Accelerated approval of aducanumab for mild Alzheimer's by the U.S. Food and Drug Administration on June 7, 2021, has generated substantial medical, scientific, and ethical controversy. That approval was contrary to the nearly unanimous judgment of the FDA's Advisory Committee that little reliable evidence existed of significant benefit, even though the drug did reduce β‐amyloid. Three major ethical problems were created by this approval: (1) Medicare resources would be unjustly squandered, given the drug's $56,000 annual price and the 3.1 (...) million older potential American patients needing the drug; (2) physicians will feel ethically compelled to provide the drug to desperate, insistent patients, given FDA approval and in spite of side effects of brain bleeds and brain swelling; (3) and false hopes are generated for patients. A needed corrective by the federal government would reduce reimbursement to the bare cost of producing the drug (plus only a modest profit) until a phase IV trial has been successfully completed. (shrink)

Impairment of the Self has been described in frontal–temporal dementia but little research has been carried out in patients with Alzheimer’s disease. Objective. The aim of this study was to explore changes in the self in patients with AD. Method. Forty-seven patients with mild to moderate AD were examined using a semi-structured scale designed to assess the self-concept along three dimensions, namely, the Material Self, the Social Self and the Spiritual Self. Results. The majority of patients presented impairment of (...) at least one dimension of the Self. When only one dimension was affected, it was always the Social Self. The severity of impairment of the Self was correlated to the impairment of the semantic autobiographical memory and apathy. The Self is impaired in AD and the Social Self dimension appears to be more vulnerable in AD than other dimensions. (shrink)

Philosophers have debated whether the advance directives of Alzheimer’s patients should be enforced, even if patients seem content in their demented state. The debate raises deep questions about the nature of human autonomy and personal identity. But it tends to proceed on the assumption that the advance directive’s terms are clear, whereas in practice they are often vague or ambiguous, requiring the patient’s healthcare proxy to make difficult judgment calls. This practical wrinkle raises its own, distinct but related, philosophical (...) question: what criteria may the proxy bring to bear when making such interpretive judgments on which the patient’s life may depend? After defending a general policy of enforcing advance directives on normative (rather than metaphysical) grounds, I argue that when advance directives are vague, a patient’s proxy may permissibly make her own fresh evaluation of the patient’s life as a whole and, in so doing, consider how the patient’s character as a demented person contributes or fails to contribute to that life. (shrink)

There is a flood of papers being published on new ways to diagnose Alzheimer disease before it is symptomatic, involving a combination of invasive tests , and pen and paper tests. This changes the landscape with respect to genetic tests for risk of AD, making rational suicide a much more feasible option. Before the availability of these presymptomatic tests, even someone with a high risk of developing AD could not know if and when the disease was approaching. One could (...) lose years of good life by committing suicide too soon, or risk waiting until it was too late and dementia had already sapped one of the ability to form and carry out a plan. One can now put together what one knows about one's risk, with continuing surveillance via these clinical tests, and have a good strategy for planning one's suicide before one becomes demented. This has implications for how these genetic and clinical tests are marketed and deployed, and the language one uses to speak about them. The phrase ‘there is nothing one can do’ is insulting and disrespectful of the planned suicide option, as is the language of the Risk Evaluation and Education for Alzheimer's Disease studies and others that conclude that it is ‘safe’ to tell subjects their risk status for AD. Further, the argument put forward by some researchers that presymptomatic testing should remain within research protocols, and the results not shared with subjects until such time as treatments become available, disrespects the autonomy of people at high risk who consider suicide an option. (shrink)

Consumer demand for health information and health services has rapidly evolved to capture and even propel the movement to online health information seeking. Seventeen percent of health information internet users will look for information about memory loss, dementia and Alzheimer’s disease. We examined the content of the 25 most frequently retrieved websites marketing AD dietary supplements. We found that the majority of websites and their products claimed AD-related benefits, including improvement and enhancement of function, treatment for AD, prevention of (...) AD, maintenance of function, delayed progression of AD, and decreased symptoms. Supplements were described as effective, natural, powerful or strong, dependable and pure or of high quality. Peer reviewed references to proper scientific studies were infrequent on websites. Statements highlighting the risks of dietary supplements were as common as statements mitigating or minimizing these risks. Different strategies were used to promote supplements such as popular appeals and testimonials. Further enforcement of relevant policy is needed and preparation of clinicians to deal with requests of patients and caregivers is indicated. (shrink)

