BackgroundThe quantification of cerebrospinal fluid (CSF) biomarkers (Amyloid beta peptides [Aß1‐40 and Aß1‐42], t‐tau and p‐tau(181)) is progressively implemented in specialized laboratories as an aid for the multidisciplinary diagnosis of Alzheimer’s disease (AD). There is however a diversity of practices between centers related to pre‐analytical and analytical conditions, the calculation of ratios between analytes, the applied cut‐off, or the use of interpretation scales. Finally, for the same biochemical profile, the interpretation and reporting of results may differ from one center to another, which may raise questions about the commutability of the tests. So far, no consensus has been reached between the different laboratories involved to define the most appropriate conclusions/comments based on the profile of the quantified biomarkers.This work is an essential step towards a consensual harmonization of clinical reporting after CSF analysis in the context of AD diagnosis, as advocated by the "Biofluid Based Biomarkers PIA" working group of the Alzheimer's Association.MethodWe obtained, by means of a questionnaire, a description of the pre‐analytical and analytical protocols and examples of reporting from 40 centers located in 15 countries, i.e. in the majority of countries that have implemented clinical CSF tests for the diagnosis of AD. We then adopted a consensus approach to propose harmonized comments corresponding to different AD CSF biomarker profiles observed in patients.ResultPre‐analytical procedures were very similar, among the centers. Regarding the analytical part, more than 88% of the laboratories use automatized immunoassays and more than 83% measure Aß1‐40 and compute the Aß1‐42/Aß1‐40 ratio, in addition to the three core biomarkers (Aß1‐42, t‐tau and p‐tau(181)). The cut‐off values of biomarkers used by the different laboratories are widely dispersed. Delay before sending back the results is lower than 1 week in more than 34% of the laboratories.ConclusionOur results highlight the state of the art in terms of clinical CSF analysis in the context of AD. Harmonization of clinical reporting between different centers could benefit AD care, prevention and treatment strategies, as a common terminology will allow a better assessment of the prevalence of AD and the contribution of biochemical biomarkers to its diagnosis.

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Introduction: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to ADrelated biomarker traits indicative of AD-relevant pathophysiological processes. Methods: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).Results: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.Discussion: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

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Background: The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to effectively treat potentially life threatening etiologies or identify underlying neurodegenerative disease. We intended to evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric patients hospitalized due to acute or subacute admission indications (WHO Trials Registry DRKS00005041). Methods: Eighty-one inpatients (55 females, 86.1 6 5.5 years) without history of cognitive complaints prior to hospitalization were recruited in 10 different acute geriatric centers. Primary inclusion criterion was a clinical hypothesis of Alzheimer's disease (AD), cerebrovascular disease (CVD) or mixed AD+CVD etiology (MD) which remained uncertain after standard diagnostic workup. Additional diagnostic testing performed after enrollment into the study included detailed neuropsychological testing, structural magnetic resonance imaging (MRI) for characterization of cerebrovascular pathology and brain atrophy as well as positron emission tomography (PET) with the glucose analog 2-[F-18]-fluoro-2-deoxy-Dglucose (FDG) for the detection of a regional metabolic pattern of synaptic dysfunction indicative of AD. An interdisciplinary academic expert team established a probable etiological diagnosis (non-neurodegenerative, AD, CVD, MD) integrating all available data from diagnostic standard procedures and additional tests. Fully automatic multimodal classification based on a Random Undersampling Boosting (RUSBoost) approach was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis. Results: Automatic classification based on all diagnostic standard procedures combined reproduced the etiologic expert diagnosis in 31.4 % of the patients (p ¼ 0.100, chance level is 25 %). Automatic classification based on MRI (cerebrovascular scores) or FDG PET alone provided an accuracy of about 45 % (both p ¼ 0.001). A statistically significant improvement to 76.4 % accuracy was achieved by the integration of all modalities (p ¼ 0.001). Conclusions: These findings indicate a substantial improvement of diagnostic accuracy in the assessment of uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG PET into the diagnostic process.Background: Subjects with mild cognitive impairment (MCI) and abnormal levels of CSF Ab42, Ab42/t-tau and/or Ab42/p-tau ratios are at higher risk of cognitive decline. Diffusion tensor imaging (DTI) is a quantitative MRI technique that enables the in vivo identification of white matter (WM) tissue alterations and can help in identifying early changes in MCI. The goal of this study was to characterize microstructural features of amnestic MCI patients with three different risk of cognitive decline, defined accordingly to their bas...

Background Neuronal cell death during Alzheimer disease (AD) causes the release of cytosolic proteins, particularly glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which forms highly cytotoxic detergent-insoluble complexes with amyloid-β (Aβ) and promotes neurodegeneration. Methods We detected and quantified the complex formation between Aβ and GAPDH released from brain tissue of patients with AD using ultrafiltration, and fluorescence resonance energy transfer (FRET). To explore the biochemical and structural features of Aβ-GAPDH complexes we employed novel immunoenzyme assays and atomic force microscopy. Lentiviral infection in situ was used to elevate GAPDH in brain tissue of rat and mouse models of AD. The Morris maize water test, MRI, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and lactate dehydrogenase (LDH)-activity assays were used to characterize the effects of Aβ-GAPDH complexes in animal and cellular models of AD. Results Here we report that GAPDH forms stable aggregates with extracellular Aβ. We detected these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of Aβ that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aβ and GAPDH and reduces Aβ-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal neurons, neuronal degeneration, and cognitive dysfunction. In contrast, in vivo knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in Aβ-stimulated neurodegeneration. CSF obtained from animals with enhanced GAPDH expression demonstrated increased cytotoxicity in vitro . Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of Aβ aggregates and reversed memory deficit in AD transgenic mice. Conclusions Extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, thus representing a promising pharmacological target for AD.

BackgroundAlzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases are responsible for considerable morbidity and mortality. With incidence rising with aging, these also represent a growing societal challenge. Pathophysiology involves accumulation of tau (neurofibrillary tangles) and Amyloid‐β‐rich (amyloid plaques) aggregates in AD, α‐synuclein‐rich aggregates (Lewy bodies) in PD and TDP‐43 aggregates in ALS, although co‐presence of these aggregates may occur. Consensus is also growing that tau may also play a key role in PD and ALS.MethodUsing genome‐wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with PD or Alzheimer’s AD disease versus controls across ancestry groups.ResultA shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10‐13; AD: OR=0.91[0.89; 0.93]; p=1.8x10‐22), and with a protective HLA association recently reported in ALS. Hierarchical protective effects of HLA‐DRB1*04 subtypes best accounted for the association, strongest with HLA‐DRB1*04:04 and HLA‐DRB1*04:07, intermediary with HLA‐DRB1*04:01 and HLA‐DRB1*04:03, and absent for HLA‐DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA‐DRB1*04 subtypes strongly bound the aggregation‐prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation.ConclusionAn HLA‐DRB1*04‐mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.