Ebook: Alzheimer's Disease: A Century of Scientific and Clinical Research

The history of Alzheimer's disease (AD) is typically formulated as the history of great doctors and scientists in the past making great discoveries that are in turn taken up by great doctors and scientists in the present – all sharing the aim of unraveling the mysteries of the disease and discovering how it can be prevented or cured. While it can certainly be edifying to study the “great men” and how their contributions laid the foundation for current work, there are problems with this approach to history. First, it oversimplifies the actual historical development of science. Second, using history to legitimate the present can keep us from asking critical questions about the aims and limits of contemporary research. This chapter urges a broader view of the history of AD, one that recognizes that context is as important as the great doctors to the historical development of the concept of AD. Thought of this way, I argue that it is useful to divide of the history of AD into three periods. First there was the period in which Alzheimer and Kraepelin laid the clinical and pathological foundations of the disease concept. Then there is our own period, which began in the late 1970s and has emphasized the biological mechanisms of dementia. In between, there is the period – almost completely ignored in most histories of AD – that conceptualized dementia in psychodynamic terms. It is true that the psychodynamic model of dementia did not directly contribute to the concepts and theories that dominate AD research today. But it did change the context of aging and dementia in important ways, without which AD could not have emerged as a major disease worthy of a massive, publicly supported research initiative.

As we commemorate the first centennial since Alzheimer's disease (AD) was first diagnosed, this article casts back into the past while also looking to the future. It reflects on the life of Alois Alzheimer (1864–1915) and the scientific work he undertook in describing the disorder suffered by Auguste D. from age 51 to 56 and the neuropathological findings revealed by her brain, reminding us of the origin of the eponym. It highlights how, throughout the 1960's, the true importance of AD as the major cause of late life dementia ultimately came to light and narrates the evolution of the concepts related to AD throughout the years and its recognition as a major public health problem. Finally, the article pays homage to the work done by the Alzheimer's Association and the research undertaken at the Alzheimer's Disease Centres within the framework of the National Institute on Aging (NIA) Program, briefly discussing the long road travelled in the fight against AD in the past 25 years and the scientific odyssey that we trust will result in finding a cure.

In the absence of any naturally occurring animal model of Alzheimer's disease (AD), the British conviction in the 1970's that clinico-pathological investigations of human cases offered the best approach to unraveling the pathogenesis of AD rapidly influenced clinical neuroscientists, neuropathologists and funding agencies in Canada and the USA. But as with my confreres, years of our quantifying AD lesions in autopsy brains have yet to yield definitive conclusions about what is the most important neuronal abnormality. However, during my elusive search, evidence has been slowly gathered that reactivation of latent Herpes simplex virus, traveling from trigeminal ganglia into neighbouring mesial temporal cortex, might best explain the limbic predilection for and earliest site of neurofibrillary tangle formation. This maturing hypothesis may serendipitously prove to have been a more essential byproduct of generating the voluminous data than all the publications from our laboratory that reflected endless hours of quantitative morphometry.

Alzheimer's disease (AD) and sporadic Parkinson's disease (PD) are the most frequently occurring degenerative illnesses of the human nervous system. Both involve multiple neuronal systems, but only a few types of nerve cells are prone to develop the disease-associated intraneuronal alterations. In AD affected neurons produce neurofibrillary tangles and neuropil threads, while in PD they develop Lewy bodies and Lewy neurites. In both illnesses select types of projection cells that generate long, unmyelinated or sparsely myelinated axons are particularly susceptible. This kind of selective vulnerability induces a distinctive lesional pattern which evolves slowly over time and remains remarkably consistent across cases. In the present review, lesions developing in the cerebral cortex are described against the backdrop of the internal organisation and interconnectivities linking involved cortical areas and subcortical nuclei. In AD, six and in PD, three stages can be distinguished, reflecting the predictable manner in which the proteinaceous intraneuronal inclusions spread through the cerebral cortex. In AD stages I–II and in PD stage 4, the pathological process makes inroads into the anteromedial temporal mesocortex, entorhinal allocortex, and Ammon's horn; thereafter, in AD stages III–IV and in PD stage 5, it proceeds into the adjoining high order association areas of the basal temporal neocortex. In AD stages V–VI and in PD stage 6, the damage affects additional neocortical association areas including first order association areas and eventually extends into the primary areas of the neocortex. The gradually evolving lesional pattern in AD and PD mirrors the ground plan of the cerebral cortex. The highest densities of lesions occur in the anterior mesocortical transitional zone between allo- and neocortex. From there, the involvement diminishes by degrees and extends into both the hippocampal formation and the neocortex. The severity of the neocortical lesions decreases in inverse proportion to the trajectories of increasing cortical differentiation and hierarchical refinement.