The world population aged significantly over the twentieth century, leading to an increase in the number of individuals presenting progressive, incapacitating, incurable chronic-degenerative diseases. Advances in medicine to prolong life prompted the establishment of instruments to ensure their self-determination, namely the living will, which allows for an informed person to refuse a type of treatment considered unacceptable according to their set of values. From the knowledge on the progression of Alzheimer disease, it is possible to plan the medical care, (...) even though there is still no treatment available. Irreversible cognitive incapacity underlines the unrelenting loss of autonomy of the demented individual. Such a loss requires the provision of specific and permanent care. Major ethical issues are at stake in the physician–patient–family relationship, even when dementia is still at an early stage. The authors suggest that for an adequate health care planning in Alzheimer disease the living will can be presented to the patient in the early days of their geriatric care, as soon as the clinical, metabolic or even genetic diagnosis is accomplished. They also suggest that the appointment of a health care proxy should be done when the person is still in full enjoyment of his cognitive ability, and that the existence and scope of advance directives should be conveyed to any patient in the early stages of the disease. It follows that ethical guidelines should exist so that neurologists as well as other physicians that deal with these patients should discuss these issues as soon as possible after a diagnosis is reached. (shrink)

Partiendo del reconocimiento de la alteridad y heterogeneidad como parte constitutiva de la sociedad, se encuentra en la educación inclusiva una manera de construir condiciones para hacer posible la integración de lo diverso. El aprendizaje de la filosofía no escapa a este gran reto, adquiriendo relevancia la pregunta por sus sentidos y dinámicas en un caso con una persona con una deficiencia cognitiva como el Alzheimer, en el que se toma el contexto familiar como un espacio pedagógico desde el (...) que se proponen estrategias que respondan a las necesidades de inclusión. Se utiliza entonces la fotografía como estrategia hermenéutica para comprender la perspectiva del “otro” e interpretarla por medio de la creación de obra. Este proceso de apropiación lleva a una reflexividad y autocomprensión que termina por transformar, tanto la relación cuidadora-adulto mayor, como los conceptos de los sujetos implicados, volviendo, efectivamente, toda esta experiencia en general, una oportunidad de aprendizaje filosófico. (shrink)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in (...) aged monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

Alzheimer's disease (AD) is the most common cause of dementia, and there is currently no cure. The “β‐amyloid cascade hypothesis” of AD is the basis of current understanding of AD pathogenesis and drug discovery. However, no AD models have fully validated this hypothesis. We recently developed a human stem cell culture model of AD by cultivating genetically modified human neural stem cells in a three‐dimensional (3D) cell culture system. These cells were able to recapitulate key events of AD pathology (...) including β‐amyloid plaques and neurofibrillary tangles. In this review, we will discuss the progress and current limitations of AD mouse models and human stem cell models as well as explore the breakthroughs of 3D cell culture systems. We will also share our perspective on the potential of dish models of neurodegenerative diseases for studying pathogenic cascades and therapeutic drug discovery. (shrink)

The leading accounts of the ethics of proxy decision making implicitly draw on internalist conceptions of the philosophy of mind, or so this essay tries to demonstrate. Using the views of Ronald Dworkin as its jumping‐off point, the essay argues that accepting the sort of externalism associated with writers such as Putnam and Burge would alter Dworkin's conclusions concerning how we should respond to the current or precedent decisions of people suffering from dementia. Building on the views of Agnieszka Jawarska, (...) it argues that accepting “active” externalism à la Clark and Chambers would provide currently competent people with new resources for establishing the authority of their present values over inconsistent values they might come to entertain should they become demented. (shrink)

Existing accounts of the early history of Alzheimer’s disease have focused on Alois Alzheimer’s (1864–1915) publications of two ‘peculiar cases’ of middle-aged patients who showed symptoms associated with senile dementia, and Emil Kraepelin’s (1856–1926) discussion of these and a few other cases under the newly introduced name of ‘Alzheimer’s disease’ in his Textbook of Psychiatry. This article questions the underpinnings of these accounts that rely mainly on publications and describe ‘presenility’ as a defining characteristic of the disease. (...) Drawing on archival research in the Munich psychiatric clinic, in which Alzheimer and Kraepelin practised, this article looks at the use of the category as a diagnostic label in practice. It argues that the first cases only got their exemplary status as key referents of Alzheimer’s disease in later readings of the original publications. In the 1900s, the published cases rather functioned as material to think about the limits of the category of senile dementia. The examination of paper technologies in the Munich psychiatric clinic reveals that the use of the clinical diagnosis of Alzheimer’s disease was not limited to patients of a certain age and did not exclude ‘senile’ cases. Moreover, the archival records reflect that many diagnoses of Alzheimer’s disease were noted in the medical records as suspicions rather than conclusions. Against this background, the article argues that in theory and practice, Alzheimer’s disease was not treated as a well-defined disease entity in the Munich clinic, but as an exploratory category for the clinical and histopathological investigation of varieties of organic brain diseases. (shrink)

