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Research on disease-modifying treatments for Alzheimer’s disease has resulted in a series of failures over the past 20 years. However, in the last 4 years, five molecules have shown significant effects in phase II or III trials on clinical endpoints (i.e., slowing of cognitive decline). Among these five molecules, three are anti-amyloid immunotherapies: aducanumab, donanemab, and lecanemab responsible for a significant clearance of cerebral amyloid deposits. These results are still awaiting confirmation in order to put an end to the controversy surrounding the Food and Drug Administration’s decision to give conditional approval to aducanumab, which is considered premature by many specialists. Confirmation is also necessary to assess the benefit (magnitude of the slowing of decline) and risk (edema and cerebral hemorrhage induced by these treatments) balance of these molecules, which appears to be so far questionable after 18 months. Masitinib, a treatment whose probable mechanism of action is neuroinflammation, has also shown positive effects that need to be confirmed. Treatments targeting the tau protein are less advanced but weak signals are emerging from immunotherapies in the moderate stages of the disease (semorinemab). There is renewed hope for patients since it may not be unreasonable that these disease-modifying therapies will be part of the French therapeutic arsenal within the next five years.La recherche de traitements de fond (disease modifiers) de la maladie d'Alzheimer s'est soldée depuis 20 ans par une série d'échecs. Ces quatre dernières années, cinq molécules ont néanmoins présenté, lors d'essais de phase II ou III, des effets significatifs sur des critères cliniques (c'est-à-dire sur le ralentissement du déclin cognitif). Parmi ces cinq molécules, trois sont des immunothérapies anti-amyloïdes (l'aducanumab, le donanemab et le lecanemab) entraînant une clairance majeure des dépôts amyloïdes cérébraux. Néanmoins, ces résultats attendent encore confirmation afin de mettre fin à la controverse quant à la décision de la Food and Drug Administration de donner d'ores et déjà une autorisation conditionnelle à l'aducanumab, jugée prématurée par de nombreux spécialistes, et de pouvoir juger de la balance bénéfice (amplitude du ralentissement du déclin cognitif)-risque (œdèmes et hémorragies cérébrales induites par ces traitements) de ces molécules qui semble pour le moment discutable. Le masitinib, un traitement dont le mécanisme d'action probable est celui de la neuroinflammation, a aussi montré des effets positifs à confirmer. Quant aux traitements ciblant la protéine tau, leur développement est moins avancé mais des signaux faibles émergent d'immunothérapies aux stades modérés de la maladie (semorinemab). L'espoir renaît donc pour les patients avec la possibilité non déraisonnable de voir apparaître des traitements de fond de maladie d'Alzheimer au sein de l'arsenal thérapeutique français dans les 5 années à venir.

In recent years, failures in clinical settings to treat Alzheimer's disease (AD), create an urge for researchers to better understand AD pathophysiology. The toxic accumulation of amyloid-β peptide (Aβ) is one of the core features of this disease. Amyloidogenesis is involved in the disruption of neuronal network homeostasis and ultimately contributes to the cognitive impairments found in AD patients. To maintain this homeostasis, D-serine is essential; indeed, this amino acid is the preferential co-agonist of the glutamate N-methyl-D-aspartate receptor (NMDA-R) - a key player in the control of the functional plasticity of hippocampal neuronal networks. Several studies have directly associated D-serine with AD by reporting changed levels of D-serine or its converting enzyme - serine racemase (SR) - in blood, CSF or patients' brain tissue. However, the direction of the changes and the actual involvement of D-serine in AD are still debated. The aim of this thesis was to clarify the role of D-serine using an innovative animal model which displays amyloidogenesis with a deletion of SR (5xFAD/SR-KO mice). In vivo, ex vivo, and in vitro studies were conducted to have the most integrated view possible. To begin, this work showed the involvement of D-serine in several cognitive deficits found in aged 5xFAD mice with accentuated amyloidogenesis. These deficits were associated with an alteration in functional plasticity at the CA3-CA1 synapses of the hippocampus. Behavioral and functional impairments were not found in the 5xFAD/SR-KO mouse, indicating a major contribution of D-serine in amyloid pathophysiology. To finish, one of the major results of this work is the demonstration of an early and transient increase in hippocampal D-serine levels occuring together with the onset of amyloid accumulation in 5xFAD mice and which correlates with a progressive decrease in the recruitment of synaptic NMDA-Rs. The present work provides in vivo evidence of early involvement of D-serine in the functional disorders of hippocampal networks, induced in a context of accentuated amyloidogenesis and resulting cognitive deficits. Taken together, these results present a better understanding of AD pathophysiology associated with the early increase in Aβ level., Les échecs cliniques de ces dernières années concernant le traitement de la maladie d’Alzheimer (MA) poussent aujourd’hui les chercheurs à mieux en comprendre la physiopathologie. L’accumulation toxique du peptide amyloïde-β (Aβ) est l’une des caractéristiques cardinales de la MA. L’amyloïdogénèse est impliquée dans la perturbation de l’homéostasie des réseaux neuronaux et contribue à terme aux déficits cognitifs retrouvés chez les patients. L’acide aminé D-sérine est important pour cette homéostasie en étant le co-agoniste préférentiel du récepteur N-methyl-D-aspartate (NMDA-R) du glutamate, un acteur indispensable au contrôle de la plasticité fonctionnelle des réseaux neuronaux de l’hippocampe. Plusieurs études ont directement lié la D-sérine à la MA en rapportant une modification de ses taux ou ceux de son enzyme de conversion – la sérine racémase (SR) – dans le sang, le LCR ou bien le tissu cérébral de patients. Cependant, la direction des modifications et l’implication réelle de la D-sérine dans la MA restent encore débattues. Ce travail de thèse à préciser le rôle de cet acide aminé à l’aide d’un modèle animal innovant associant une amyloïdogénèse à une délétion de la SR (souris 5xFAD/SR-KO). Des études in vivo, ex vivo et in vitro ont été menées de manière à avoir une vision la plus intégrée possible. Dans un premier temps, les travaux ont montré l’implication de la D-sérine dans de nombreux déficits cognitifs retrouvés chez les souris 5xFAD âgées présentant une amyloïdogénèse accentuée. Ces déficits étaient associés à une altération de la plasticité fonctionnelle au niveau des synapses CA3-CA1 de l’hippocampe. Ces atteintes comportementales et fonctionnelles n’étaient pas retrouvées chez la souris 5xFAD/SR-KO indiquant une contribution majeure de la D-sérine dans la physiopathologie amyloïde. Un des résultats majeurs de ce travail est la mise en évidence d’une augmentation précoce et transitoire des taux hippocampiques de D-sérine apparaissant conjointement au début de l’accumulation amyloïde chez les souris 5xFAD et qui se corrèle à une diminution progressive du recrutement des NMDA-R synaptiques. L’ensemble de ces résultats permet une meilleure compréhension de la physiopathologie associée à l'augmentation précoce des taux d’Aβ, en apportant la preuve in vivo d'une implication précoce de la D-sérine dans les désordres fonctionnels des réseaux hippocampiques induits dans un contexte d’amyloïdogénèse accentuée et dans les déficiences cognitives qui en résultent.