The invitation to participate in the commemorative issue celebrating the 100^th anniversary of Dr. Alois Alzheimer's report on the disease that would later bear his name has evoked memories of my early experiences in the study of dementia, my teachers, my role-models, my aspirations and my accomplishments. Early in my career, I was fascinated with the study of hereditary neurological disorders. The observation of families in which dementia was inherited in an autosomal dominant pattern excited my scientific curiosity. Three very different phenotypes in patients from three separate families have been the basis for novel scientific discovery, which has taken place over the past 30 years. This could not have taken place without the help of many generous patients and their families as well as wonderful colleagues for whom I am deeply grateful. Some of the original observations inthese families have ledtothe discovery of genetic mutations in three genes that are among the most commonly affected in hereditary dementia. The work on these families has enriched the scientific community and our knowledge of dementing illnesses.

Argentophilic neurofibrillary tangles were described in the cerebral cortex of Alzheimer's disease and later in the pigmented neurons in the brain stem of postencephalitic parkinsonism. In 1961, wide distribution of Alzheimer's neurofibrillary tangles in the central nervous system was observed in endemic fatal neurodegenerative diseases affecting the native Chamorro population on Guam: amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam. Abundant neurofibrillary tangles were found but no senile plaques. A topographic analysis of tangles in cases inGuam and at Montefiore were published in 1962 [23]. Thereafter, Alzheimer's neurofibrillary changes were documented in various areas of the nervous system of many other diseases. This communication is a brief review of the topographic investigation of Alzheimer's neurofibrillary changes. Occurrence of tangles in various conditions seems to indicate that various pathological agents can induce tangles. On the other hand, Alzheimer's neurofibrillary tangles, in general, show a rather striking predilection to affect particular neurons in the involved regions.

A retrospective clinico-pathological study of a consecutive autopsy series of 1050 elderly dementedindividuals(mean age 83.4±6.0 years; MMSE < 20) was performed. Clinical diagnoses were probable or possible Alzheimer disease (62.9%), nonspecific degenerative dementia (10.4%), vascular dementia (10%), Parkinson disease with dementia (9.5%), 1.5% mixed dementia, and 5.7% other disorders. At autopsy, 86% revealed Alzheimer-related pathology, but only 42.8% showed “pure” Alzheimer disease, with additional cerebrovascular lesions in 22.6% and Lewy body pathology in 10.8%, while among 660 cases of clinically suspected Alzheimer disease, Alzheimer pathology was seen in 93%, only 44.7% in “pure” form, and additional vascular lesions and Lewy bodies in 27.7 and 10%, respectively. The non-Alzheimer cases included Huntington and Creutzfeldt-Jakob disease, frontotemporal dementias, and others. These and other recent data indicate that in patients with the clinical diagnosis of Alzheimer disease its combination with cerebrovascular lesions and Lewy body pathologies is rather frequent. Comparison of clinical and postmortem diagnoses revealed postmortem confirmation of Alzheimer disease in 93%, of mixed and vascular dementia in 60 and 52.3%, respectively. 78% of clinically suspected degenerativedementias were pathologically definite Alzheimer disease, while in the clinical Parkinson + dementia group dementia with Lewy bodies accounted for 35%, Parkinson+Alzheimer disease, and “pure” Alzheimer disease for 29%, each. A sample of 207 prospectively studied elderly showed significant negative correlation between the preterminal psychostatus assessed by MMSE and the neuritic Braak stages, with a broad “gray” zone of Alzheimer lesions in mildly to moderately demented subjects. Similar relations between CDR and Braak stages were seen in very old subjects. The present study and the results of other recent series indicate increasing agreement between clinical and autopsy diagnoses in demented aged individuals with variable accuracy rates for different forms of dementia disorders.

