INTRODUCTION:Functional prognosis of early-onset neurodegenerative dementia (EOD) remains poorly understood. METHODS:The Neurodegenerative Early-Onset Dementia (NEODEM) study is an ongoing prospective multicenter cohort study investigating factors associated with decline in daily activities in EOD. Detailed information on behavioral and psychological symptoms of dementia (BPSD) is collected as prognostic factor. RESULTS:Between May 2020 and May 2023, 162 patients with EOD, including 111 patients with early-onset Alzheimer's disease (AD) and 40 with frontotemporal dementia (FTD) variants, were enrolled in seven tertiary memory clinics in France. The median time from symptom onset to diagnosis was 3 years. By design, Clinical Dementia Rating (CDR) scale score was 0.5 or 1 at inclusion. Baseline level of autonomy was similar in early-onset AD and FTD, but MMSE scores were lower in AD. Baseline BPSD results are presented in the manuscript. CONCLUSION:Four-year longitudinal data, available from 2027, will help clarify the impact of baseline factors on future functional status, institutionalization, morbidity, and mortality.

Genetic factors play an important role in frontotemporal lobar degeneration (FTLD) with about 20 genes reported to be involved. Although it is known that genetic diagnostic yield depends on age at onset, clinical subtype and family history, there are no precise indication criteria for a cost-effective and efficient strategy in clinical setting. We report the molecular diagnostic experience in a French clinical laboratory in a large cohort of 2747 probands with sporadic or familial FTLD. We used a three-step genetic screening strategy. First, measurement of plasma progranulin assay was performed in all cases (n=2747), followed by screening of GRN when plasma progranulin was below the threshold. If GRN screening was negative, the second step consisted of the investigation of the G4C2 repeat expansion in C9orf72 (n= 2675). In a third step, targeted sequencing of 14 FTLD genes was performed in 1279 individuals depending on age at onset and family history. Diagnostic yield of this strategy was 12.2% (n=334). GRN (n=73) and C9orf72 (n=200) represent 81.7% of genetic diagnoses. Diagnostic yield of the panel sequencing was 4.8% (62/1279). Family history was the strongest factor related to genetic diagnosis, with four to five times more genetic diagnoses in cases with a family history of FTLD (32.1%) compared with sporadic cases (7.2%). Although the clinical presentation is not significantly associated with identifying a genetic mutation, behavioural variant of frontotemporal dementia (bvFTD) associated with amyotrophic lateral sclerosis (FTD/ALS) or not produced a higher diagnostic yield (15.5% and 13.3%, respectively) than the primary progressive aphasia subgroup (9.9% for semantic variant and 8.8% for non-fluent variant) and others (8.3% and 4.2% for progressive supranuclear palsy and corticobasal syndrome, respectively). Interestingly, the genetic distribution varies greatly between clinical subtypes. FTD/ALS and bvFTD were mostly driven by C9orf72 (82.1% and 63.5%, respectively). In contrast, GRN is the dominant gene in nfvPPA (41.2%). C9orf72, MAPT, GRN and TBK1 equally contributes to svPPA (around 20% each). These results allow us to show the phenotype-genotype architecture of FTLD and to provide data to establish a cost-effective genetic diagnostic strategy in clinical settings for FTLD.

Abnormal brain accumulation of amyloid-β peptides, represents one of the earliest biological indicators of Alzheimer’s disease (AD) risk. Estimation on amyloid positivity (A+) prevalence among older adults without dementia are needed to assess the epidemiological impact of AD diagnosis solely through biological markers. We combined data from the French MEMENTO clinical cohort, where amyloid status was assessed through reference procedures, with the nationally representative SHARE-HCAP survey. Using stabilized inverse odds of selection weights, we adjusted the MEMENTO sample to estimate the prevalence of A+ in the French population aged 65–85 without dementia and their five-year risk of developing AD dementia. A+ prevalence was 21.4% (95% CI: 18.4–24.7) in French adults aged 65–85 without dementia i.e. approximately 2.5 million individuals, reaching 27.5% in the 80–85 age group. Over five years of follow-up, the cumulative incidence of AD dementia was 22.7% among A+ individuals, 8.0% among cognitively normal A+ adults and 62.3% among those with mild cognitive impairment. While A+ is common in older adults without dementia, most do not develop dementia within five years. Defining AD by A+ could substantially increase diagnoses, raising major public health, ethical, and health system challenges, especially as new anti-amyloid therapies emerge.