Alzheimer's disease: a biological disorder? Alzheimer's disease often begins clinically with memory problems progressively followed by aphasia, apraxia, agnosia and behavioral disturbances. Recent studies of biological markers of cerebrospinal fluid or amyloid and tau PET imaging have shown that abnormalities can begin one to two decades before the onset of symptoms. This clinically silent phase is a biological phase where neurons fight the toxic effects of amyloid and tau accumulations as well as neuroinflammation. An ATN biological classification has been proposed (A: amyloid, T tau, N: neurodegeneration). The discovery of blood or other biomarkers should allow detection of this silent phase leading to the setup of therapeutic trials when brain lesions are minimal and neurons less affected, to be able to prevent the late cognitive decline of this disease.Maladie d’Alzheimer : une maladie biologique ? La maladie d’Alzheimer débute souvent cliniquement par des troubles de la mémoire suivis progressivement par une aphasie, une apraxie, une agnosie et des perturbations comportementales. Des études récentes de marqueurs biologiques du liquide cérébrospinal ou par tomographie par émission de positions (TEP) amyloïde et tau ont montré que les anomalies pouvaient commencer une à deux décennies avant l’apparition des premiers symptômes. Cette phase cliniquement silencieuse est une phase biologique où les neurones combattent les effets toxiques de l’accumulation amyloïde et tau ainsi que la neuro-inflammation. Une classification biologique ATN a été proposée (A : amyloïde, T : tau, N : neurodégénérescence). La découverte de biomarqueurs sanguins ou autres devrait permettre de détecter cette phase silencieuse et faciliter la mise en place d’essais thérapeutiques à un moment de l’évolution de la maladie par TEP où les lésions cérébrales sont plus minimes et les neurones moins atteints afin de prévenir le déclin cognitif ultérieur de cette maladie.