The original recognition of the paired helical filaments is discussed and amplified. The original description of what are now the neuropil threads is mentioned. The ensuing importance of both these structures is emphasised and a morphology-based hypothesis of the development of the disease from the original stimuli is offered.

Two principal findings in the Pearson et al. paper [73] are commented on here. The first is the regional selectivity within the cerebrum of neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD) which targets association cortex and the primary olfactory cortex alone among regions of primary sensory cortex. The second finding is the clustering of NFT in columns of supra- and infra-granular layers of association cortex. We review recent evidence confirming these findings and comment on their possible significance. We consider that the most attractive hypothesis to explain the vulnerability of the olfactory system and association cortex is the persistent neural plasticity of these regions. On this basis there would be no need to postulate a progressive spreading process. The columnar distribution of clustered NFT can be well understood in the context of recent concepts of columnar organization of the cerebral cortex. The original interpretation that this distribution of NFT reflects pathology in neurons subserving cortico-cortical and cortico-subcortical connections seems to us to have stood the test of time.

Cognitive functioning is dependent on synapse density in the brain. Factors modulatingsynapse density might include the balance between synaptic pruning and sprouting. Loss of synapses during aging might explain cognitive decline and while previous reports have suggested a 10–15% synapse loss occurs during the normal aging process, more recent studies have found that decline in synaptic density only occurs after 65 years of age. In this context, the main objective of this manuscript is to discuss the findings of our 1993 study in light of more recent studies in aging, synapses and Alzheimer's disease.

Alzheimer's disease (AD) is a progressive disorder that is characterized by the accumulation of neuropathologiclesions and neurochemical alterations. Ultrastructural investigations in many association regions of the neocortex and the hippocampal dentate gyrus have demonstrated a disease-related decline in numerical synaptic density. This decline in brain connectivity occurs early in the disease process and strongly correlates with the cognitive decline observed in AD. The synapse loss does not appear to be an inevitable consequence of the aging process. This article reviews the ultrastructural studies assessing AD-related synaptic loss and the possible compensatory changes in the synaptic complex that occur as a result of the loss in brain connectivity.

This brief paper reviews the work on dementia by the Neuropathology group at the Einstein College of Medicine and later at the University of California, San Diego, from the time of our first approaches to Alzheimer Disease in 1959. The electron microscope studies concerned the tangle (got it wrong) and then the plaque (got it right). Lysosomes and active microglia were noted in the plaques. Axoplasmic transport was suggested to be abnormal. We studied the plaques in old dogs and old monkeys, and then went on to use image analysis to count neurons in the neocortex of Alzheimer cases and in examples of normal aging. Later in San Diego we quantified presynaptic boutons and recognized their loss as the major direct cause of dementia. Many collaborators including Henry Wisniewski participated in these early attempts to understand the disease.

