Thibaud Lebouvier

Background: Anti‐amyloid therapies (AATs), such as lecanemab and donanemab, represent a major therapeutic development for early Alzheimer's disease (AD). However, safety risks and uncertainties regarding long‐term effects make treatment decisions complex. These decisions arise when patients remain legally capable of providing informed consent but may experience cognitive vulnerabilities affecting their ability to engage in complex decisions. Shared decision‐making (SDM) is therefore particularly relevant, yet its implementation raises ethical and practical challenges. Methods: This position paper draws on a multidisciplinary reflection on decision‐making, informed consent, and cognitive vulnerability in early AD and AATs. The authors, with expertise in neurology, geriatrics, law, and history, examined challenges to patient participation and developed a relational framework integrating SDM and supported decision‐making. Results: Impairments in memory, insight, and executive function, together with cognitive biases, stigma, and the complexity of AAT‐related information, may compromise patient participation despite preserved legal capacity. Formal capacity assessments and improved information delivery may address some difficulties but are unlikely to provide comprehensive support. We propose a relational framework involving assessment of patients' cognitive vulnerabilities, values, preferences, and informational needs; tailored information; and involvement of a patient‐designated care partner to support information exchange, deliberation, and expression of preferences. Consent should be iterative, with safeguards to preserve autonomy and confidentiality, prevent coercion, and avoid excluding socially isolated individuals. Conclusion: Combining SDM with supported decision‐making may provide an ethical and practical framework for autonomous treatment decisions regarding AATs in early AD.

C9orf72 encodes a protein that is important for both typical neurodevelopment and homeostatic processes across the lifespan. Pathogenic C9orf72 repeat expansions constitute the most common genetic cause of frontotemporal lobar degeneration (FTLD). Collectively, preclinical models and clinical neuroimaging studies have observed smaller thalamic volumes in C9orf72 -associated FTLD, including in asymptomatic young adult C9orf72 repeat expansion carriers across 18 to 30 years old, supportive of potential neurodevelopmental origins. However, it is unknown whether asymptomatic young adult C9orf72 expansion carriers demonstrate volume differences in specific thalamic nuclei, as reported in older asymptomatic carriers and symptomatic patients; if so, normative transcriptomic patterns could reveal relevant neurodevelopmental and/or FTLD-related neurodegenerative processes. This study investigated volumetric MRI differences of the thalamic nuclei in asymptomatic young adult C9orf72 expansion carriers compared to non-carriers, and examined spatial associations with normative thalamic transcriptomics from 8 weeks post-conception through middle age. Young adult C9orf72 expansion carriers ( n =72) and non-carriers ( n =48) were enrolled in the Frontotemporal Dementia Prevention Initiative across Europe, Canada, and the USA (ages: 18-30 years; sex: 57% female). Spatial associations between young adult thalamic nuclei volumes and normative transcriptomics from the Allen Human Brain Atlas were examined using complementary data-driven and hypothesis-driven approaches. Spatial expression patterns of transcripts of interest were characterized across prenatal and postnatal neurodevelopment using BrainSpan data. Smaller volumes of the pulvinar, mediodorsal, and lateral nuclei were observed in young adult C9orf72 expansion carriers compared to non-carriers. These nuclei showed higher normative expression of transcripts involved concurrently in neurodevelopmental and C9orf72 -associated FTLD neurodegenerative processes (including lysosomal, autophagic, and small GTPase functions), and lower normative expression of CALB1 , a marker of prenatal human thalamic development. Normative expression of CALB2 (another human thalamic development marker) yielded positive correlations with C9orf72 across prenatal development to adulthood. These findings identify candidate transcripts that may provide insight into the molecular architecture leading to smaller thalamic nuclei volumes in C9orf72 -associated FTLD.

Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementias marked by progressive declines in behavior, cognition, and/or movement. FTLD neuropathologies, including TDP-43 proteinopathies and primary tauopathies, do not have reliable fluid biomarkers for in-vivo diagnosis nor biomarkers that directly correspond to FTLD clinical features. Fluid biomarkers that forecast and track FTLD clinical progression, irrespective of pathology or clinical syndrome, are urgently needed to improve clinical trial designs. We previously identified the ratio between two cerebrospinal fluid (CSF) synaptic proteins, YWHAG and NPTX2, as a prognostic biomarker of cognitive decline in Alzheimer’s disease (AD), independent of core AD pathologies, amyloid and tau. Here, we evaluate its utility in sporadic and familial FTLD compared to other neurodegenerative diseases. Using CSF assays from four independent cohorts (UCSF-MAC, ALLFTD, GENFI, PDBP), we find CSF YWHAG:NPTX2 is substantially elevated across all sporadic and familial FTLD syndromes, AD, and dementia with Lewy bodies. CSF YWHAG:NPTX2 robustly correlates with clinical severity across sporadic and familial FTLD ( C9orf72 , GRN , or MAPT mutations), independent of current gold-standard neurodegeneration biomarker neurofilament light (NfL). In presymptomatic familial FTLD, CSF YWHAG:NPTX2 is estimated to rise roughly a decade before symptom onset and improves prediction of imminent symptomatic conversion by 1.7-fold compared to plasma NfL alone, more than halving the estimated sample size required for an FTLD prevention clinical trial. These findings underscore CSF YWHAG:NPTX2 as a cross-dementia synaptic biomarker of cognitive decline and a promising biomarker for disease staging and prognosis across the clinico-pathological continuum of FTLD.

Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm ³ , SE=317.0, p= 0.0046, f ² =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm ³ , SE=29.9, p= 0.035, f ² =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

INTRODUCTION: Affective disturbances are common across behavioral variant frontotemporal degeneration (bvFTD), primary psychiatric disorders (PPD), and Alzheimer's disease (AD). Objective markers are needed for differential and transdiagnostic characterization. We tested whether artificial intelligence (AI)‐based analysis of natural speech could provide such markers. METHODS: Speech from 112 participants (bvFTD = 31, AD = 28, PPD = 15, controls = 39) was analyzed using a fine‐tuned speech emotion recognition model estimating valence, arousal, dominance, and entropy. Group differences were assessed with analyses of covariance, diagnostic utility with logistic regression, and neuroanatomical correlates with voxel‐based morphometry. RESULTS: Group‐specific affective profiles emerged. Overall, PPD exhibited a lower valence. bvFTD and AD showed a reduced arousal and a higher dominance. Affective dimensions predicted bvFTD with 80.4% accuracy (area under the curve = 0.732) and mapped onto fronto‐insular and temporal networks. Entropy was identified as a transdiagnostic marker. DISCUSSION: AI‐based speech analysis provides objective, scalable biomarkers for differential diagnosis, transdiagnostic characterization, and disease monitoring.

Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of neurodegenerative disorders, including a wide range of clinical, neuropathological, and genetic entities, whose late-onset forms remain underdiagnosed in clinical practice. Although FTLD is less frequent than Alzheimer's disease (AD) in older adults, recent epidemiological studies indicate that its incidence increases with age, peaking around the seventh decade, thereby challenging the traditional view of FTLD as a disorder predominantly affecting younger individuals. In older patients, diagnostic accuracy is reduced by the frequent absence of typical early-onset features. Late-onset FTLD often presents with less characteristic clinical phenotypes, including attenuated behavioural symptoms, misleading memory impairment suggestive of AD, and subtle motor or language manifestations, all of which contribute to delayed recognition. From a neuropathological perspective, late-onset FTLD displays distinct features compared with earlier-onset forms, including less pronounced frontotemporal atrophy, a higher frequency of mixed pathologies, and the presence of age-related lesions, which may influence clinical expression. In clinical practice, the identification of FTLD in older adults relies on a multimodal approach integrating detailed clinical and neuropsychological evaluation with structural or functional neuroimaging. In the absence of FTLD-specific biomarkers, cerebrospinal fluid biomarkers of AD are frequently used to support the diagnostic process, primarily to identify or exclude concomitant AD pathology, although their interpretation requires caution in this age group. Genetic analyses may also contribute to the diagnostic assessment, particularly in presentations compatible with the behavioural variant of FTLD, including late-onset cases. Overall, integrating clinical, neuropsychological, imaging, biomarker, and genetic data is essential to improve the recognition of late-onset FTLD and optimize patient management in this population.