In the hope of future treatments to prevent or slow down the disease, there is a strong movement towards an ever-earlier detection of Alzheimer's disease. In conjunction with scientific developments, this has prompted a reconceptualization of AD, as a slowly progressive pathological process with a long asymptomatic phase. New concepts such as "preclinical" and "prodromal" AD have been introduced, raising a number of conceptual and ethical questions. We evaluate whether these new concepts are theoretically defensible, in light of theories (...) of health and disease, and whether they should be understood as disease or as an at-risk state. We introduce a pragmatic view on disease concepts and argue that an evaluation of the reconceptualization of AD should also take its aims and effects into account, and assess their ethical acceptability. The reconceptualization of AD is useful to coordinate research into preventive strategies, and may potentially benefit future patients. However, in the short term, early detection and labelling of "preclinical AD" can potentially harm people. Since there is no treatment available and the predictive value is unclear, it may only create a group of "patients in waiting" who may suffer from anxiety, uncertainty and stigmatization, but will never actually develop dementia. We conclude that only if the promise of preventive medication materializes, will the reconceptualization of AD turn out unequivocally to be for the better. Otherwise, the reconceptualization may do more harm than good. (shrink)

Alzheimer disease is a huge and growing societal problem with upwards of 35% of the population over the age of 80 developing the disease. AD results in a loss of memory, the ability to make reasoned and sound decisions, and ultimately the inability to take care of oneself. AD has an impact not only on the sufferer, but their caretakers and loved ones, who must take on a costly and time-consuming burden of care. AD is found in virtually all (...) racial and ethnic groups. Genetic influences on AD are substantial, and there has been a 30 year history of both success and failure. Mutations for rare early onset forms of the disease have been identified, but this information has not yet led to an effective treatment. Multiple common genetic variations have also been identified, and have led to new insights into the potential role of microglia cells in addition to neuronal cells in the brain. Despite intensive efforts, a significant portion of the genetic etiology of AD remains unknown and must be identified. (shrink)

The authority of the intact self over the future severely demented self is based on notions of integrity and precedent autonomy. Despite criticism of this authority, the principle of precedent autonomy in the care of people with Alzheimer disease or other progressive and irreversible dementias retains its moral significance.

A new therapeutic approach is being developed for the treatment of Alzheimer's disease (AD). This approach involves the deliberate induction of an autoimmune response to amyloid‐β (Aβ) peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD. If this approach is to be effective, antibodies must be produced that can selectively target the toxic forms of Aβ, while leaving the functionally‐relevant forms of Aβ and its precursor protein untouched. Furthermore, an approach needs (...) to be found that avoids provoking an acute neuroinflammatory response. The situation is made even more challenging by uncertainty regarding which isoforms of Aβ contribute to the pathogenesis of AD. BioEssays 25:283–288, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

In this article, I consider my relationship with my father who developed Alzheimer's disease and criticize dominant models of social interactions and relationships. I argue that the point of a relationship is not what we exchange or achieve within it. The point is not even that we depend on others for our vital needs. The point is simply that a relationship is valuable in and of itself.

This chapter contains sections titled: Semantic Externalism: A Rough Sketch and a Gesture at Motivation Interests, Values, and the Mind's End Beyond Externalism About Mental Contents Acknowledgments References.

