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On page 1 showing 1 ~ 20 papers out of 106 papers

Museomics identifies genetic erosion in two butterfly species across the 20th century in Finland.

  • Jérémy Gauthier‎ et al.
  • Molecular ecology resources‎
  • 2020‎

Erosion of biodiversity generated by anthropogenic activities has been studied for decades and in many areas at the species level, using taxa monitoring. In contrast, genetic erosion within species has rarely been tracked, and is often studied by inferring past population dynamics from contemporaneous estimators. An alternative to such inferences is the direct examination of past genes, by analysing museum collection specimens. While providing direct access to genetic variation over time, historical DNA is usually not optimally preserved, and it is necessary to apply genotyping methods based on hybridization-capture to unravel past genetic variation. In this study, we apply such a method (i.e., HyRAD), to large time series of two butterfly species in Finland, and present a new bioinformatic pipeline, namely PopHyRAD, that standardizes and optimizes the analysis of HyRAD data at the within-species level. In the localities for which the data retrieved have sufficient power to accurately examine genetic dynamics through time, we show that genetic erosion has increased across the last 100 years, as revealed by signatures of allele extinctions and heterozygosity decreases, despite local variations. In one of the two butterflies (Erebia embla), isolation by distance also increased through time, revealing the effect of greater habitat fragmentation over time.


Changes in the fine-scale genetic structure of Finland through the 20th century.

  • Sini Kerminen‎ et al.
  • PLoS genetics‎
  • 2021‎

Information about individual-level genetic ancestry is central to population genetics, forensics and genomic medicine. So far, studies have typically considered genetic ancestry on a broad continental level, and there is much less understanding of how more detailed genetic ancestry profiles can be generated and how accurate and reliable they are. Here, we assess these questions by developing a framework for individual-level ancestry estimation within a single European country, Finland, and we apply the framework to track changes in the fine-scale genetic structure throughout the 20th century. We estimate the genetic ancestry for 18,463 individuals from the National FINRISK Study with respect to up to 10 genetically and geographically motivated Finnish reference groups and illustrate the annual changes in the fine-scale genetic structure over the decades from 1920s to 1980s for 12 geographic regions of Finland. We detected major changes after a sudden, internal migration related to World War II from the region of ceded Karelia to the other parts of the country as well as the effect of urbanization starting from the 1950s. We also show that while the level of genetic heterogeneity in general increases towards the present day, its rate of change has considerable differences between the regions. To our knowledge, this is the first study that estimates annual changes in the fine-scale ancestry profiles within a relatively homogeneous European country and demonstrates how such information captures a detailed spatial and temporal history of a population. We provide an interactive website for the general public to examine our results.


Are infant mortality rate declines exponential? The general pattern of 20th century infant mortality rate decline.

  • David Bishai‎ et al.
  • Population health metrics‎
  • 2009‎

Time trends in infant mortality for the 20th century show a curvilinear pattern that most demographers have assumed to be approximately exponential. Virtually all cross-country comparisons and time series analyses of infant mortality have studied the logarithm of infant mortality to account for the curvilinear time trend. However, there is no evidence that the log transform is the best fit for infant mortality time trends.


Tracing and tracking the emergence, epidemiology and dispersal of dengue virus to Africa during the 20th century.