Background and Objectives Blood-based biomarkers (BBMs), especially tau phosphorylated at threonine 217 (p-tau217), offer a minimally invasive approach to diagnose Alzheimer's disease (AD) with strong potential for clinical implementation. However, the robustness and transferability of diagnostic thresholds across sites remain uncertain. This study aimed to evaluate BBMs' ability to predict amyloid and tau status in a deeply phenotyped AD research cohort and to test p-tau217 cutoffs across diverse clinical populations and analytical instruments. Methods We included four Western European cohorts (total n=411): an exploration cohort from Brussels with amyloid and tau-positron emission tomography (PET) data (n=215), and clinical validation cohorts from Paris (memory clinic, n=117, and monogenic FTLD, n=43) and Bordeaux (early-onset neurodegenerative disorders, n=36). BBMs concentrations (p-tau217, p-tau181, NfL, BD-tau, ABeta42, ABeta40) were measured. Of these, p-tau217 was measured at each site using three Lumipulse analyzers (G600II in Brussels and Bordeaux; G1200 in Paris). Amyloid status was determined by PET or CSF ABeta42, and tau status by tau-PET or CSF p-tau181. Results Plasma p-tau217 outperformed other BBMs, and their related ratios. In the exploration cohort, p-tau217 closely related to amyloid and tau PET, clearly separating ABeta+ from ABeta- individuals (AUC=0.96; optimal cutoff 0.193 pg/mL with ~92% sensitivity/specificity) and tracking tau-PET Braak stages (AUC=0.93-0.98). Using amyloid-derived thresholds, p-tau217 detected medial temporal and neocortical tauopathy with >90% sensitivity and specificity at stricter dual 95-97.5% sensitivity/specificity cutpoints (0.142/0.256 pg/mL and 0.110/0.319 pg/mL). In validation cohorts, the 0.193 pg/mL cutoff accurately discriminated clinical-biological AD from non-AD in routine care (AUC=0.98; ~93% sensitivity/specificity), in early-onset dementia (AUC=0.94; >92% sensitivity/specificity), and in the monogenic FTLD cohort (89% specificity). In routine care, gray zones (8-25%) were largely resolved with second-line CSF testing (>75%). Elevated p-tau217 was rare in non-AD, mainly in FTLD-ALS and some older individuals with possible AD copathology. p-tau217/ABeta42 and p-tau217/ABeta42/ABeta40 ratios added no diagnostic value. Discussion p-tau217 thresholds maintained high diagnostic accuracy (>90%) across independent sites, analytical platforms, and various clinical situations, supporting their robustness and transferability. These observations support implementing p-tau217 as a reliable, scalable test for detecting AD pathology, for diagnostic work-ups of patients with objective cognitive impairment, not for general population screening. ### Competing Interest Statement J.L.B received speaker fees from Siemens Healthineers, The Binding Site Company and Fujirebio, outside the submitted work. Independent of this work, NV received research support from Fondation Bettencourt-Schueller, Fondation Servier, Union Nationale pour les Interets de la Medecine (UNIM), Fondation Claude Pompidou, Fondation Alzheimer, Banque Publique d'Investissement, Lion's Club Alzheimer and Fondation pour la Recherche sur l'Alzheimer; travel grant from the Movement Disorders Society, Merz-Pharma, UCB Pharma, and GE Healthcare SAS; is an unpaid local principal investigator or sub-investigator in [NCT05531526][1] (AR1001, AriBio), [NCT06079190][2] (AL101, GSK), [NCT04241068][3] and [NCT05310071][4] (aducanumab, Biogen), [NCT05399888][5] (BIIB080, Biogen), [NCT03352557][6] (gosuranemab, Biogen), [NCT04592341][7] (gantenerumab, Roche), [NCT03887455][8] (lecanemab, Eisai), [NCT03828747][9] and [NCT03289143][10] (semorinemab, Roche), [NCT04619420][11] (JNJ-63733657, Janssen - Johnson & Johnson), [NCT06544616][12] (JNJ-64042056, Janssen - Johnson & Johnson), [NCT04374136][13] (AL001, Alector), [NCT04592874][14] (AL002, Alector), [NCT04867616][15] (bepranemab, UCB Pharma), [NCT04777396][16] and [NCT04777409][17] (semaglutide, Novo Nordisk), [NCT05469360][18] (NIO752, Novartis), [NCT06647498][19] (remternetug, Washington University School of Medicine); is the unpaid French national coordinator in [NCT05564169][20] (VHB937, Novartis); has given unpaid lectures in symposia organized by Eisai and the Servier Foundation; has been an unpaid expert for Janssen - Johnson & Johnson, Eli-Lilly, Novartis. During the past three years, V.P. was a local unpaid investigator or sub-investigator for clinical trials granted by Novo Nordisk, Janssen, Alector, BMS and Roche. During the past three years, SB was investigator without personal fees in Alzheimer Disease therapeutical trials from Biogen, Roche, Eisai, Eli Lilly, Janssen, Johnson & Johnson, Alector, UCB, NovoNordisk, Novartis, GlaxoSmithKline, and expert without personal fees for GE-Healthcare and Eli-Lilly, all outside the submitted work. B.J.H. has been a consultant for Biogen, Eisai and Lilly, has received fees as a speaker from Roche over the past five years. ### Clinical Trial NCT04254094 ### Funding Statement This study was not funded by Fujirebio. The Brussels Tau-PET study (UCL-2016-121) has been funded thanks to the StopAlzheimer Foundation (PI: Hanseeuw, 2022-2027) as well as a WelBio Starting Grant from the WEL Research Institute (PI: Hanseeuw, 2022-2026). The BioNEODEM biobank, an ancillary study of the NEODEM cohort (early-onset dementias in Bordeaux), was funded by the French Rotary Club; the measurement of pTau-217 was funded by Lions Alzheimer. