History in perspective: How Alzheimer's Disease came to be where it is?

Treatment of Alzheimer's Disease (AD) remains an unsolved issue despite the pronounced global attention it has received from researchers over the last four decades. Determining the primary cause of the disease is challenging due to its long prodromal phase and multifactorial etiology. Regardless, academic disagreements amongst the scientific community have helped in making significant advancements in underpinning the molecular basis of disease pathogenesis. Substantial development in fluid and imaging biomarkers for AD led to a sharp turn in defining the disease as a molecular construct, dispensing its clinical definition. With conceptual progress, revisions in the diagnostic criteria of AD were made, culminating into the research framework proposed by National Institute on Aging and Alzheimer's Association in 2018 which unified different stages of the disease continuum, giving a common language of AT(N)1 classification to researchers. With realization that dementia is the final stage of AD spectrum, its early diagnosis by means of cerebrospinal fluid biomarkers, Positron Emission Tomography and Magnetic Resonance Imaging of the brain holds crucial importance in discovering ways of halting the disease progression. This article maps the insights into the pathogenesis as well as the diagnostic criteria and tests for AD as these have evolved over time. A contextualized timeline of how the understanding of AD has matured with advancing knowledge allows future research to be directed and unexplored avenues to be prioritized.

Evolution of the Research Literature and the Scientific Community of Alzheimer's Disease from 1983-2017: A 35-Year Survey.

This study surveys the development of Alzheimer's disease (AD) in the research literature, the scientific community, and the journals containing AD papers over a 35-year period. Research papers on AD published from 1983 to 2017 in journals indexed in the Web of Science were analyzed in seven five-year periods. The number of AD papers increased from 1,095 in 1983-1987 to 50,532 by 2013-2017 and in the same time period, the number of participating countries went from 27 to 152. The US was the most prolific country throughout, followed by several European countries, Canada, Australia, and Japan. Asian countries have emerged and by 2013-2017, China surpassed all but the US in productivity. Countries in Latin America and Africa have also contributed to AD research. Additionally, several new non-governmental institutions (e.g., ADNI, ADI) have emerged and now play a key role in the fight against AD. Likewise the AD scientific publishing universe evolved in various aspects: an increase in number of journals containing AD papers (227 journals in 1983-1987 to 3,257 in 2013-2017); appearance of several AD-focused journals, e.g., Alzheimer's & Dementia, Journal of Alzheimer's Disease; and the development of special issues dedicated to AD. Our paper complements the numerous extant papers on theoretical and clinical aspects of AD and provides a description of the research landscape of the countries and journals contributing papers related to AD.

Historic concepts of dementia and Alzheimer's disease: From ancient times to the present.

The aim of this work is to describe the history of dementia and Alzheimer's disease (AD) concepts, from early descriptions in antiquity, through studies and authors from different historical periods throughout the centuries, to the latest updates of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). The article also presents the inclusion of the biomarkers from the cerebrospinal fluid, such as Tau and phosphorylated Tau proteins and beta-amyloid peptide in the most recent diagnostic criteria. A literature search was carried out in order to construct a reflexive narrative review of studies dated up to 2015 in the LILACS and Medline databases and with the inclusion of bibliographical references of the area. The different terms used throughout the history of the dementia and Alzheimer's disease concepts were contextualized according to the scientific perspective of a given epoch and its way of producing and reproducing knowledge. The concepts of dementia and AD continue to evolve, largely due to their complexity. Considering the importance and the growth of AD cases in the last and the next decades, this review may contribute in practice with the historical knowledge of the concepts related to dementia and AD.

Avicenna (980-1037 CE) and his Early Description and Classification of Dementia.

According to the World Health Organization (WHO), dementia is a disorder that occurs as result of a neurodegenerative process in brain, and usually is chronic or progressive by nature. Most descriptions of senile dementia date back to Alois Alzheimer. In 1906, Alzheimer described the first patient, Auguste Deter, who suffered from the disorder that later became known as Alzheimer's disease. Although, the history of the disease before 1906 is quite rich, little has been said about the contributions of ancient and medieval physicians to the understanding of dementia. Over the centuries, the concept of senile dementia changed from an inevitable mental decline with aging, to different sets of clinical features with narrow limits of diagnosis of a disease in its own right. Documentation of the historical origins of prevention, diagnosis, and therapies of dementia would make an important contribution to a more complete understanding of this pathological degeneration of dementia. The present review focuses on the contributions of Avicenna (AD 980-1037) to the development of diagnosis and the discovery of etiology of different forms of dementia, with the goal of revealing the extent to which dementia was understood in the golden age of Islam in Persia.