Therapeutic perspectives in Alzheimer's disease. Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders, affecting millions of people worldwide and leads to irreversible cognitive decline. The main neuropathological features of AD are the production of abnormal conformational protein (Amyloid Peptide, abnormally phosphorylated tau protein) leading to brain deposits, neuronal and synaptic loss and neurotransmitter deficiency including acetylcholine. The lesions occur 10 to 15 years before the first symptoms. The presence of specific markers in the cerebrospinal fluid is reflecting AD abnormalities (allow determining the presence of these abnormalities in living patients). Currently, only symptomatic treatments (acetylcholinesterase inhibitors and anti-glutamatergics) have been shown to be effective and have been marketed since the late 1990s. Since the early 2000s, therapeutic research has focused on the development of treatments that could modify the evolution of the disease either by increasing the elimination of abnormal proteins, or by decreasing their production and/or their diffusion into the brain. The two current targets are Aβ peptide and the abnormally phosphorylated Tau protein. Regarding the Aβ peptide, the therapeutic trials aimed at increasing its elimination were negative (ineffective) at the stage of major cognitive impairment but give hope for efficacy at the early stage of the disease. Therapeutic trials to reduce its production have been shown to be ineffective or deleterious to patients. Concerning the tau protein, the molecules under development aim at reducing its dissemination in the brain. Altogether, all potential disease modifying treatments are under development.Perspectives thérapeutiques dans la maladie d’alzheimer. La maladie d’Alzheimer est la cause la plus fréquente de troubles neurocognitifs majeurs, affectant des millions de personnes dans le monde et conduisant à un déclin cognitif irréversible. Les principales caractéristiques neuropathologiques de cette maladie sont la production de protéine de conformation anormale (peptide amyloïde, protéine tau anormalement phosphorylée) conduisant à des dépôts cérébraux, à une perte neuronale et synaptique et à un déficit en neurotransmetteur, notamment l’acétylcholine. Les lésions surviennent 10 à 15 ans avant les premiers symptômes, l’existence de marqueurs dans le liquide cérébrospinal spécifiques de la présence des anomalies de la maladie d’Alzheimer permettent de les objectiver chez les patients. Actuellement, seuls des traitements symptomatiques (inhibiteurs de l’acétylcholinestérase et antiglutamatergiques) ont démontré leur efficacité et sont commercialisés depuis la fin des années 1990. Depuis le début des années 2000, la recherche thérapeutique se concentre sur la modification des accumulations anormales en espérant modifier le cours évolutif de la maladie. Les essais thérapeutiques anti-Aβ visant à augmenter son élimination ont été négatifs (inefficaces) au stade d’altération cognitive majeure mais donnent un espoir d’efficacité à un stade plus précoce. Les essais thérapeutiques visant à diminuer sa production se sont révélés inefficaces ou délétères pour les patients. Les immunothérapies anti-tau en cours de développement ont pour objectif de diminuer sa dissémination dans le cerveau. Tous ces traitements potentiels sont encore en cours de développement.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in older patients, leading to progressive cognitive impairment. Brain amyloid and tau deposits are the main pathological features of the disease and may appear several decades before the onset of clinical symptoms. The biomarkers of AD, measured in the plasma or in the cerebrospinal fluid, reflect the brain accumulation of beta-amyloid and tau. Therefore, they enable early and more accurate etiological diagnosis when combined with brain neuroimaging and neuropsychological assessment. The new definition of AD brings biomarkers forward, shifting the focus from symptoms to brain changes in living patients. The growing body of evidence from longitudinal studies has established their ability to improve the accuracy of AD diagnosis but also to predict the progression of cognitive impairment. The biomarkers of AD are also important for recruiting participants who are at increased risk of developing AD dementia in drug trials. Beyond their role in clinical research, these tools have been increasingly used for several years in clinical practice in secondary and tertiary-referral memory clinics. However, interpreting the results of AD biomarkers may be delicate in the oldest old patients with comorbidity. A tailored, patient-centered decision is mandatory in these situations. Complicated ethical issues may also arise in using these biomarkers in asymptomatic subjects. In the absence of clear guidelines for their utilization, we hereby discuss their potential interests and limitations in older adults.

Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease caused by vascular deposits of Aß-amyloid peptides in the walls of cortical and leptomeningeal vessels. Advancing age is the strongest known clinical risk factor for developing CAA. This devastating disease occurs frequently in elderly people, and is a frequent cause of symptomatic lobar intracerebral hemorrhage (ICH), cognitive impairment and transient focal neurological episodes. Typical cerebral MRI findings include lobar intracerebral hemorrhages and neuroimaging biomarkers of CAA (lobar cerebral microbleeds, cortical superficial siderosis, white matter hyperintensities, dilated perivascular spaces and microinfarcts). In the absence of direct neuropathological examination, the most commonly used criteria for CAA diagnosis are the modified Boston criteria based on clinical and MRI data. To date, no specific treatment is available to prevent bleeding or cognitive decline. Thus, management is mainly based on strict blood pressure control. Anticoagulation should usually be avoided in patients with a diagnosis of CAA and symptomatic lobar ICH. The risk/benefit ratio evaluation at individual level of antiplatelet agents is also required.

International audience; The role of biomarkers in clinical research was recently highlighted in the new criteria for the diagnosis of Alzheimer's disease. Cerebro-spinal fluid (CSF) biomarkers (total Tau protein, threonine 181 phosphorylated Tau protein and amyloid Aβ1-42 peptide) are associated with cerebral neuropathological lesions observed in Alzheimer's disease (neuronal death, neurofibrillary tangle with abnormal Tau deposits and amyloid plaque). Aβ1-40 amyloid peptide dosage helps to interpret Aβ1-42 results. As suggested in the latest international criteria and the French HAS (Haute Autorité de santé) recommendations, using theses CSF biomarkers should not be systematic but sometimes could be performed to improve confidence about the diagnostic of Alzheimer's disease in young subjects or in complex clinical situations. Future biomarkers actually in development will additionally help in diagnostic process (differential diagnosis) and in prognostic evaluation of neurodegenerative diseases.

To improve the clinical detection of Alzheimer's disease (AD) new diagnostic criteria have been proposed, based on biomarkers of synaptic dysfunction, AD-related neurodegeneration, and Aβ cerebral amyloidosis. Magnetic resonance imaging (MRI) and position emission tomography (PET) neuroimaging can be configured as powerful means for the detection of medial-temporal atrophy, reduced uptake of 18F-FDG PET or and increased retention of Aβ amyloid protein by amyloïd-PET. In this review, we will discuss these promising techniques that allow assessing in vivo AD pathology and help clinicians to better diagnose and follow-up patients, particularly in clinical trials using disease-modifying treatments.