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Brussels, Belgium (prospective research cohort): The study was reviewed and approved by the Comite d'ethique hospitalo-facultaire (CEHF), the hospital-faculty ethics committee affiliated with the Cliniques universitaires Saint-Luc and the Universite catholique de Louvain (UCLouvain), Brussels, Belgium (protocol UCL-2016-121; registered in the EU clinical trials database European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2018-003473-94; ethical approval granted). All participants provided written informed consent. Bordeaux, France (NEODEM/BioNEODEM): The NEODEM and BioNEODEM studies were reviewed and approved by the Comite de Protection des Personnes (CPP; French regional research ethics committee), CPP Ile-de-France VI, France (favorable opinion/ethical approval granted). The CPP registered these protocols under dossier references 60-19 and 74-20, respectively, within the French "Jarde law" framework (Law governing recherches impliquant la personne humaine, i.e., research involving the human person; RIPH), as RIPH category 2 and RIPH category 1 studies, hors produits de sante (HPS, i.e., not primarily evaluating a medicinal product or medical device). All participants provided written informed consent. Paris, France (routine-care cohort; secondary use of care data/surplus samples): Data and surplus plasma/CSF samples were collected strictly as part of routine clinical care at Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Pitie-Salpetriere, Paris, France. Patients were informed of secondary use and could opt out. Secondary use of routinely collected clinical data and surplus samples was conducted under the Commission nationale de l'informatique et des libertes (CNIL; the French data-protection authority) Reference Methodology MR-004 (MR-004), a standard compliance framework for certain health studies/evaluations based on reuse of existing data. Because this component was considered outside the scope of the Jarde law RIPH framework, formal ethics approval by a CPP or an Institutional Review Board (IRB) was not required (waived). AP-HP acted as the data controller. Paris, France (monogenic frontotemporal lobar degeneration cohort): Participants provided written consent for secondary use of diagnostic samples and associated data. Data processing complied with CNIL MR-004; no additional CPP/IRB ethics approval was required for this secondary use (waived). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Deidentified data are available upon reasonable request to the corresponding author. 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Purpose: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) <= 65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). Results: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. Conclusion: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Diet is a major route of exposure to potentially neurotoxic chemicals, yet the epidemiological association of diet contaminants with dementia is unknown. We studied the link between dietary exposure to multiple chemicals and dementia risk in older persons, considering interaction with dietary fat content, which may modify the bioavailability and toxicity of (lipophilic) chemicals. Methods We included 1,288 non-demented participants from the French Three-City cohort who answered a food frequency questionnaire and 24-hour recall at baseline and were followed for incident dementia. Dietary exposure to 167 contaminants was assessed by combining food intakes with food chemical content from the French second Total Diet Study. We assessed the relation of each individual contaminant with dementia risk using multivariable-adjusted Cox models, exploring effect modification by high-fat diet (>35 % energy from fat). Among high-fat diet consumers, we looked for a signature of contaminants associated with dementia using elastic-net penalization and assess their joint effect. Results Participants were 76 years-old on average at baseline and 62 % were women. In total, 314 individuals developed dementia over a median 10 years. No contaminant was associated with dementia in the whole population. However, having a high-fat diet was a strong effect modifier for 85 contaminants (FDR-corrected p < 0.05 for interactions) in single-chemical analyses, so that higher intakes were significantly associated with higher dementia risk among high-fat consumers only (n = 386). Among them, a multi-chemical approach revealed a signature of 9 contaminants related to dementia, including 4 perfluoroalkyl substances, 2 flame retardants hexabromocyclododecane (HBCDD) congeners, 2 mycotoxins, and nitrites. This selection included two top hits from the single-chemical analyses (α-HBCDD and perfluorooctanesulfonic acid [PFOS]), and was mainly provided by delicatessen meat, seafood and bread/crispbread. Conclusion In this large population-based study, dietary exposure to several chemicals was associated with higher dementia risk among older persons consuming > 35 % energy from fat in diet.

GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases. We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography. Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers. This study evidences an age-dependent increase of β-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases.

Key Points Question What is the safety, tolerability, pharmacodynamic, and pharmacokinetic profile of the histone deacetylase inhibitor FRM-0334 in participants with progranulin gene (GRN) haploinsufficiency? Findings In this randomized placebo-controlled clinical trial including 27 participants with GRN haploinsufficiency, FRM-0334 was safe and well tolerated; however, it failed to increase plasma progranulin and cerebrospinal fluid progranulin and failed to demonstrate dose-dependent oral bioavailability. Meaning The studied formulation of FRM-0334 should not be investigated in future clinical trials enrolling participants with GRN haploinsufficiency; this study did not fully address the potential of histone deacetylase inhibition to alter GRN expression.

Objective To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates. Methods Patients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. Results Among the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). Conclusions This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene–specific therapies.

OBJECTIVE:Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages. METHODS:We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical-genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index. RESULTS:pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades. CONCLUSIONS:This study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression. TRIAL REGISTRATION NUMBERS:NCT02590276 and NCT04014673.

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72-related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

Background: The frontal variant of Alzheimer’s disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD. Objective: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD. Methods: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients. Results: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion. Conclusion: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD.

The apolipoprotein E ε4 allele (APOE4), vascular risk factors and neurodegenerative factors are known to be associated with dementia. This study aimed at identifying any mediating effect of those risk factors in the association existing between APOE4 and dementia.

GRN mutations are frequent causes of familial frontotemporal degeneration. Although there is no clear consensual threshold, plasma progranulin levels represent an efficient biomarker for predicting GRN mutations when decreased. We evaluated plasma levels to determine whether it could also predict age at onset, clinical phenotype, or disease progression in 160 GRN carriers. Importantly, progranulin levels were influenced by gender, with lower levels in male than in female patients in our study. Although we found no correlation with age at onset or with clinical phenotype, we confirmed that decreased level predicts GRN mutations, even in presymptomatic carriers more than four decades before disease onset. We also provided first evidence for the stability of levels throughout longitudinal trajectory in carriers, over a 4-year time span. Finally, we confirmed that progranulin levels constitute a reliable, cost-effective marker, suitable as a screening tool in patients with familial frontotemporal degeneration, and more broadly in patients without family history or with atypical presentations who are less likely to be referred for molecular diagnosis.

Amnesia is a key component of Alzheimer's disease (AD) and the most important feature of its clinical diagnosis but its specificity has recently been challenged. This study investigated the ability of amnesia to predict AD in a clinicopathological dementia series. Ninety-one patients to which free and cued verbal memory assessment was administered during early cognitive decline, were followed until autopsy. Patients' histological diagnoses were classified as pure AD, mixed AD, and non-AD pathologies. Data-driven automated classification procedures explored the correspondence between memory performance and pathological diagnoses. Classifications revealed 3 clusters of performance reflecting different levels of amnesia. Little correspondence between these clusters and the presence of AD pathology was retrieved. A third of patients with pure/mixed AD pathology were non-amnesic at presentation and ≈45% of patients without AD pathology were amnesic. Data-driven prediction of AD pathology based on memory also had a poor accuracy. Free and cued memory assessments are fair tools to diagnose an amnesic syndrome but lack accuracy to predict AD pathology.