A Particularly Tragic Case of Possible Alzheimer's Disease, that of Marshal Pétain.

After World War I and more particularly in June 1940, the prestige of French Marshal Philippe Pétain, considered as the winning general the battle of Verdun, was very high. He became President of Council while the French army was unable to stop the German offensives. But five years later he was sentenced to death for high treason. By rereading his bibliography from a medical perspective, it is possible to find multiple suggestive events and to affirm a posteriori Pétain suffered from a neurodegenerative disorder, whose first signs appeared in the 1930s, suggestive of Alzheimer's disease, which had an impact on French politics. The modern medical knowledge of this disease casts a new light on the behavior of Petain during the last war.

Remembering Robert D. Terry at a Time of Change in the World of Alzheimer's Disease.

Dr. Robert Terry (January 14, 1924-May 20, 2017) studied normal aging and Alzheimer's disease for more than five decades. He was at a visionary neuropathologist who trained generations of researchers in the field of neurodegenerative disorders and was always at the cutting edge of incorporating ever advancing technology into the fields of neuroscience and neuropathology. He was among the first to study plaques and tangles using electron microscopy, described the effects of aluminum on neurons, and collaborated to develop new approaches to study synaptic pathology in the context of cognitive impairment in Alzheimer's disease. Dr. Terry made indelible contributions to our understanding of Alzheimer's disease and dementia. In memory of Bob: veteran, physician-scientist, collaborator, friend, husband, and father.

History of Dementia.

The term dementia derives from the Latin root demens, which means being out of one's mind. Although the term "dementia" has been used since the 13th century, its mention in the medical community was reported in the 18th century. Even though the Greeks postulated a cerebral origin, the concept was not restricted to senile dementia and included all sorts of psychiatric and neurological conditions leading to psychosocial consequences. In the 19th century, individuals with dementia were recognized as patients, deserving medical care from specialists called alienists, and senile dementia became a medical disease. Subsequently, progresses in neuropathology allowed its fragmentation into different neuropathological conditions. Senile dementia was considered as a distinct entity from Alzheimer's seminal case published in 1906, and was first attributed to a vascular origin. However, from the late 1960s and for 20 subsequent years, Alzheimer's disease became the prototypical senile dementia. Only recently, the term dementia was abandoned for major neurocognitive disorder and the heterogeneity of the syndrome acknowledged again at the phenotypical and molecular levels. We hope a better understanding of this fascinating history will improve scientific research and impose humility towards the complex underpinnings of age-related cognitive decline.

The Nucleus Basalis of Meynert and Its Role in Deep Brain Stimulation for Cognitive Disorders: A Historical Perspective.

The nucleus basalis of Meynert (nbM) was first described at the end of the 19th century and named after its discoverer, Theodor Meynert. The nbM contains a large population of cholinergic neurons that project their axons to the entire cortical mantle, the olfactory tubercle, and the amygdala. It has been functionally associated with the control of attention and maintenance of arousal, both key functions for appropriate learning and memory formation. This structure is well-conserved across vertebrates, although its degree of organization varies between species. Since early in the investigation of its functional and pathological significance, its degeneration has been linked to various major neuropsychiatric disorders. For instance, Lewy bodies, a hallmark in the diagnosis of Parkinson's disease, were originally described in the nbM. Since then, its involvement in other Lewy body and dementia-related disorders has been recognized. In the context of recent positive outcomes following nbM deep brain stimulation in subjects with dementia-associated disorders, we review the literature from an historical perspective focusing on how the nbM came into focus as a promising therapeutic option for patients with Alzheimer's disease. Moreover, we will discuss what is needed to further develop and widely implement this approach as well as examine novel medical indications for which nbM deep brain stimulation may prove beneficial.

A brief history of "Alzheimer disease": Multiple meanings separated by a common name.