  • Kristian Alfsnes‎ et al.
  • One health (Amsterdam, Netherlands)‎
  • 2021‎

The four mosquito-borne dengue virus serotypes (DENV1-DENV4) cause a high burden of disease throughout the tropical and sub-tropical regions of the world. Nevertheless, their precise epidemiological history in Africa, including when and where they originated and were distributed during the 20th century, remains unclear stressing the need for One Health focused research. Accordingly, we conducted a time-scaled molecular epidemiological reconstruction using publicly available and newly sequenced dengue virus genomes of African origin representing all four serotypes to deduce the most likely temporal and spatial transmission routes of each DENV serotype from their ancestral regions to, within and from Africa. Our analyses suggest that during the 20th century, serotypes DENV1-DENV3 were introduced to Africa from South East Asia on multiple occasions. The earliest evidence recorded indicates introduction of DENV2 during the early-1940s and of DENV1 during the mid-1940s to Western Africa from South East Asia. The analysis also implies an early introduction of DENV4 during the mid-1940s to Western Africa, alongside DENV1, probably originating in South East Asia. Establishment of DENV3 in Africa appears to have occurred later in the 1960s, apparently originating from South East Asia. However, with the re-establishment of DENV in the Americas, following the cessation of the PAHO mosquito control programme during the mid-20th century, evidence of introductions of DENV1 and DENV2 from the Americas to Western Africa was also observed. The data also identify intra-regional circulation of DENV, but also inter-regional dispersal of all four serotypes within Africa, which has led to a high degree of geographical overlap among serotypes. It is also noteworthy that DENV from both Eastern and Western Africa, have been introduced into Central Africa but there is no support for the converse relationship. For serotypes DENV1-DENV3, we observed probable exports from within established African DENV clusters (≥2 sequences) primarily to Eastern and Southern Asia. Collectively, our findings support the view that all DENV serotypes, apart from DENV4, have been introduced on multiple occasions to Africa, primarily originating from South East Asia, and subsequently to neighbouring regions within Africa.


Impact of the Finnish Maternity Grant on infant mortality rates in the 20th century: a natural experimental study.

  • Ronan McCabe‎ et al.
  • Journal of epidemiology and community health‎
  • 2022‎

Baby boxes provide goods to new parents and a space for infant sleeping. They were first introduced in Finland, and it has been argued that the policy helped reduce infant mortality. We evaluated the impact of the Finnish Maternity Grant (which includes the Finnish Baby Box) on infant mortality rates (IMRs) at the points of introduction (disadvantaged mothers only) in 1938 and universalisation in 1949.


17th Century Variola Virus Reveals the Recent History of Smallpox.

  • Ana T Duggan‎ et al.
  • Current biology : CB‎
  • 2016‎

Smallpox holds a unique position in the history of medicine. It was the first disease for which a vaccine was developed and remains the only human disease eradicated by vaccination. Although there have been claims of smallpox in Egypt, India, and China dating back millennia [1-4], the timescale of emergence of the causative agent, variola virus (VARV), and how it evolved in the context of increasingly widespread immunization, have proven controversial [4-9]. In particular, some molecular-clock-based studies have suggested that key events in VARV evolution only occurred during the last two centuries [4-6] and hence in apparent conflict with anecdotal historical reports, although it is difficult to distinguish smallpox from other pustular rashes by description alone. To address these issues, we captured, sequenced, and reconstructed a draft genome of an ancient strain of VARV, sampled from a Lithuanian child mummy dating between 1643 and 1665 and close to the time of several documented European epidemics [1, 2, 10]. When compared to vaccinia virus, this archival strain contained the same pattern of gene degradation as 20th century VARVs, indicating that such loss of gene function had occurred before ca. 1650. Strikingly, the mummy sequence fell basal to all currently sequenced strains of VARV on phylogenetic trees. Molecular-clock analyses revealed a strong clock-like structure and that the timescale of smallpox evolution is more recent than often supposed, with the diversification of major viral lineages only occurring within the 18th and 19th centuries, concomitant with the development of modern vaccination.


Biomonitoring of Polycyclic Aromatic Hydrocarbon Deposition in Greenland Using Historical Moss Herbarium Specimens Shows a Decrease in Pollution During the 20th Century.

  • Karen Martinez-Swatson‎ et al.
  • Frontiers in plant science‎
  • 2020‎

Although most point sources of persistent organic pollutants (POPs), including polycyclic aromatic hydrocarbons (PAHs), are at lower latitudes, the Arctic region is contaminated. In particular, PAHs now dominate the POP body burden of the region's marine biota at the lower trophic levels. Greenlandic Inuits have the most elevated levels of POPs in their blood compared to any other population, due to their consumption of seal meat and other marine mammals. PAHs, the by-products of the incomplete combustion of petroleum products, are known carcinogens and have been shown to affect the immune system, reproduction, endocrine functions, and the nervous system. With industrial activities and climate change set to increase local PAH emissions, it is paramount to document changes in atmospheric PAH deposition to further investigate PAH exposure in the region and attribute contaminations to their sources. As a measure of atmospheric pollution, we sampled bryophyte herbarium specimens of three common and widespread species collected in Greenland between the 1920s and 1970s after which time new collections were not available. They were analyzed for 19 PAHs using GC-MS (gas chromatography mass spectrometry). The presence of more low-molecular-weight PAHs than high-molecular-weight PAHs is evidence that the PAH contamination in Greenland is due to long-range transport rather than originating from local sources. The results show peaks in PAH atmospheric deposition in the first part of the 19th century followed by a trend of decrease, which mirror global trends in atmospheric pollution known from those periods. PAHs associated with wood and fossil-fuel combustion decrease in the 1970s coinciding with the disappearance of charcoal pits and foundries in Europe and North America, and a shift away from domestic heating with wood during the 19th century. The results highlight the value of bryophytes as bioindicators to measure PAH atmospheric pollution as well as the unrealized potential of herbaria as historical records of environmental change.