A new therapeutic approach is being developed for the treatment of Alzheimer's disease (AD). This approach involves the deliberate induction of an autoimmune response to amyloid‐β (Aβ) peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD. If this approach is to be effective, antibodies must be produced that can selectively target the toxic forms of Aβ, while leaving the functionally‐relevant forms of Aβ and its precursor protein untouched. Furthermore, an approach needs (...) to be found that avoids provoking an acute neuroinflammatory response. The situation is made even more challenging by uncertainty regarding which isoforms of Aβ contribute to the pathogenesis of AD. BioEssays 25:283–288, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Gil R, Arroyo-Anllo EM, Ingrand P, Gil M, Neau JP, Ornon C, Bonnaud V. Self-consciousness and Alzheimer’s disease. Acta Neurol Scand 2001: 104: 296–300. # Munksgaard 2001. Objectives – To propose a neuropsychological study of the various aspects of self-consciousness (SC) in Alzheimer’s disease. Methods – Forty-five patients with probable mild or moderate AD were included in the study. Severity of their dementia was assessed by the Mini Mental State (MMS). Fourteen questions were prepared to evaluate SC. Results (...) – No significant correlations were found between SC score and educational level, age, and duration of disease. A significant correlation was found between SC score and the severity of dementia, whereas frontal disturbances were just short of the significance threshold. The various aspects of SC were not impaired to the same degree. The most disturbed ones were awareness of cognitive deficiencies, moral judgements and prospective memory. The least disturbed aspects were awareness of identity and of mental representation of the body. Items relating to anosognosia and moral judgements were significantly correlated with the MMS score, whereas affective state, body representation disorders, prospective memory, and capacities for introspection were not related to the severity of the dementia. Consciousness of identity was sound, regardless of MMS score. Conclusions – AD clearly induces an heterogeneous impairment of SC. SC requires a convergence of many neural networks. In AD, neuronal alterations involve many cortical areas and information sent to the associative frontal cortex from memory, language and visuospatial areas is lacking or disturbed. Thus, the sequential order of successive stimuli cannot be maintained by the heteromodal associative cortex (dorsal convexity of the prefrontal cortex), and the supramodal associative cortex (located rostrally in the frontal lobes) is unable to provide reliable monitoring and assessment of simultaneous neural cognitive networks carrying insufficient and inadequate input. The core deficiency in AD patients might be impaired SC equated with the disability to maintain sequential and simultaneous ‘‘attention to life’’. The Self-Consciousness Questionnaire, a clinical scale providing multidimensional measurement, indicates that different aspects of consciousness are not correlated with overall cognitive deficiency as determined by the MMSE. (shrink)

As in the United States, the Dutch conversation about assisted suicide emerged primarily in the context of cancer. At least in that context, before acceding to a request for assistance in dying, caregivers must be sure that the person has made a voluntary and carefully considered request, and that her suffering is unbearable and without prospect of improvement. The Dutch have recently been trying to use those criteria in the context of Alzheimer's disease. Given the wave of Alzheimer's (...) cases poised to crash onto wealthy countries, along with emerging technology to detect the disease process before symptoms appear, we should be grateful to the Dutch for that attempt. As a newcomer to this discussion, however, I was struck that those criteria may have a somewhat odd result. A patient with Alzheimer's disease can easily meet the conditions in the early stage of the disease, when one usually has the mental capacity to request assistance in dying and to make the case that one's existential suffering is unbearable. If one is in the late stage, though, it can be much harder to get such assistance because one does not have that capacity. (shrink)

Alzheimer's Disease is a form of dementia that affects the memory, cognition, and motor skills of patients. Extensive research has been done to develop accessible, cost-effective, and non-invasive techniques for the automatic detection of AD. Previous research has shown that speech can be used to distinguish between healthy patients and afflicted patients. In this paper, the ADReSS dataset, a dataset balanced by gender and age, was used to automatically classify AD from spontaneous speech. The performance of five classifiers, as (...) well as a convolutional neural network and long short-term memory network, was compared when trained on audio features and text features. The same audio and text features were used to train five regression models to predict the Mini-Mental State Examination score for each patient, a score that has a maximum value of 30. The top-performing classification models were the support vector machine and random forest classifiers trained on BERT embeddings, which both achieved an accuracy of 85.4% on the test set. The best-performing regression model was the gradient boosting regression model trained on BERT embeddings and CLAN features, which had a root mean squared error of 4.56 on the test set. The performance on both tasks illustrates the feasibility of using speech to classify AD and predict neuropsychological scores. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a (...) perspective on this debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