The field of Alzheimer disease (AD) has a nosologic problem: The diagnostic label "Alzheimer disease" has several distinctive meanings. The term probable AD was introduced in 1984 to designate a clinically diagnosed acquired and progressive amnestic dementia for which there was no evidence for another etiology. Probable AD represented a clinicopathologic entity that assumed a specific and sensitive linkage between amnestic dementia and the neuropathology of ß-amyloid-containing neuritic plaques and tau-containing neurofibrillary tangles. The clinicopathologic model represented by probable AD was adapted in abbreviated form for population-based studies and general clinical practice, although the uncertainty connoted by "probable" was often overlooked. Representing the growing public awareness of later life cognitive impairment, a vernacular meaning of AD arose out of the clinicopathologic model in which AD represented all dementia not due to another clinically apparent cause. In contrast, by the 1990s, neuropathologists settled on a definition of AD based entirely on a sufficient burden of neuritic plaques and neurofibrillary tangles at postmortem examination, regardless of antemortem clinical status. In the last decade, the availability of fluid and imaging biomarkers that measure ß-amyloid and tau abnormalities has enabled antemortem pathobiological diagnoses, highlighting the divide between the clinicopathologic model, the vernacular usage, and the pathobiological models. Each definition has value. However, the meanings of AD as defined by each of these models are not interchangeable. The pathobiological one is the only one that is unambiguous.

The de-Alzheimerization of age-related dementias: implications for drug targets and approaches to effective therapeutics.

Alzheimer's disease (AD) was differentiated from senile dementia (SD) in 1910 due to its early onset and pathological severity. In 1976, this distinction was upended when SD was redesignated as AD to focus efforts and funding in dementia-related research. AD then became conflated with amyloid plaques and, to a lesser degree, neurofibrillary tangles complicating efforts in understanding dementia causality and its treatment. The resultant four-decade search for therapies-based almost exclusively on amyloid was an exercise in futility. While dementia is a complex, multifactorial syndrome, AD is viewed as a homogeneous, linear disease. An amyloid-agnostic approach is necessary to discover therapeutics for age-related dementias.

What is 'Alzheimer's Disease'? The 'Auguste D' Case Re-opened.

What is Alzheimer's: an organic, neuropathological psychiatric disease, caused by plaques and tangles in aging brains or/and an existential condition affecting the minds of aging persons experiencing disconnection from meaning-bearing networks of social relations? Reviewing current research and revisiting Alzheimer's original case of 'Auguste D' this paper offers an historical-sociological genealogy that raises fundamental questions of causality, and even of the ontological status of Alzheimer's and the dementia reputed to it as a disease entity. Drawing on Kuhn's notion of 'science as usual' and Foucault's notion of the discursive formation of 'regimes of truth', our analysis seeks to understand how a sole medical focus on either bio-markers of neurological disease or genetic association was accomplished in the absence of sufficient and robust evidence. To counter the exclusion of psychosocial considerations, this paper offers two original hypotheses on the iconic case of 'Auguste D', taking into account the social milieu in which she lived and the specific circumstances of her life. It goes on to suggest the way in which the contemporary socio-cultural context may have dementiagenic tendencies. This research supports Gaines and Whitehouse's argument that research into the phenomenon and symptoms of Alzheimer's should focus on extracorporal and psychosocial factors.

How early can we diagnose Alzheimer disease (and is it sufficient)? The 2017 Wartenberg lecture.

A seismic shift in our understanding of the ability to diagnose Alzheimer disease (AD) is occurring. For the last several decades, AD has been a clinical-pathologic diagnosis, and this conceptualization of the disease has served the field well. Typically, the clinician would identify a syndrome such as mild cognitive impairment or dementia, and label the condition as "probable AD" since the diagnosis of definite AD could not be made until an autopsy revealed the presence of amyloid plaques and tau-based neurofibrillary tangles. However, with the advent of biomarkers for AD including neuroimaging and CSF, the identification of AD pathology can be made in life, which greatly enhances the ability of clinicians to be precise about the underlying etiology of a clinical syndrome. Hypothetical models of the temporal relation among the pathologic elements and the clinical symptoms have been proposed and have influenced the field enormously. This has enabled clinicians to be specific about the underlying cause of a given clinical syndrome. As such, the diagnostic capability of the clinician is evolving. However, AD pathology is only a component of the puzzle describing the causes of cognitive changes in aging. Most often, there is a multitude of pathologic entities contributing to the neuropathologic explanation of cognitive changes in aging. AD changes contribute important elements to the diagnosis, but the final answer is more complex. The field of aging and dementia will have to incorporate these additional elements.