Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

Report of the task force on designing clinical trials in early (predementia) AD.

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

Toward a comprehensive theory of Alzheimer's disease--challenges, caveats, and parameters.

The task of developing a unifying theory of Alzheimer's disease faces several impediments. The most difficult include: the impact of scientific orthodoxy on the acceptance of new ideas; the uncertain relationship between aging and disease(s); the long time course of the degenerative process; the heterogeneity in the genotype and phenotype of the disease; the complex interactions among genetic and other risk factors (many of which are not yet known); the poorly understood nonlinear relationships between the neurobiological and the clinical phenotypes of the disease--namely, viewing clinical symptoms as emergent behavior(s) of a complex system; and the paucity of appropriate models or modeling systems for human disease(s) such as Alzheimer's.

Alzheimer's disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities.

Alzheimer's disease (AD) can be diagnosed with a considerable degree of accuracy. In some centers, clinical diagnosis predicts the autopsy diagnosis with 90% certainty in series reported from academic centers. The characteristic histopathologic changes at autopsy include neurofibrillary tangles, neuritic plaques, neuronal loss, and amyloid angiopathy. Mutations on chromosomes 21, 14, and 1 cause familial AD. Risk factors for AD include advanced age, lower intelligence, small head size, and history of head trauma; female gender may confer additional risks. Susceptibility genes do not cause the disease by themselves but, in combination with other genes or epigenetic factors, modulate the age of onset and increase the probability of developing AD. Among several putative susceptibility genes (on chromosomes 19, 12, and 6), the role of apolipoprotein E (ApoE) on chromosome 19 has been repeatedly confirmed. Protective factors include ApoE-2 genotype, history of estrogen replacement therapy in postmenopausal women, higher educational level, and history of use of nonsteroidal anti-inflammatory agents. The most proximal brain events associated with the clinical expression of dementia are progressive neuronal dysfunction and loss of neurons in specific regions of the brain. Although the cascade of antecedent events leading to the final common path of neurodegeneration must be determined in greater detail, the accumulation of stable amyloid is increasingly widely accepted as a central pathogenetic event. All mutations known to cause AD increase the production of beta-amyloid peptide. This protein is derived from amyloid precursor protein and, when aggregated in a beta-pleated sheet configuration, is neurotoxic and forms the core of neuritic plaques. Nerve cell loss in selected nuclei leads to neurochemical deficiencies, and the combination of neuronal loss and neurotransmitter deficits leads to the appearance of the dementia syndrome. The destructive aspects include neurochemical deficits that disrupt cell-to-cell communications, abnormal synthesis and accumulation of cytoskeletal proteins (e.g., tau), loss of synapses, pruning of dendrites, damage through oxidative metabolism, and cell death. The concepts of cognitive reserve and symptom thresholds may explain the effects of education, intelligence, and brain size on the occurrence and timing of AD symptoms. Advances in understanding the pathogenetic cascade of events that characterize AD provide a framework for early detection and therapeutic interventions, including transmitter replacement therapies, antioxidants, anti-inflammatory agents, estrogens, nerve growth factor, and drugs that prevent amyloid formation in the brain.

Prospects of developing interventions to prevent Alzheimer's disease.

Based largely on recommendations of scientists from around the world, it is possible to discover treatments designed to maintain independent functioning of patients with Alzheimer's disease. It is hoped that discussion of critical targets for intervention, and possible strategies for altering the degenerative course of the disease will spur interested groups into action.

Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society.

OBJECTIVE: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research? PARTICIPANTS: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy. EVIDENCE: The expert presenters summarized data from the world scientific literature on the questions posed to the panel. CONSENSUS PROCESS: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached. CONCLUSIONS: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness.

Diagnostic criteria for dementia in clinical trials. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.

Some of the issues associated with standardizing the diagnosis of dementia in clinical trials are outlined. Deliberations of the Working Group on Diagnostic Criteria and their recommendations for future actions needed to develop a consensus are described.

Fisher symposium: strategies for the prevention of Alzheimer disease--overview of research planning meeting III.

Even though the prospect for preventing Alzheimer disease seems remote now, a plan must be developed to reach this goal in order to avoid a fiscal crisis in the health care system. The goals of delaying Alzheimer disease and eventually preventing it will become possible as more is learned about the brain mechanisms and risk factors involved. In response to a 1994 Congressional report, the National Institute on Aging in cooperation with the Zachary and Elizabeth M. Fisher Medical Foundation sponsored a workshop to address potential strategies for the prevention of Alzheimer disease. The workshop helped to identify the necessary resources and the types of technical problems involved in developing methods to prevent Alzheimer disease. This volume presents the position papers which served as the springboard for the discussions at the workshop, out of which developed a number of specific recommendations including new epidemiological studies for well defined population groups, identification of high risk populations for treatment and prevention studies, and coupling of new questions and add-on investigations to in-progress studies.

Overview of basic research on Alzheimer disease: implications for cognition.

During the past 12 years, research on the etiology of Alzheimer disease (AD) has made dramatic advances. Although we still do not have a clear picture of what factor(s) cause AD, growing evidence indicates that the fundamental problem in AD is associated with the death of neurons. The purpose of this article is to re-evaluate in detail how the regulation of intracellular free calcium might play a critical role in cell death and in the expression of AD neuropathology. There is an urgent need to find means to ameliorate the symptoms of AD and ways to slow the progression of the disease process. Unfortunately, AD appears to be a very complex neurochemical puzzle.

A proposed strategy for international collaborative research in brain aging and Alzheimer's disease.

A description and discussion are given of several of the programmes initiated by the United States' National Institute on Aging that could be expanded to facilitate multicentre collaboration studies. It includes: the Alzheimer's Disease Research Centers; the Alzheimer's Disease Patient Registry Program; the World Health Organization Special Programme for Research on Aging; and how collaborative links with scientists working on this disease in other countries may be established.