The implications of Pope John Paul II's 2004 Allocution on vegetative states remain unclear despite dozens of articles and a recent clarifying statement from the Vatican. Yet few have considered its implications for those with end-stage progressive dementia, such as Alzheimer's disease. Although recent studies suggest tube feeding is burdensome and not beneficial for such patients, the Allocution would nonetheless seem to forbid patients from forgoing it. But this seems to be in tension with the Catholic bioethical tradition as (...) a whole and may therefore be a consequence that the pope did not intend. Because the recent Vatican clarification specifically addresses Alzheimer’s, it is especially important to know what duties it intends to impose on those with dementia. Problems with how it would apply to such patients casts doubt on whether it should be applied to patients in vegetative states at all. (shrink)

With more people in the world living into older age, Alzheimer's and other Dementias: The Facts takes a comprehensive look at the spread of dementia, and provides authoritative information and practical advice for sufferers, their families, and the medical professionals who care for them. -/- Written by a consultant in old age psychiatry, the book provides an overview of all the different types of dementia (including younger-onset dementias), from the most-recognized - Alzheimer's - to the less-frequent types, such (...) as those caused by inherited metabolic disorders or HIV. The book guides the reader step-by-step through how the brain works, and explains in clear and simple language the effect of dementias on the brain, and the impact on an individual's cognitive function. -/- A dedicated chapter explains how a diagnosis is reached, including the different modes of assessment, from blood tests carried out by a GP, to specialist scans, highlighting how the brain actually works. Detailed sections cover the latest treatments available, including the controversial use of antipsychotic medication, and the possibility of disease-modifying treatments in the future. -/- The book also explains how the multi-disciplinary team works together to look after the sufferer's social needs, such as bathing and washing, as well as their spiritual and palliative needs. Alzheimer's and other Dementias: The Facts provides all the relevant information and guidance for sufferers, family and their care-givers to choose the right intervention at the right time, to create - as the book advocates - a unique and personalized management plan. (shrink)

The introduction of National Institute for Health and Clinical Excellence (NICE) guidance on Alzheimer's medication in November 2006 will have a significant effect on the treatment of patients, and is opposed by the Royal College of Psychiatrists and many charities dealing with the elderly. The use of the Quality-Adjusted Life Year (QALY) in the guidance formulation is much debated due to questions of ageism. This article seeks to examine the basis of these accusations and whether NICE can be justified (...) using a utilitarian calculation in a principally egalitarian system such as the NHS. (shrink)

The rate of individuals diagnosed with Alzheimer’s disease is expected to increase significantly in the coming decades. As more attention is paid to end-of-life care for these patients, questions about the use of assisted nutrition and hydration will become more prevalent. Two recent articles that discuss the use of ANH in patients suffering from advanced Alzheimer’s disease are discussed. The author argues that Pope John Paul II’s designation of medically assisted nutrition and hydration as “ordinary care” does not (...) alleviate the ethical necessity of discerning the benefits and burdens of the procedure for these patients. He argues that tube feeding of patients with advanced Alzheimer’s disease should be considered extraordinary, non-obligatory treatment, but future research is still needed to assess the objective and subjective criteria for making this judgment. National Catholic Bioethics Quarterly 13.3 (Autumn 2013): 469–482. (shrink)

A través del presente trabajo se aborda el papel de la musicoterapia en la enfermedad de alzheimer (EA) desde el ámbito del trabajo social. Para ello, se lleva a cabo una revisión bibliográfica y se identifican conceptos claves como musicoterapia, EA e intervención del trabajo social. La información recogida lleva a considerar la musicoterapia como tratamiento coadyuvante en la enfermedad de Alzheimer a través de áreas como la integración social, la autoestima, la comunicación o la reducción del estrés. (...) Por ello, se concluye que la estimulación musical mejora la calidad de vida en pacientes con EA. (shrink)

Early last year, the GenEthics Consortium (GEC) of the Washington Metropolitan Area convened at George Washington University to consider a complex case about genetic testing for Alzheimer disease (AD). The GEC consists of scientists, bioethicists, lawyers, genetic counselors, and consumers from a variety of institutions and affiliations. Four of the 8 co-authors of this paper delivered presentations on the case. Supplemented by additional ethical and legal observations, these presentations form the basis for the following discussion.