The recombinogenic history of turnip mosaic potyvirus reveals its introduction to Japan in the 19th century.

  • Shusuke Kawakubo‎ et al.
  • Virus evolution‎
  • 2022‎

Characterizing the detailed spatial and temporal dynamics of plant pathogens can provide valuable information for crop protection strategies. However, the epidemiological characteristics and evolutionary trajectories of pathogens can differ markedly from one country to another. The most widespread and important virus of brassica vegetables, turnip mosaic virus (TuMV), causes serious plant diseases in Japan. We collected 317 isolates of TuMV from Raphanus and Brassica plants throughout Japan over nearly five decades. Genomic sequences from these isolates were combined with published sequences. We identified a total of eighty-eight independent recombination events in Japanese TuMV genomes and found eighty-two recombination-type patterns in Japan. We assessed the evolution of TuMV through space and time using whole and partial genome sequences of both nonrecombinants and recombinants. Our results suggest that TuMV was introduced into Japan after the country emerged from its isolationist policy (1639-1854) in the Edo period and then dispersed to other parts of Japan in the 20th century. The results of our analyses reveal the complex structure of the TuMV population in Japan and emphasize the importance of identifying recombination events in the genome. Our study also provides an example of surveying the epidemiology of a virus that is highly recombinogenic.


Remnants from the Past: From an 18th Century Manuscript to 21st Century Ethnobotany in Valle Imagna (Bergamo, Italy).

  • Fabrizia Milani‎ et al.
  • Plants (Basel, Switzerland)‎
  • 2023‎

This project originated from the study of an 18th century manuscript found in Valle Imagna (Bergamo, Italy) which contains 200 plant-based medicinal remedies. A first comparison with published books concerning 20th century folk medicine in the Valley led to the designing of an ethnobotanical investigation, aimed at making a thorough comparison between past and current phytotherapy knowledge in this territory.


14th century Yersinia pestis genomes support emergence of pestis secunda within Europe.

  • Cody E Parker‎ et al.
  • PLoS pathogens‎
  • 2023‎

Pestis secunda (1356-1366 CE) is the first of a series of plague outbreaks in Europe that followed the Black Death (1346-1353 CE). Collectively this period is called the Second Pandemic. From a genomic perspective, the majority of post-Black Death strains of Yersinia pestis thus far identified in Europe display diversity accumulated over a period of centuries that form a terminal sub-branch of the Y. pestis phylogeny. It has been debated if these strains arose from local evolution of Y. pestis or if the disease was repeatedly reintroduced from an external source. Plague lineages descended from the pestis secunda, however, are thought to have persisted in non-human reservoirs outside Europe, where they eventually gave rise to the Third Pandemic (19th and 20th centuries). Resolution of competing hypotheses on the origins of the many post-Black Death outbreaks has been hindered in part by the low representation of Y. pestis genomes in archaeological specimens, especially for the pestis secunda. Here we report on five individuals from Germany that were infected with lineages of plague associated with the pestis secunda. For the two genomes of high coverage, one groups within the known diversity of genotypes associated with the pestis secunda, while the second carries an ancestral genotype that places it earlier. Through consideration of historical sources that explore first documentation of the pandemic in today's Central Germany, we argue that these data provide robust evidence to support a post-Black Death evolution of the pathogen within Europe rather than a re-introduction from outside. Additionally, we demonstrate retrievability of Y. pestis DNA in post-cranial remains and highlight the importance of hypothesis-free pathogen screening approaches in evaluations of archaeological samples.


History of Inflammatory Bowel Diseases.

