Committee of Ministers of the 47 Member States of the Council of Europe adopted the first international legally binding document concerning genetic testing for health purposes (Lwoff, 2009). The Additional Protocol to The Convention on Human Rights and Biomedicine about Genetic Testing for Health Purposes addresses some of the issues raised by genetic testing, from quality and clinical utility, to public information and genetic screening programmes for health purposes (Council of Europe, 2008). According to the Protocol, a health-screening programme that uses genetic tests can only be implemented if approved by the competent body, after independent evaluation of its ethical acceptability and fulfilment of specific conditions. These include the health relevance, scientific validity and effectiveness, availability of appropriate preventive or treatment measures, equitable access to the programme and availability of adequate measures to inform the population about the existence, purpose and accessibility of the screening programme, as well as the voluntary nature of participation in it.Two particular issues were discussed during the development of the Protocol: direct access to tests by individuals; and information and genetic counselling (Lwoff, 2009). The Protocol includes some debated restrictions to DCGT (Borry, 2008), to guarantee the proper interpretation of predictive test results and appropriate counselling to understand their implications. According to Article 7, with few exceptions “[a] genetic test for health purposes may only be performed under individualized medical supervision.” In order to assure quality of information and support for the patient, Article 8 states that “the person concerned shall be provided with prior appropriate information in particular on the purpose and the nature of the test, as well as the implications of its results.” Moreover, for tests for monogenic diseases, tests that aim to detect a genetic predisposition or genetic susceptibility to a disease, or tests to identify the subject as a healthy carrier of a gene responsible for a disease, appropriate genetic counselling should be available. It states that “the form and extent of this genetic counselling shall be defined according to the implications of the results of the test and their significance for the person or the members of his or her family, including possible implications concerning procreation choices.” According to this document, genetic counselling could thus go from being a “very heavy and long” procedure to a “lighter” one, but should be guaranteed in any case. The Protocol has already influenced legislation, but it will apply only in countries that have ratified it, which, so far, is only Slovenia.Companies that offer DCGTs are harbingers of change for personalized medicine. Their increasing popularity—owing not least to the ease with which their services can be obtained over the Internet—shows that the public is willing to pay for this kind of personal information. Nevertheless, healthcare systems and regulators must ensure that developments in this area benefit patients. Experience from genetic testing for neurological diseases—given their particularly severe impact on patients and their families—highlights both the current lack of proper regulation and oversight, as well as the potential health benefits that can be reaped from genetic tests.? Open in a separate windowDonato RamaniOpen in a separate windowChiara Saviane     

Overrepresentation of Glutamate Signaling in Alzheimer's Disease: Network-Based Pathway Enrichment Using Meta-Analysis of Genome-Wide Association Studies

Genome-wide association studies (GWAS) have successfully identified several risk loci for Alzheimer''s disease (AD). Nonetheless, these loci do not explain the entire susceptibility of the disease, suggesting that other genetic contributions remain to be identified. Here, we performed a meta-analysis combining data of 4,569 individuals (2,540 cases and 2,029 healthy controls) derived from three publicly available GWAS in AD and replicated a broad genomic region (>248,000 bp) associated with the disease near the APOE/TOMM40 locus in chromosome 19. To detect minor effect size contributions that could help to explain the remaining genetic risk, we conducted network-based pathway analyses either by extracting gene-wise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent gene-based association p-value using the extended Simes (GATES) procedure. Comparison of these strategies revealed that ontological sub-networks (SNs) involved in glutamate signaling were significantly overrepresented in AD (p<2.7×10⁻¹¹, p<1.9×10⁻¹¹; GW and GATES, respectively). Notably, glutamate signaling SNs were also found to be significantly overrepresented (p<5.1×10⁻⁸) in the Alzheimer''s disease Neuroimaging Initiative (ADNI) study, which was used as a targeted replication sample. Interestingly, components of the glutamate signaling SNs are coordinately expressed in disease-related tissues, which are tightly related to known pathological hallmarks of AD. Our findings suggest that genetic variation within glutamate signaling contributes to the remaining genetic risk of AD and support the notion that functional biological networks should be targeted in future therapies aimed to prevent or treat this devastating neurological disorder.     

Alzheimer's disease: Old problem,new views from transgenic and viral models

Alzheimer's dementia is developing ever more as a complex syndrome with various unknown genetic and epigenetic contributions. These are compounded on and exacerbating the underlying amyloid and tau pathology that remain the basis of the pathological definition of Alzheimer's disease. Here, we present a selection of aspects of recent bigenic and virus-based mouse strains, developed as pre-clinical models for Alzheimer's disease. We discuss newer features in the context of the characteristics defined in previously validated transgenic models. We focus on specific aspects of single and multiple transgenic mouse models for Alzheimer's disease and for tauopathies, rather than providing an exhaustive list of all available models. We concentrate on the content of information related to neurodegeneration and disease mechanisms. We pay attention to aspects and defects that are predicted by the models and can be tested in humans. We discuss implications that help translate the fundamental knowledge into clinical, diagnostic and therapeutic applications. We elaborate on the increasing knowledge extracted from transgenic models and from newer adeno-associated viral models. We advocate this combination as a valuable strategy to study molecular, cellular and system-related pathogenic mechanisms in AD and tauopathies. We believe that innovative animal models remain needed to critically test current views, to identify and validate therapeutic targets, to allow testing of compounds, to help understand and eventually treat tauopathies, including Alzheimer's disease.