FTLD is a common cause of dementia in individuals whose symptoms begin prior to age 65. Autosomal dominant mutations in the progranulin gene (GRN) cause up to 3-5% of FTLD by reducing progranulin protein (PGRN) production, leading to lysosomal dysfunction, neurodegeneration, inflammation and death. In preclinical models, HDACi have been found to increase GRN expression. FRM-0334 is a brain penetrant HDACi that elevated PGRN mRNA levels in human FTLD-GRN patient fibroblasts and PGRN protein in mouse brains. 28 individuals with FTLD- causing GRN mutations were randomized to either 300 or 500mg of FRM-0334 or placebo (12 drug : 3 placebo) taken orally daily for 28 days in two sequential dose cohorts. Primary objectives were to assess safety and tolerability, and the ability of FRM-0334 to increase plasma PGRN concentration. Secondary objectives were to assess FRM-0334 effects on CSF PGRN, as well as FRM-0334 pharmacokinetics. Exploratory objectives were to examine FRM-0334 effects on clinical measures, CSF biomarkers of neurodegeneration and FDG-PET scans. FRM-0334 was safe and well tolerated in asymptomatic and symptomatic GRN mutation carriers. There were no treatment related changes in blood or CSF PGRN levels, which remained stable in each individual over 28 days. Systemic and CSF FRM-0334 levels were not proportional to the administered dose and did not reach exposures which would be necessary based on preclinical experimentation to increase GRN mRNA & PGRN. No changes in exploratory outcomes were observed. There was considerable heterogeneity in clinical and imaging findings between participants at baseline. FRM-0334 was safe and well tolerated in GRN mutation carriers but had no effect at doses tested on PGRN levels. Systemic and CSF FRM-0334 levels were lower than expected suggesting insufficient FRM-0334 exposure. Therefore the hypothesis that HDAC inhibition can increase PGRN expression in humans was not fully tested. Additional studies with brain permeant HDACi should be pursued. Improved methods to measure treatment effects in heterogeneous FTLD-GRN populations are needed.

Amnesia is the most prominent symptom of typical AD. An amnestic syndrome (AS) characterized by a deficit in both free and cued verbal memory recalls has been considered to be highly suggestive of AD and a key component of its clinical diagnosis. In this context, the Free and Cued Selective Reminding Test (FCSRT) was established as a reference tool. While the sensitivity of this test to AD has only rarely been questioned, the specificity of the AS has recently been challenged by studies showing that non-AD diseases could also present with a genuine AS. The absence of pathological confirmation of clinical diagnoses is a common limit to both sides of this debate and thus, whether AS specifically relate to AD pathology and whether a particular memory profile is retrieved in AD remain elusive. This study aimed to investigate the diagnostic value of AS for AD in 91 patients who were administered the FCSRT at first presentation during the early stages of cognitive decline (average MMSE 25.53 ± 2.81) and followed until the autopsy. We classified the histological diagnoses as pure-AD (16.5%), mixed-AD (28.6%) and non-AD (54.9%) pathologies. Through the use of automated data-driven classification procedures, we also investigated the specific memory profile of each pathological group at the FCSRT and studied the correspondence between the FCSRT-defined memory profiles and pathological diagnoses. Factorial analyses did not retrieve any memory profile specific to AD pathology. Classification procedures revealed three distinct clusters of performance reflecting different levels of amnesia, but little correspondence between these clusters and the presence of AD pathology. Overall, a third of patients with pure and mixed AD pathology were non-amnestic at presentation and ≈45% of patients without AD pathology were amnestic. In addition, data-driven prediction of AD pathology based on FCSRT scores had a poor accuracy to predict the presence or absence of AD pathology. This first specific investigation of the diagnostic value of amnesia to predict AD pathology showed that the FCSRT and the AS lack of accuracy to predict AD pathology as it is too frequently observed in other pathology to be specific.

Background: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. Objective: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. Conclusion: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.