  • Giovanni Clemente Actis‎ et al.
  • Journal of clinical medicine‎
  • 2019‎

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal mucosa and unknown etiology. In this review, we identified three main eras in the IBD history. Between the 19th and the 20th century, the primary task had been the definition of the diagnostic criteria in order to differentiate the new entity from intestinal tuberculosis. In the 20th century, an intense and prolific therapeutic research prevailed, culminating in the introduction of biological drugs in the clinical setting. Since the beginning of the 21st century, traditional definition criteria have been challenged by holistic criteria in an effort to seek a still unattained cure. Centuries of worldwide efforts on IBD etiology and therapy search have culminated in this novel strategy.


Signatures of increasing environmental stress in bumblebee wings over the past century: Insights from museum specimens.

  • Andres N Arce‎ et al.
  • The Journal of animal ecology‎
  • 2023‎

Determining when animal populations have experienced stress in the past is fundamental to understanding how risk factors drive contemporary and future species' responses to environmental change. For insects, quantifying stress and associating it with environmental factors has been challenging due to a paucity of time-series data and because detectable population-level responses can show varying lag effects. One solution is to leverage historic entomological specimens to detect morphological proxies of stress experienced at the time stressors emerged, allowing us to more accurately determine population responses. Here we studied specimens of four bumblebee species, an invaluable group of insect pollinators, from five museums collected across Britain over the 20th century. We calculated the degree of fluctuating asymmetry (FA; random deviations from bilateral symmetry) between the right and left forewings as a potential proxy of developmental stress. We: (a) investigated whether baseline FA levels vary between species, and how this compares between the first and second half of the century; (b) determined the extent of FA change over the century in the four bumblebee species, and whether this followed a linear or nonlinear trend; (c) tested which annual climatic conditions correlated with increased FA in bumblebees. Species differed in their baseline FA, with FA being higher in the two species that have recently expanded their ranges in Britain. Overall, FA significantly increased over the century but followed a nonlinear trend, with the increase starting c. 1925. We found relatively warm and wet years were associated with higher FA. Collectively our findings show that FA in bumblebees increased over the 20th century and under weather conditions that will likely increase in frequency with climate change. By plotting FA trends and quantifying the contribution of annual climate conditions on past populations, we provide an important step towards improving our understanding of how environmental factors could impact future populations of wild beneficial insects.


Truffle renaissance in Poland - history, present and prospects.

  • Aleksandra Rosa-Gruszecka‎ et al.
  • Journal of ethnobiology and ethnomedicine‎
  • 2017‎

The use of truffles in Poland has a long tradition, yet due to some historical aspects, this knowledge was lost. Currently, truffles and truffle orchards are again receiving attention, and thanks to, e.g., historical data, they have solid foundations to be established. Publications relating to truffles between 1661 and 2017 were searched for in international and national databases, such as the database of PhD theses, Google Scholar, and catalogues of the National Library of Poland, the Jagiellonian Digital Library, the University Library of J. Giedroyc in Bialystok and the Lower Silesian Digital Library (DBC). A very meticulous survey of the literature on truffles showed that truffles have been known since at least 1661. In the 18th century, the fungi were considered a non-timber forest product. It is interesting to mention the impact of Polish Count Michał Jan Borch in understanding the nature of truffles. The whitish truffle (Tuber borchii) is named after him. The greatest number of publications regarding truffles can be observed at the first half of the 19th and 20th centuries. The fungi were present not only in cookbooks but also in scientific literature, and aspects of their ecology and medicinal use are considered. The "dark ages" for truffles, mainly for social reasons, occurred after the Second World War. In tough times, when Poland was under Soviet communist control (1945-1989), truffles as a luxurious product have been completely forgotten. However, at the end of the 20th century, truffles started receiving attention in Polish society. Yet, the real awakening began in the first decade of the twenty-first century when the first truffle orchards were established. One of them has already produced the first fruit bodies of summer truffle (Tuber aestivum). Truffles have been present in Polish culture for centuries. Their renaissance indicates the need for fostering sustainable agroforestry-centred initiatives aimed at helping truffle growers in growing the precious fungi and thus meeting market demands.


The history of the case report: a selective review.

  • Trygve Nissen‎ et al.
  • JRSM open‎
  • 2014‎

The clinical case report is a popular genre in medical writing. While authors and editors have debated the justification for the clinical case report, few have attempted to examine the long history of this genre in medical literature. By reviewing selected literature and presenting and discussing excerpts of clinical case reports from Egyptian antiquity to the 20th century, we illustrate the presence of the genre in medical science and how its form developed. Central features of the clinical case report in different time periods are discussed, including its main components, structure, style and author presence.