Understanding the pathophysiology and treatment of Alzheimer's disease is vitally important. Alzheimer's disease threatens to affect currently at least 30% of all individuals currently alive in the 12 most financially developed countries, unless interventions are discovered to prevent or treat the disease. Although memory loss is the cardinal symptom of Alzheimer's disease, the pathophysiological mechanisms leading to cognitive deficits are poorly understood. It is difficult to address this problem in human studies, and impossible in cultured cells. Therefore, animal models are needed to elucidate the molecular mechanisms leading to dementia. A large number of animal models have focussed upon the role of amyloid plaques in the pathogenesis of Alzheimer's disease, because amyloid plaques are an essential diagnostic feature of the disease. However, the mechanism by which amyloid plaques or their principal molecular constituent, the amyloid-β protein (Aβ), disrupt cognitive function is not well understood. Herein, I describe my perspectiveon what we have learned about how Aβ impairs memory from research on Alzheimer's disease in mice and rats.

Researchers since the 1990shave predominantly focused on the amyloid hypothesis and the formation of amyloid fibrils as the culprit behind AD when we began working on soluble Aβ (sAβ). Unexpectedly, this work produced several novel findings. First, we observed that N-terminal truncated peptides are the major components of soluble and insoluble Aβ in AD; secondly, that all sAβ species belong to the 42 form and the sAβ x-40 species is virtually absent in AD parenchyma; thirdly, that Aβ 42 in the soluble form is non-detectable by immunoblots in plaque-free, normal brains. The later observation that sAβ 42 species is present in amyloid β protein precursor (AβPP) over-expressing brains of patients with Down syndrome in prenatal and early postnatal development argued that sAβ is present in brain in abnormal conditions and that its appearance seeds Aβ aggregation and accumulation. Although the sAβ we described in intact brain tissue appeared to match the soluble Aβ oligomers detected in cell media, which were subsequently shown to be the most toxic form of Aβ, our research has been virtually ignored by the Alzheimer field. It continues nevertheless. Recently we demonstrated that the sAβ species present in physiologically aging brains are different from those present in brains with sporadic AD as the latter form oligomers more quickly, are more toxic to neurons, and produce more severe membrane damage than the Aβ species associated with normal brain aging. Furthermore, in familial AD, the composition of soluble Aβ appears to dictate distinctive features of the disease phenotype introducing the notion of Aβ strains, a concept well established in prion diseases.

Progress in understanding and treating Alzheimer's disease (AD) has been tremendously bolstered by the era of transgenic models of AD. The identification of disease-causingmutationsin proteinssuch as amyloid-β precursor protein (βAPP) and presenilin1 (PS1), together with the discovery of other high risk factors (e.g., Apolipoprotein E4), as well as pathogenic mutations in the tau protein has led to the creation of several transgenic mice, including those expressing bi- and tri-genic constructs. Each model has unique pathologies that provide insights into disease mechanisms and interactive features of neuropathologic cascades. More importantly, therapeutic hypotheses are now testable in a manner unheard of less than 15 years ago. The wealth of new approaches currently in clinical and preclinical evaluations can be directly attributed to the impact of these animals on our ability to model relevant aspects of the disease. As a result, we may see containment or even the elimination of AD in the near future as a direct consequence of these advances.

Here I recap the scientific and personal background of the delineation of the amyloid cascade hypothesis for Alzheimer's disease that I wrote with Gerry Higgins and the events leading to the writing of that influential review.

Many participants played a role in discovering the composition and sequence of the Aβ amyloid of Alzheimer's disease. This sequence enabled the cloning of the amyloid precursor protein (APP), which elucidated its proteolytic origin from the membrane of neurons. The proteolytic enzymes which process APP and the Aβ fragment itself are now the prime validated drug targets for therapeutic intervention.

In the twenty years since George Glenner identified the amyloid β-protein (Aβ), advances in understanding the biochemical pathology, genetics and cell biology of Alzheimer's disease have led to a detailed molecular hypothesis for the genesis of AD and brought us into human trials of antiamyloid agents. The ability to study Aβ dynamically in cultured cells and in vivo derives from the recognition in 1992 that Aβ is a normal product of cellular metabolism throughout life and circulates as a soluble peptide in biological fluids. Here, I review the background underlying this discovery and then discuss its implications for research on Alzheimer's disease, particularly for the development of disease-modifying therapies.