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Aging, Chance, and RaceAtwood D. Gaines (bio)KeywordsAlzheimer’s disease, chance, mild cognitive impairment, racism, social constructionsThomas Kirkwood's comments are a welcome, articulate detailing of how and why we age with special reference to the brain. As well, his paper indicates clearly that processes reified as pathology and disease, such as Alzheimer's disease (AD), are in fact common and inevitable as the human brain ages. Doubtless, this (...) is the reason that aging is by far the greatest risk factor for the development of AD. A key notion, briefly mentioned by Kirkwood, is that of chance. He points out that, "cells (will be) burdened with protein aggregates and similar materials that will increase with aging. Once again, which cells will experience this fate and which will continue to function healthily is strongly influenced by chance" (Kirkwood 2006, 80–81). This mention of chance is most important for our paper, "Building a Mystery," and for an understanding of science as well. In "Building a Mystery," Peter Whitehouse and I sought to show that the history of AD was not inevitable and demonstrates a variety of chance and singular decisive occurrences of encounters, interpretations, social movements, government initiatives, and technological developments. Such decisive moments do not occur by virtue of some (natural) lawful process that is unfolding, but rather, these are chance events that could have happened in other ways. Indeed, science has been viewed as human attempts to "tame chance" (Hacking 1990). However, it often does so by sleight of hand, misinterpretation, and the biomedical discourse of hope. Increasingly, we are learning that chance is a commonality, not a rarity, in social and biological domains. The biomedical approach assumes the opposite. For example, it seeks to tame the chance appearance of AD in the case of Auguste D, and does so in part by reifying differences that exist, as Kirkwood notes, along a continuum rather than as the discrete entities implied by the labels Alzheimer's disease or mild cognitive impairment (MCI).We thus stand with Kirkwood's bold recognition of chance (see also Kirkwood 2003) in the biological domain and have applied the same idea to the social domain in which we consider the practice of biomedical science. We have elsewhere emphasized consensus statements in the making of AD (Gaines and Whitehouse 1998). In the present article, we add a number of other chance, decisive sociocultural moments to the mix of social processes producing AD and MCI. We have not considered in detail here a host of cultural features in the theory and practice of biomedicine with respect to AD. These include implicit, yet highly [End Page 83] implicative, cultural notions of bilateral kinship employed in genetic research on AD considered elsewhere (Gaines 1998).Bavidge's comments are cogent as well. With respect to the notion of my concept of the local biology of "race" (Gaines 2005), it is germane to point out here that such culturally constructed biologies are relevant to a discussion of AD and other dementias. Such constructions represent culture in science. We used the dramatic example of "race" in US biomedicine because it is experiencing a resurgence as an explanatory tool. For example, recently Haiman et al. (2006) presented research that suggests that "Among cigarette smokers, African Americans and native Hawaiians are more susceptible to lung cancer than whites, Japanese Americans and Latinos." The authors assert, as have many US studies, that their findings show differences relate to the alleged biology of the social groups concerned. Their problem and that of others, is that the groups are social, not biological, and most have mixed ancestry and do not stem from distinct groups. This is particularly true of African Americans and Latinos; both groups are substantially composed of individuals with European, West African, and Native American ancestry in widely varying proportions (Gaines 2005). Thus, they are different only in terms of their classification. Such work regularly overlooks influences, such as environmental racism, discrimination, poverty, and a lack of medical care, as well as other practices. These might include, in a study of smoking, pakalolo smoking (local marijuana) among Hawaiians, who themselves are usually part Portuguese, Japanese, Chinese, and or European... (shrink)

The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms (...) of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (shrink)

We propose protein localization dependent signal activation (PLDSA) as a model to describe pre‐existing protein partitioning between the cytosol, and membrane surface, as a means to modulate signal activation, specificity, and robustness. We apply PLDSA to explain possible molecular links between type II diabetes mellitus (T2DM) and Alzheimer's disease (AD) by describing Ca+2‐mediated interactions between the Src non‐receptor tyrosine kinase and p52Shc adaptor protein. We suggest that these interactions may serve as a contributing factor to disease development and progression. (...) In particular, we propose that signaling response is regulated, in part, by Ca+2‐mediated partitioning of lipid‐bound and soluble forms of Src and p52shc. Thus, protein‐protein interactions that drive signaling in response to extracellular ligand binding are also mediated by partitioning of signaling proteins between membrane‐bound and soluble populations. We propose that PLDSA effects may explain, in part, the evolutionary basis of promiscuous protein interaction domains and their importance in cellular function. (shrink)