Dynamic colonization history in a rediscovered Isle Royale carnivore.

  • Philip J Manlick‎ et al.
  • Scientific reports‎
  • 2018‎

Island ecosystems are globally threatened, and efforts to restore historical communities are widespread. Such conservation efforts should be informed by accurate assessments of historical community composition to establish appropriate restoration targets. Isle Royale National Park is one of the most researched island ecosystems in the world, yet little is actually known about the biogeographic history of most Isle Royale taxa. To address this uncertainty and inform restoration targets, we determined the phylogeographic history of American martens (Martes americana), a species rediscovered on Isle Royale 76 years after presumed extirpation. We characterized the genetic composition of martens throughout the Great Lakes region using nuclear and mitochondrial markers, identified the source of Isle Royale martens using genetic structure analyses, and used demographic bottleneck tests to evaluate (eliminate redundancy of test). 3 competing colonization scenarios. Martens exhibited significant structure regionally, including a distinct Isle Royale cluster, but mitochondrial sequences revealed no monophyletic clades or evolutionarily significant units. Rather, martens were historically extirpated and recolonized Isle Royale from neighbouring Ontario, Canada in the late 20th century. These findings illustrate the underappreciated dynamics of island communities, underscore the importance of historical biogeography for establishing restoration baselines, and provide optimism for extirpated and declining Isle Royale vertebrates whose reintroductions have been widely debated.


Turning the tide: a history and review of hyperhidrosis treatment.

  • Kevin Yc Lee‎ et al.
  • JRSM open‎
  • 2014‎

Hyperhidrosis is a potential cause of severe physical and psychological distress, interfering in activities of daily living. Over the past 100 years, advances have been made regarding the treatment of this debilitating condition with some success. Surgical treatment with sympathectomy was successfully performed for hyperhidrosis in the early part of the 20th century, with various modifications of the technique over the past 100 years. Topical aluminium salt antiperspirants, anticholinergic medications, iontophoresis and botulinum toxin introduced less invasive ways to manage this condition. This historical review will enable dermatologists and non-dermatologists to manage this distressing condition.


Niche partitioning in sympatric Gorilla and Pan from Cameroon: implications for life history strategies and for reconstructing the evolution of hominin life history.

  • Gabriele A Macho‎ et al.
  • PloS one‎
  • 2014‎

Factors influencing the hominoid life histories are poorly understood, and little is known about how ecological conditions modulate the pace of their development. Yet our limited understanding of these interactions underpins life history interpretations in extinct hominins. Here we determined the synchronisation of dental mineralization/eruption with brain size in a 20th century museum collection of sympatric Gorilla gorilla and Pan troglodytes from Central Cameroon. Using δ13C and δ15N of individuals' hair, we assessed whether and how differences in diet and habitat use may have impacted on ape development. The results show that, overall, gorilla hair δ13C and δ15N values are more variable than those of chimpanzees, and that gorillas are consistently lower in δ13C and δ15N compared to chimpanzees. Within a restricted, isotopically-constrained area, gorilla brain development appears delayed relative to dental mineralization/eruption [or dental development is accelerated relative to brains]: only about 87.8% of adult brain size is attained by the time first permanent molars come into occlusion, whereas it is 92.3% in chimpanzees. Even when M1s are already in full functional occlusion, gorilla brains lag behind those of chimpanzee (91% versus 96.4%), relative to tooth development. Both bootstrap analyses and stable isotope results confirm that these results are unlikely due to sampling error. Rather, δ15N values imply that gorillas are not fully weaned (physiologically mature) until well after M1 are in full functional occlusion. In chimpanzees the transition from infant to adult feeding appears (a) more gradual and (b) earlier relative to somatic development. Taken together, the findings are consistent with life history theory that predicts delayed development when non-density dependent mortality is low, i.e. in closed habitats, and with the "risk aversion" hypothesis for frugivorous species as a means to avert starvation. Furthermore, the results highlight the complexity and plasticity of hominoid/hominin development.


Phylogeny and History of the Lost SIV from Crab-Eating Macaques: SIVmfa.