The cerebrospinal fluid levels of amyloid beta 1-42 (Aβ1-42), total tau and tau phosphorylated at threonine 181 (ptau181) are well established biomarkers of cerebral amyloid pathology and tau related neurodegeneration, two hallmarks of Alzheimer's disease. These biomarkers can help to improve diagnostic accuracy and consequent decisions on counseling, support, and therapy of patients with mild cognitive impairment and dementia. The use of biomarkers is part of the proposed new criteria of AD diagnosis. It may be particularly helpful in cases of atypical clinical presentation and uncertain diagnosis, and if an important benefit for the patient is expected. The ongoing development of new biomarkers based on less or non-invasive procedures will allow for a larger use of biomarkers to improve the diagnosis of cognitive impairment.

Improvement of the analytical methods and routine use of immunohistochemistry have demonstrated that most neurodegenerative diseases, known to-day, are characterized by the accumulation of one or several specific proteins for example Abeta peptide and Tau protein in Alzheimer disease, alpha-synuclein in Parkinson disease and dementia with Lewy bodies, TDP-43 in a large group of fronto-temporal dementia. In the case of Alzheimer and Lewy body disease, recent data suggest that misfolding of Abeta peptide, of Tau protein or of alpha-synuclein may propagate to the normal protein of the host in a way that reminds the propagation observed in prion diseases.

The aim of this article is a critical review of the main pathogenetic issues debated in Alzheimer disease, with a focus on the clinical perspectives that could derive from. The pertinence of the amyloid cascade hypothesis as a unique and causal explanation of cognitive deterioration is challenged in the light of recent therapeutic failures of clinical trials and increasing role of tau protein in clinical expression. The detection of very early and possibly preclinical stages of the disease emerges as a necessary condition for the efficacy of future amyloid or tau-oriented curative strategies. In this respect, the possibility of finding individual vulnerability markers--in the group of patients with "mild cognitive impairment" or even in cognitively intact subjects--represents a major challenge of the clinical research in this field.

The diagnosis of Alzheimer's disease has long been considered a diagnosis of probability, as the definitive diagnosis can only be established by histopathological examination. However, the development of in-vivo biomarkers, considered a reflection of physiopathological processes, has changed our view of the disease. New criteria have recently been proposed that integrate such biomarkers as found in the cerebrospinal fluid (CSF) using new diagnostic tools such as magnetic resonance imaging (MRI), brain scintigraphy, FDG-positron emission tomography (PET) and PET amyloid ligand uptake studies. The value of these new criteria for the diagnosis of prodromal Alzheimer's disease and the prospect of disease-modifying drugs are also discussed.

The treatment and the diagnosis of brain diseases like Alzheimer's are nowadays a real challenge. In fact the brain delivery of drugs or contrast agents is very difficult due to the low permeability of the blood brain barrier (BBB) which is situated in brain capillaries and assures a high protection of the brain against exogenous molecules or particles. Among the different strategies that have been proposed to increase the passage of drugs through the barrier, a non-invasive one is based on the use of colloidal carriers called nanoparticles. These nanometric objects chosen for their biocompatibility and biodegradation exhibit several fates and distributions according to their composition and structures, defining the three generations of nanoparticles described up to now. The application of nanoparticles to the treatment and diagnosis of Alzheimer's disease is actually investigated in a European project. Recent studies reveal that more than 3 million people in Europe are afflicted with Alzheimer's disease. New treatments are urgently needed, as are diagnostic tests that can detect the disease earlier. The strategies developed in this project are based on the design of new carriers able to pass through the BBB and to interact with β-amyloid peptide in order to (1) detect already formed brain plaques, aiming to diagnose the disease and (2) avoid peptide aggregation which is toxic for neurons, for the purpose of discovering a new therapeutic approach for Alzheimer's disease.

The blood-brain barrier (BBB), which isolates the brain from the whole body, restricts exchanges between the brain and the peripheral compartments. Several studies highlight the importance of this barrier in neurodegenerative diseases such as Alzheimer's disease (AD). This pathology is characterized by an abnormal accumulation and aggregation of Aβ peptides which contribute to the neurodegenerative processes and the BBB seems to play a key role for the brain Aβ peptides metabolism. This review focuses on recent data demonstrating the important role of the BBB in AD, suggesting that this barrier is a possible new therapeutic target in this disease.

Alzheimer's disease (AD) is the first cause of dementia that leads to insidious and progressive loss of memory and cognitive functions. In the early stages of AD, there is a strong correlation between memory impairment and cortical levels of soluble amyloid-β peptide oligomers (Aβ). It has become clear that Aβ disrupt glutamatergic synaptic function, which in turn may lead to the characteristic cognitive deficits. Conversely, experiments in rodents have conforted the notion that Aβo impairs synaptic transmission and plasticity, and that mouse models with increased production of these oligomers display cognitive impairment. Many studies have attempted to determine the mechanisms by which Aβo disrupt synaptic plasticity and mediate their detrimental effect, but the actual pathways are still poorly understood. Here we review this thriving area of research which aims at understanding the mechanisms of synaptic dysfunction in the early phase of AD, and its consequences on the activity of neural circuits.

