During most of the 20th century, neurodegenerative diseases remained among the most enigmatic disorders of medicine. The scientific study of these conditions was descriptive in nature, detailing the clinical and neuropathological phenotypes associated with various diseases, but etiologies and pathogenic mechanisms remained obscure. Beginning in the 1970s, advances in two principal areas biochemical pathology and molecular genetics combined to yield powerful clues to the molecular underpinnings of several previously "idiopathic" brain disorders. Among the classical neurodegenerative diseases, perhaps the most rapid progress occurred in research on Alzheimer s disease (AD). In disorders like Huntington s disease, amyotrophic lateral sclerosis and even Parkinson s disease, unbiased genetic screens, linkage analysis and positional cloning have identified causative genes that subsequently allowed the formulation of specific biochemical hypotheses. In sharp contrast, modern research on AD developed in the opposite order: the identification of the protein subunits of the classical brain lesions guided geneticists to disease-inducing genes, for example, APP, apolipoprotein E and tau. Thus, a biochemical hypothesis of disease - that AD is a progressive cerebral amyloidosis caused by the aggregation of the amyloid b-protein (Ab) - preceded and enabled the discovery of etiologies.

As progress in deciphering genotype-to-phenotype relationships in AD accelerated during the last two decades, it became apparent that the key challenge for understanding and ultimately treating AD was to focus not on what was killing neurons over the course of the disease but rather on what was interfering subtly and intermittently with episodic declarative memory well before widespread neurodegeneration had occurred . In other words, one wishes to understand the factors underlying early synaptic dysfunction in the hippocampus and then attempt to neutralize these as soon as feasible, perhaps even before a definitive diagnosis of AD can be made. This steady movement of the field toward ever-earlier stages of the disorder is exemplified by the recognition and intensive study of minimal cognitive impairment amnestic type (MCI; . And yet patients who die with a diagnosis of MCI have been found to already have a histopathology essentially indistinguishable from classical AD . Therefore, even earlier phases of this continuum are likely to become recognized, and these might show milder histopathology and might have biochemically, but not yet microscopically, detectable Ab species that mediate synaptic dysfunction.

This volume serves as a record focused on bringing together investigators at the forefront of elucidating the structure and function of hippocampal synapses with investigators focused on understanding how early assemblies of Ab may compromise some of these synapses. "

Like the unflinching gaze of Captain Ahab walking the deck of the Pequod, Alzheimer researchers have had their sights fixed firmly on the disease for many years. Now, as this volume amply demonstrates, accomplished researchers from other fields, who have thought deeply about cell biological problems are applying their insights to Alzheimer's disease. The contri butions here represent the text versions of the proceedings from the tenth "Colloque medecine et recherche" of the Fondation IPSEN devoted to research on Alzheimer's disease. The symposium, entitled "Alzheimer's Disease: Lessons from Cell Biology" was held in Paris on April 25, 1994. As is apparent from the varied backgrounds of the contributors, the scientific pursuit of Alzheimer's disease has begun to meld with more basic disciplines, particularly cell biology. While on the one hand, new areas of specialization are continuously emerging, the boundaries of older disciplines are increas ingly blurred. Perhaps for most of the years since the first descriptions of the disease in 1907, the science of Alzheimer's disease was descriptive, and lay in the province of pathologists. This time period, during which a great deal was learned about the topography of senile plaques and neurofibrillary tangles, culminated with an ultrastructural description of these hallmark structures. The modern era of Alzheimer's disease research opened with the iden tification of the component proteins in plaques and tangles.

During most of the 20th century, neurodegenerative diseases remained among the most enigmatic disorders of medicine. The scientific study of these conditions was descriptive in nature, detailing the clinical and neuropathological phenotypes associated with various diseases, but etiologies and pathogenic mechanisms remained obscure. Beginning in the 1970s, advances in two principal areas biochemical pathology and molecular genetics combined to yield powerful clues to the molecular underpinnings of several previously "idiopathic" brain disorders. Among the classical neurodegenerative diseases, perhaps the most rapid progress occurred in research on Alzheimer s disease (AD). In disorders like Huntington s disease, amyotrophic lateral sclerosis and even Parkinson s disease, unbiased genetic screens, linkage analysis and positional cloning have identified causative genes that subsequently allowed the formulation of specific biochemical hypotheses. In sharp contrast, modern research on AD developed in the opposite order: the identification of the protein subunits of the classical brain lesions guided geneticists to disease-inducing genes, for example, APP, apolipoprotein E and tau. Thus, a biochemical hypothesis of disease - that AD is a progressive cerebral amyloidosis caused by the aggregation of the amyloid b-protein (Ab) - preceded and enabled the discovery of etiologies.

As progress in deciphering genotype-to-phenotype relationships in AD accelerated during the last two decades, it became apparent that the key challenge for understanding and ultimately treating AD was to focus not on what was killing neurons over the course of the disease but rather on what was interfering subtly and intermittently with episodic declarative memory well before widespread neurodegeneration had occurred . In other words, one wishes to understand the factors underlying early synaptic dysfunction in the hippocampus and then attempt to neutralize these as soon as feasible, perhaps even before a definitive diagnosis of AD can be made. This steady movement of the field toward ever-earlier stages of the disorder is exemplified by the recognition and intensive study of minimal cognitive impairment amnestic type (MCI; . And yet patients who die with a diagnosis of MCI have been found to already have a histopathology essentially indistinguishable from classical AD . Therefore, even earlier phases of this continuum are likely to become recognized, and these might show milder histopathology and might have biochemically, but not yet microscopically, detectable Ab species that mediate synaptic dysfunction.

This volume serves as a record focused on bringing together investigators at the forefront of elucidating the structure and function of hippocampal synapses with investigators focused on understanding how early assemblies of Ab may compromise some of these synapses. "

Promising effects in mice of immunization by ss-amyloid stimulated substantial research efforts and high hopes. In retrospect, this study appears simultaneously logical, consistent as it is with the amyloid theory central today in the field of Alzheimer's disease studies, and paradoxical, because it involved using the toxic substance itself for a treatment benefit. The research thus begun opens up multiple perspectives for experimentation and for treatment. Clinical trials began, but had to be stopped in January 2002 because of serious side effects. The editors' objective for this book is not to arouse false hopes for a therapeutic project that must still be proven, but to discuss the available information and the questions it raises."

Alzheimer disease causes the gradual deterioration of cognitive function, including severe memory loss and impairments in abstraction and reasoning. Understanding the complex changes that occur in the brain as the disease progressesincluding the accumulation of amyloid plaques and neurofibrillary tanglesis critical for the development of successful therapeutic approaches.
Written and edited by leading experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine includes contributions covering all aspects of Alzheimer disease, from our current molecular understanding to therapeutic agents that could be used to treat and, ultimately, prevent it. Contributors discuss the biochemistry and cell biology of amyloid ss-protein precursor (APP), tau, presenilin, ss-secretase, and apolipoprotein E and their involvement in Alzheimer disease. They also review the clinical, neuropathological, imaging, and biomarker phenotypes of the disease; genetic alterations associated with the disorder; and epidemiological insights into its causation and pathogenesis. This comprehensive volume, which includes discussions of therapeutic strategies that are currently used or under development, is a vital reference for neurobiologists, cell biologists, pathologists, and other scientists pursuing the biological basis of Alzheimer disease, as well as investigators, clinicians, and students interested in its pathogenesis, treatment, and preventio