  • Kevin R McCarthy‎ et al.
  • PloS one‎
  • 2016‎

In the 20th century, thirteen distinct human immunodeficiency viruses emerged following independent cross-species transmission events involving simian immunodeficiency viruses (SIV) from African primates. In the late 1900s, pathogenic SIV strains also emerged in the United Sates among captive Asian macaque species following their unintentional infection with SIV from African sooty mangabeys (SIVsmm). Since their discovery in the 1980s, SIVs from rhesus macaques (SIVmac) and pig-tailed macaques (SIVmne) have become invaluable models for studying HIV pathogenesis, vaccine design and the emergence of viruses. SIV isolates from captive crab-eating macaques (SIVmfa) were initially described but lost prior to any detailed molecular and genetic characterization. In order to infer the origins of the lost SIVmfa lineage, we located archived material and colony records, recovered its genomic sequence by PCR, and assessed its phylogenetic relationship to other SIV strains. We conclude that SIVmfa is the product of two cross-species transmission events. The first was the established transmission of SIVsmm to rhesus macaques, which occurred at the California National Primate Research Center in the late 1960s and the virus later emerged as SIVmac. In a second event, SIVmac was transmitted to crab-eating macaques, likely at the Laboratory for Experimental Medicine and Surgery in Primates in the early 1970s, and it was later spread to the New England Primate Research Center colony in 1973 and eventually isolated in 1986. Our analysis suggests that SIVmac had already emerged by the early 1970s and had begun to diverge into distinct lineages. Furthermore, our findings suggest that pathogenic SIV strains may have been more widely distributed than previously appreciated, raising the possibility that additional isolates may await discovery.


The Hylemon-Björkhem pathway of bile acid 7-dehydroxylation: history, biochemistry, and microbiology.

  • Jason M Ridlon‎ et al.
  • Journal of lipid research‎
  • 2023‎

Bile acids are detergents derived from cholesterol that function to solubilize dietary lipids, remove cholesterol from the body, and act as nutrient signaling molecules in numerous tissues with functions in the liver and gut being the best understood. Studies in the early 20th century established the structures of bile acids, and by mid-century, the application of gnotobiology to bile acids allowed differentiation of host-derived "primary" bile acids from "secondary" bile acids generated by host-associated microbiota. In 1960, radiolabeling studies in rodent models led to determination of the stereochemistry of the bile acid 7-dehydration reaction. A two-step mechanism was proposed, which we have termed the Samuelsson-Bergström model, to explain the formation of deoxycholic acid. Subsequent studies with humans, rodents, and cell extracts of Clostridium scindens VPI 12708 led to the realization that bile acid 7-dehydroxylation is a result of a multi-step, bifurcating pathway that we have named the Hylemon-Björkhem pathway. Due to the importance of hydrophobic secondary bile acids and the increasing measurement of microbial bai genes encoding the enzymes that produce them in stool metagenome studies, it is important to understand their origin.


Controversial Past, Splendid Present, Unpredictable Future: A Brief Review of Alzheimer Disease History.

  • Félix Bermejo-Pareja‎ et al.
  • Journal of clinical medicine‎
  • 2024‎

Background: The concept of Alzheimer disease (AD)-since its histological discovery by Alzheimer to the present day-has undergone substantial modifications. Methods: We conducted a classical narrative review of this field with a bibliography selection (giving preference to Medline best match). Results: The following subjects are reviewed and discussed: Alzheimer's discovery, Kraepelin's creation of a new disease that was a rare condition until the 1970's, the growing interest and investment in AD as a major killer in a society with a large elderly population in the second half of the 20th century, the consolidation of the AD clinicopathological model, and the modern AD nosology based on the dominant amyloid hypothesis among many others. In the 21st century, the development of AD biomarkers has supported a novel biological definition of AD, although the proposed therapies have failed to cure this disease. The incidence of dementia/AD has shown a decrease in affluent countries (possibly due to control of risk factors), and mixed dementia has been established as the most frequent etiology in the oldest old. Conclusions: The current concept of AD lacks unanimity. Many hypotheses attempt to explain its complex physiopathology entwined with aging, and the dominant amyloid cascade has yielded poor therapeutic results. The reduction in the incidence of dementia/AD appears promising but it should be confirmed in the future. A reevaluation of the AD concept is also necessary.


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