The last year has seen major advances in the study of Alzheimer's disease (AD).† Four mutations involving amino acid substitutions in axons 16 and 17 of the amyloid precursor protein (APP) gene, have been identified which co‐segregate with the disease in some families multiply affected by early onset Alzheimer's disease. These mutations are strongly suggestive of a causative role for the amyloid preursor protein in Alzheimer's disease. Despite their rarity, these mutations are important because they represent the (...) first known cause of Alzheimer's disease. Processing of APP must be central to the pathogenesis of the disease although the precise effects of these amino acid substitutions are not understood. Work is now being undertaken to characterise the processing pathways of APP and to identify other causes of AD. The development of models of AD using the APP mutations offers the possibility of identifying drug targets and developing more effective treatments than are presently available. (shrink)

Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in Alzheimer's disease (...) (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long‐term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity‐dependent recruitment of postsynaptic AMPA‐type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory‐associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD. (shrink)

Alzheimer’s disease is a very common, progressive and still incurable disease. Future possibilities for its cure lie in the promotion of research that will increase our knowledge of the disorder’s causes and lead to the discovery of effective remedies. Such research will necessarily involve individuals suffering from Alzheimer’s disease. This raises the controversial issue of whether patients with Alzheimer’s disease are competent to give their consent for research participation.

Neurons have developed elaborate mechanisms for sorting of proteins to their destination in dendrites and axons as well as dynamic local trafficking. Recent evidence suggests that polarized axonal sorting of β‐site converting enzyme 1 (BACE1), a type I transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis, entails an unusual journey. In hippocampal neurons, BACE1 internalized from dendrites is conveyed in recycling endosomes via unidirectional retrograde transport towards the soma and sorted to axons where BACE1 becomes enriched. In comparison (...) to other transmembrane proteins that undergo transcytosis or elimination in somatodendritic compartment, vectorial transport of internalized BACE1 in dendrites is unique and intriguing. Dysfunction of protein transport contributes to pathogenesis of AD and other neurodegenerative diseases. Therefore, characterization of BACE1 transcytosis is an important addition to the multiple lines of evidence that highlight the crucial role played by endosomal trafficking pathway as well as axonal sorting mechanisms in AD pathogenesis. (shrink)

The paper outlines the policy context and summarizes the numerous policy issues that AD raises from the more generic to the unique. It posits that strong public fears of AD and its future prevalence projections and costs, raise increasingly difficult policy dilemmas. After reviewing the costs in human lives and money and discussing the latest U.S. policy initiatives, the paper presents two policy areas as examples the demanding policy decisions we face. The first focuses on the basic regulatory function of (...) protecting the public from those who would exploit these fears. The second centers on the well-debated issues of advance directives and euthanasia that surround AD. Although more dialogue, education and research funding are needed to best serve the interests of AD patients and families as well as society at large, this will be challenging because of the strong feelings and divisions AD engenders. (shrink)

Name der Zeitschrift: Deutsche Zeitschrift für Philosophie Jahrgang: 66 Heft: 1 Seiten: 75-86.

Given the past two decades of over 40 failed trials of amyloid-lowering therapies in Alzheimer’s Disease (AD), many of which succeeded in lowering amyloid as designed, we present an ethical argument for emptying the drug pipeline of tests of amyloid-lowering agents so as to end the historical dominance of the amyloid-reducing therapeutic approach in AD.

Biomarker-based predictive tests for subjectively asymptomatic Alzheimer’s disease (AD) are utilized in research today. Novel applications of artificial intelligence (AI) promise to predict the onset of AD several years in advance without determining biomarker thresholds. Until now, little attention has been paid to the new ethical challenges that AI brings to the early diagnosis in asymptomatic individuals, beyond contributing to research purposes, when we still lack adequate treatment. The aim of this paper is to explore the ethical arguments put (...) forward for AI aided AD prediction in subjectively asymptomatic individuals and their ethical implications. The ethical assessment is based on a systematic literature search. Thematic analysis was conducted inductively of 18 included publications. The ethical framework includes the principles of autonomy, beneficence, non-maleficence, and justice. Reasons for offering predictive tests to asymptomatic individuals are the right to know, a positive balance of the risk-benefit assessment, and the opportunity for future planning. Reasons against are the lack of disease modifying treatment, the accuracy and explicability of AI aided prediction, the right not to know, and threats to social rights. We conclude that there are serious ethical concerns in offering early diagnosis to asymptomatic individuals and the issues raised by the application of AI add to the already known issues. Nevertheless, pre-symptomatic testing should only be offered on request to avoid inflicted harm. We recommend developing training for physicians in communicating AI aided prediction. (shrink)