Cerebrospinal fluid (CSF) biomarkers have been extensively studied as diagnostic markers for Alzheimer's disease (AD). However, results are variable probably due to lumbar puncture (LP) procedure, CSF collection and transport. This intercenter variability highlights the need for an efficient standardization of clinical and technical procedures. The aims of this study were firstly to compare the LP procedure and CSF transport process in all French Memory Centers and secondly to evaluate the incidence of LP side effects in 100 patients with cognitive disturbances.LP practice and side effect prospective questionnaires were sent to all French Memory Centers in May 2010. Memory Centers were asked about their LP procedure. The prospective study over a three-week-period has evaluated the LP feasibility and side effects. All data were collected until the end of July 2010.The answers of 18 out of 26 Memory Centers were collected. Although, these centers did not have the same LP procedure and CSF transport, the majority of them proceeded according to Innogenetics's advices concerning the use of polypropylene tubes and transport duration but not sample conditioning. Polypropylene tubes were different from one center to the other. CSF volume, pharmacological premedication and prevention of post-LP syndrome were variable in all responding centers. The prospective study carried out in 100 patients revealed a very good LP acceptability (93/100 patients). LP feasibility was 97 % (90/93) and failed LP were consequently performed with success using radiological scopes. Three minor complications were observed.All French Centers complied with Innogenetics' recommendations for pretechnical CSF procedures; however each Center put in place its own procedure that was different one center to the other. It will be very interesting to compare cut-off and result values for Aβ, tau and phosphorylated tau protein on threonine 181 between several centers that used their own procedures. Acceptability and safety were very good in our short but significant prospective study. These results confirm the data of Zetterberg et al., 2010.

Dementia of Lewy bodies (DLB) is the second cause of degenerative dementia. There is many clinical presentation of the disease. Brain single photon computed tomography (SPECT) is a simple way to investigate routinely the cerebral blood flow. On cerebral perfusion SPECT, DLB is accompanied by diffuse cortical hypoperfusion predominantly at the posterior cortex and may affect the associative and primary visual areas in relation to neuronal loss or dysfunction. DLB patients have striatal hypofixation on cerebral neurotranmission SPECT-DaTSCAN(®), related with dopaminergic loss. Brain SPECT is useful in the differential diagnosis between DLB and other dementia.

The diagnosis of Alzheimer's disease (AD) currently relies on clinical criteria that are primarily based on the presence of an amnestic syndrome of the mesial temporal lobe type. In recent years, new diagnostic tools have been developed, such as the possibility of measuring a set of proteins directly involved in the pathophysiological process of AD. A profile suggestive of AD has been defined, characterized by decreased beta-amyloid peptide, combined with increased Tau protein and phopho-Tau.According to current data available in the medical literature, the potential usefulness of CSF biomarkers in the common forms of AD fulfilling usual clinical criteria remains modest. In contrast however, they could be of significant help in the diagnosis of early-onset AD, in particular in atypical forms with prominent non-memory impairment (involving vision, language or behavior). In addition, due to their close relationship with the pathological process, they bring useful prognosis information upon the aggressiveness of the disease.Taken together, in the current state of knowledge, use of CSF biomarkers in clinical practice should first be recommended for the assessment of early-onset cognitive disturbances, in particular when initial symptoms are of a non-memory type. Their development, however, offers new avenues in the fields of clinical and pharmacological research.

Alzheimer's disease is a neurodegenerative disorder characterized by neuropathological lesions: amyloid deposits and neurofibrillary degeneration. However, the links between these two brain hallmarks are still poorly understood. Until now, mainly amyloid pathology has been targeted un many clinical trials without any success. Both new therapeutic strategies and diagnosis improvement are needed.

Senile plaques that accumulate in cortical and sub-cortical areas of Alzheimer's disease (AD)-affected brains are mainly composed of a set of hydrophobic and aggregated peptides referred to as amyloid β-peptides (Aβ). These peptides derive from the proteolytic processing of a transmembrane precursor, the β-amyloid precursor protein (βAPP) that undergoes subsequent cleavages by β- and γ-secretases, respectively. Another enzyme called α-secretase cleaves βAPP in the middle of its Aβ sequence and thereby, lowers its production. Once produced, Aβ peptides can be cleared off by neuropeptidases, mainly insulin-degrading enzyme and neprilysin, or, alternatively, can be biotransformed upon N-terminal truncation by exopeptidases and subsequent cyclisation of the glutamate in position 3. Here, we will describe the nature of the various proteolytic activities documented above and we will discuss briefly their advantages and drawbacks as putative therapeutic targets in AD.

International audience; What is an innovative therapeutics for the Alzheimer's disease? An already used therapeutics which appeals to a recent and innovative concept or a therapeutic still putative based on tracks turned out experimentally but which still ask to be supported by man? Some therapeutic used at present are based on often former observations (anti-acetylcholinesterasic strategy) or more recent (antiglutamatergic strategy) but cannot be really considered as therapeutic innovative. They will be reviewed thus quickly because treated somewhere else. Potentially innovative therapeutics arise from recent headways and are there often only because of their stammerings. If the biology of Tau proteins is well-known, its therapeutic approach is little developed. On the contrary, therapeutics approaches turns essentially around the peptide amyloid, whether its training or the cellular consequences of its overproduction. This article is centred on the various therapeutic approaches which we can prospectively propose and which are very promising for some and for the others, collide with abstract or theoretical problems which will be approached here.

The brain lesions associated with Alzheimer's disease are caused by extracellular accumulation of Abeta peptide and intracellular accumulation of tau protein. Abeta peptide makes the core of the senile plaque (the "focal deposit"); it is also present in the extracellular "diffuse deposits" and in the vessel walls. Neurofibrillary tangles, and neuropil threads are composed of hyperphosphorylated tau that also accumulates in the processes of the corona of the senile plaque. The Abeta deposits first involve the neocortex, while the tau pathology is initially found in the hippocampal region. Abeta deposits first occur in the neocortex, while intracellular tau accumulation mainly affect the hippocampal region. Abeta peptide deposits are initially found in all the neocortical areas, then involve the hippocampus and the subcortical nuclei. Tau lesions successively involve the hippocampal regions, multi- and uni-modal areas and finally the primary cortices in stereotyped stages. Mutations of APP, the precursor of Abeta peptide, cause autosomal dominant familial Alzheimer disease, suggesting that a cascade of reactions link Abeta overproduction, tau pathology and the clinical phenotype. Transgenic mice bearing the mutated human APP gene (APP mice) develop A deposits. Systemic injection of Abeta peptide prevents the deposition of Abeta peptide. However, a clinical trial had to be interrupted when meningoencephalitis occurred in a significant proportion of treated patients. Post mortem studies showed a relative scarcity of Abeta deposits. Forthcoming immunotherapy studies should soon show whether the prevention of Abeta deposition interrupts disease progression.

Current treatments for Alzheimer's disease aim to compensate for biochemical deficits in the brain. They are purely symptomatic and restore the central cholinergic deficit. Acetylcholinesterase inhibitors have modest but significant efficacy on cognitive disorders, activities of daily living, and the global clinical impression. Glutaminergic receptor antagonists are used for more advanced forms. Future treatments may be curative, acting specifically on the amyloid cascade. Secretase inhibitors and immunotherapy are in the pipeline. Trials will begin within a few months and will open up new perspectives.

Alzheimer's disease is characterized by the presence of neurofibrillary tangles and senile plaque in the brain. Both disorders must be present in order to confirm a clinical diagnosis of Alzheimer's disease. Neurofibrillary tangles contain hyperphosphorylated microtubule-associated protein tau, while senile plaque contains a core of amyloidpeptide derived from its precursor. Phosphorylation of both amyloid precursor protein and tau represents a biochemical link between the two characteristic lesions of Alzheimer's disease.

The increased prevalence of the sporadic form of Alzheimer's disease (AD) has become a significant health issue in the elderly population. The need for early diagnosis is imperative because this, along with the development of novel therapeutic treatments, would permit the rapid and perhaps more efficient treatment of these debilitating disorders early on.Over the last decade, the potential use of certain biomarkers in the cerebrospinal fluid (CSF), and more recently, in the plasma has been investigated. Among the candidates studied includes the neurotoxic amyloid beta peptide and the Tau protein. However, although these two proteins have been clearly shown to be directly related to the pathophysiology of this disorder, it has proven difficult to establish a clear relationship between plasma or CSF levels of Abeta and Tau and the incidence and severity of AD in patients. This is due in part to differences in methodologies related to the detection sensitivity, as well as the variations in the biological data and consequent interpretation of the biochemical and biological data. Peripheral cells, in particular platelets and skin fibroblasts, could be an alternative solution as peripheral biological markers for the early diagnosis of AD. These cells are easily accessible from patients. Furthermore, they would provide a means not only to validate potential therapeutic strategies, but also to study the mechanisms involved in the development of AD, including APP processing.A combined strategy using both a fundamental mechanistic and an analytical approach of patient peripheral cells will allow the identification of new biological markers for AD, and hence permit immediate therapeutic strategies to be implemented.

Early diagnosis of Alzheimer's disease remains a tactful poser. In order to clarify the importance of beta amyloid protein dosage (Abeta1-42) and protein tau (t-tau) in such pathology, we have rigorously studied three well recruited populations that match in age: healthy controls (n = 32), Alzheimer patients (n = 87) and non Alzheimer dementia (n = 31) patients. The combination of Abeta1-42 and t-tau at baseline yielded a sensitivity of 85.29 % for detection of Alzheimer's disease and the specificity was by 96.77 % to differentiate controls. So the combination of these tow markers helps in the diagnosis of Alzheimer because of the high specificity and sensibility of this method.

Neurodegenerative diseases are more and more prevalent in our aging societies. A rapid overview of the etiology of many neurodegenerative diseases like Alzheimer, Parkinson, Huntington disease and amyotrophic lateral sclerosis suggests a tight link with mitochondrial dysfunction. Since it has been recently demonstrated that activation of the SIRT1/PGC-1 pathway, in a metabolic context promotes mitochondrial function, we performed a detailed literature review on the implication of this pathway in neurodegeneration. Interestingly, transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities. As evidenced from independent investigations, enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides, the hallmark of Alzheimer disease, in cultured murine embryonic neurons. In addition, several studies suggest that resveratrol, a specific activator of SIRT1, could have protective effects in animal models of neurodegenerative diseases. Taken together, these results strongly suggest that the modulation of the SIRT1/PGC-1 pathway, which has not been well documented in the central nervous system, could become the cornerstone for new therapeutical approaches to combat neurodegeneration.

Alzheimer's disease is worldwide the leading cause of dementia in the elderly. Senile plaques and neurofibrillary tangles are together with neuronal loss and cortical atrophy characteristic neuropathological features of the disease. Senile plaques contain beta-amyloid (Abeta) peptide which is produced by cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. Neurofibrillary tangles are twisted helicoidal strands of hyperphosphorylated tau protein, a microtubule-associated protein. Both pathogenic arms which we describe are interrelated and Abeta deposition seems to potentiate tau pathology. Tangle and plaque formation is influenced by various factors including reciprocal interactions, genetic factors, inflammation and reactive oxygen species. A better understanding of the cellular and molecular cascade which leads to the neuropathological lesions of Alzheimer's disease has led to novel disease-modifying treatment strategies. They yield varying, though encouraging, results and target various stages of the pathological process. Future cooperation between basic, clinical and pharmacological research should allow the development in a foreseeable future of strategies that can halt, or even prevent, this devastating disorder.

To review the current concepts in the biological diagnosis of Alzheimer's disease (AD) and related disorders.As new therapeutics specific of AD may be available soon, early diagnosis of AD in the context of mild cognitive impairment (MCI) or dementia appears to be challenging. The high amount of atypical clinical forms of AD leads to develop new tools allowing in vivo diagnosis. New CerebroSpinal Fluid (CSF) biomarkers seem to reflect specific aspects of deep neuropathological changes observed in AD, i.e. amyloid deposits and neurofibrillary tangles. Amyloid beta-peptide 1-42 (Abeta(1-42)) and hyperphosphorylated tubulin associated unit (tau) isoforms appear to be the most sensitive and specific CSF biomarkers, the combination of these biomarkers depicting the best diagnosis value for AD. These molecules are also efficient in the prediction of the conversion from the MCI state to the dementia state of AD. Combined to clinical and neuro-imaging information, CSF biomarkers appear thus to be highly relevant in improving the early etiological diagnosis of dementia.The current research focalises on the development of new molecules coming from Abeta and tau protein families, in the CSF and in the serum, as well as molecules reflecting other pathological metabolism changes, as alpha-synuclein in Lewy Body Disease. The diagnosis value of CSF biological markers is so promising that they have been recently included in the research diagnosis criteria of AD.

Cerebral amyloid angiopathy is characterised by the presence of protein deposits in the wall of the cerebral vessels. Sporadic forms with deposits of Abeta peptide are the most frequent. The diagnosis of cerebral amyloid angiopathy is only certain when amyloid deposits can be visualized on cerebral tissue by biopsy, that appears in most circumstances to carry too many risks for the expected benefits, or post mortem. The clinical diagnostic criteria are advanced age, morphology of the intracerebral hematomas, occurrence of several episodes of intracerebral haemorrhages and presence of dementia. Recent progresses in the field of MRI make the diagnosis of cerebral amyloid angiopathy easier and more accurate. MRI should be more frequently performed in aged patients.

Numerous evidences indicate that the phenotype of a neurodegenerative disease and its pathogenetic mechanism are only loosely linked. The phenotype is directly related to the topography of the lesions and is reproduced whatever the mechanism as soon as the same neurons are destroyed or deficient: the symptoms of Parkinson disease are mimicked by any destruction of the neurons of the substantia nigra, caused for instance by the toxin MPTP. This does not mean that idiopathic Parkinson disease is due to MPTP. In the same way, mouse lines such as Reeler, Weaver and Staggerer in which ataxia occurs spontaneously does not help to understand human ataxias: now that mutations responsible for these phenotypes have been identified, it appears that one is responsible for lissencephaly (mutation of the reelin gene) and the other two have no equivalent in man. Therapeutic attempts, however, rely on the understanding of the pathogenetic mechanisms. Introducing a mutated human transgene in the genome of an animal has, in many instances, significantly improved this understanding. Transgenic mice have proven useful in reproducing lesions seen in neurodegenerative disease such as the plaques of Alzheimer disease (in the APP mouse which has integrated the mutated gene of the amyloid protein precursor), the tau glial and neuronal accumulation (seen in cases of frontotemporal dementias due to tau mutation), the nuclear inclusions caused by CAG triplet expansion (seen in the mutation of Huntington disease and autosomal dominant spinocerebellar ataxias). These recent advances have fostered numerous therapeutic attempts. Transgenesis in drosophila and in the worm Caenorhabditis elegans have opened new possibilities in the screening of protein partners, modifier genes, and potential therapeutic molecules. However, it is also becoming clear that introducing a human mutated gene in an animal does not necessarily trigger pathogenetic cascades identical to those seen in the human disease. Human diseases have to be studied in parallel with their animal models to ensure that the model mimic at least a few original mechanisms, on which new therapeutics may be tested.

Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.

This review is devoted to the relationships between phenotype and genotype of the autosomal dominant forms of Alzheimer's disease caused by mutations of presenilins (PSs) and amyloid precursor protein (APP) genes. A first part examines the clinical characteristics mainly the early age of onset and argues about the diversity of age of onset between different mutations and also between patients bearing the same mutation in large families. The second part reports several arguments demonstrating that the main effect of the PSs and APP mutations is the elevation of Ab42 peptide. The pathological and behavioral effects observed in transgenic APP or PSs animals suggest that intra cellular deposits of Ab42 play a role in the pathophysiological process.

Peripheral markers for Alzheimer's disease are of interest to confirm the diagnosis, to perform epidemiological screening, to identify distinct groups of patients, to predict the outcome of the disease, to monitor its progression and its sensibility to treatment and to give help in performing studies on the relationship between brain and behaviour and on the pathophysiology of the Alzheimer's disease. The ideal biomarker for Alzheimer's disease should detect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases and be confirmed by at least two independent studies; should be as sensitive and specific than the clinical diagnosis (about 85% and 80%), reliable, reproducible, simple to perform, inexpensive and non invasive (studies on blood, urine, saliva, or buccal scrapings) or moderately invasive (skin, rectal biopsies, bone marrow samples, or cerebrospinal fluid). Such a marker has not yet been found. In this paper we present those markers which come closest to fulfilling criteria for a useful biomarker, keeping in mind that these criteria depends on what purpose it is used (screening, prediction, diagnosis, monitoring, pathophysiological studies.) and that the finding of a good marker depends on the understanding of the disease.

Recent data in amyloid research have shed light on the amyloid substance and have broadened our knowledge on the mechanism of amyloid deposition.Despite uniform physical properties relating to the presence of beta-pleates, amyloid deposits are chemically heterogeneous and have different origins; additional types will probably be described in the future. Immunohistochemical techniques using specific antisera for each of the major protein present in fibrils could help greatly to subclassify these disorders. In most circumstances, a circulating precursor protein may result from overproduction of either intact or aberrant molecule, a reduction in its degradation or excretion, or genetic abnormalities associated with variant proteins. The cleavage of protein precursor molecules of the protein component of amyloid fibrils characterizes amyloidogenesis, though it is not necessary for some amyloidosis forms. This review summarizes advances in the understanding of the nature of amyloid substances, the mechanism of amyloid deposition and the principal pathogenic hypothesis.SAP component is common in all amyloidosis and may be the target for future therapy.

Cerebral amyloidoses affects only the central nervous system, with rare exceptions. Most of them are related to A beta deposits. They usually occur in the absence of genetic defect in the precursor of A beta. The prevalence and density of A beta deposits increase during the aging process, and in Alzheimer's disease. This A beta amyloidosis has never been transmitted. In contrast, PrPres occurs as a sporadic or genetic event, and induces transmissible amyloidoses (Creutzfeldt-Jakob's disease and other disorders related to non conventional agents). PrPres may be the infectious agent itself (prion hypothesis). Other proteins are rarely responsible for cerebral amyloidoses. The fascinating hypothesis that a common mechanism would be acting in all cerebral amyloidoses has not yet been confirmed.

Neurofibrillary changes, labelled by antitau antibodies and deposits, labelled by anti-A beta antibodies, were counted in 6 cortical areas in 29 prospectively studied cases (Charles Foix Longitudinal Study). The intellectual status had been assessed by the Blessed test score; 10% of the cases were found to be normal (score27), 10 other percents were deeply demented (score2) and the other cases were regularly distributed over the intermediate values. Tau positive neurofibrillary changes were present in the hippocampus and in the parahippocampal gyrus even in intellectually normal cases. They were found in a primary sensory cortex (the visual cortex) only in the most severely affected cases. Associative cortices were spared in the normal cases and in the least demented patients. They were involved only at a critical value of the Blessed Test Score. A beta deposits involved more areas than the neurofibrillary pathology and their distribution was less systematically organized. Their density was poorly correlated with the intellectual status. Neuritic plaques, made of an amyloid core and of a crown of tau positive neurites, were present only in those areas that also contained neurofibrillary tangles. Our findings support the contention that neurofibrillary pathology, involving a set of short range, "feed-backward", cortico-cortical connections, is a close correlate of dementia. The role of A beta deposits remains unclear. Although poorly connected with dementia, they could be the remote initiator of the pathological cascade that leads to the neurofibrillary pathology, immediate cause of the cortical dysfunction.

Inclusion body myositis has been recently recognized as a clinical entity although its exact definition remains uncertain. Initially considered to be an inflammatory dermatomyositis, inclusion body myositis can actually take on three specific forms: disseminated muscle atrophy and weakness, pseudopolymyositis, or pseudo-degenerative disease. Inclusion body myositis is different from non-inflammatory neuromuscular diseases with vacuoles. Abnormal deposits are seen within the muscle fiber may contain amyloid substance, beta-amyloid precursor, ubiquitin, antichymotrypsin, protein tau, apolipoprotein E and even prions. The signification of these deposits is unknown. Deletions in mitochondrial DNA have been demonstrated but do not appear to play a causal role. More and more hereditary forms are being recognized and certain may be related to an abnormality in chromosome 9.