Diagnostic testing and neurosurgical management involving CSF shunting in patients with idiopathic normal pressure hydrocephalus (iNPH) offers a unique, ethically sustainable opportunity to study the aging human brain. The common co-occurrence of neurodegenerative pathologies such as amyloid-β plaques and neurofibrillary tau tangles (NFT) provides a valuable window for research into the Alzheimer’s disease-related mechanisms. Interindividual variability among iNPH patients enables investigation and validation of biomarkers and molecular mechanisms, opening possibilities for new treatments. In vitro techniques and culturing methods for living brain tissue expand the utility of samples for electrophysiological studies, drug testing, and examining genetic risk variants. Careful sectioning and processing are essential for high-quality samples with intact cells for functional analysis. A rigorous pipeline is also needed for preserving samples for transcriptomic, proteomic, and structural analyses, with emphasis on RNA integrity and tissue architecture for single-cell sequencing and spatial analysis. Here, we review the use of small cortical brain biopsies in neurodegenerative diseases research and diagnostics. Furthermore, we share our team’s experience in acquiring and preserving living brain samples during iNPH CSF shunt surgeries, along with our protocols for resection, use, and preservation of biopsies for preclinical research. We highlight the potential of living human tissue for neuroscience, early neurodegenerative disease diagnosis, and targeted therapies.

Background Plasma phosphorylated tau isoforms 181 (pTau181) and 217 (pTau217) are promising Alzheimer's disease (AD) biomarkers.Objective We evaluated the performance of pTau181 and pTau217 in the differential diagnostics between AD, other neurodegenerative diseases and non-neurodegenerative participants.Methods We included 104 patients with neurodegenerative diseases (37 with AD, 21 with synucleinopathies [SYNU], 24 with frontotemporal dementia [FTD] and 22 with idiopathic normal-pressure hydrocephalus [iNPH]) and 50 participants without neurodegenerative disorders (33 individuals undergoing knee arthroplasty and 17 with psychiatric diagnoses). pTau181 and pTau217 were measured via single-molecule array.Results pTau181 differentiated AD patients from psychiatric patients with an area under the curve (AUC) of 0.879 and AD patients from all other participants with an AUC of 0.685. pTau181 was higher in patients with AD compared to FTD, iNPH, and non-neurodegenerative (ND) patients. pTau217 differentiated AD patients from psychiatric patients, with an AUC of 0.998, and AD patients from all other groups, with an AUC of 0.835. pTau217 was higher in AD patients compared to ND, FTD, and SYNU patients, but it did not differ between AD and iNPH patients without adjustment for age as a covariate.Conclusions Our prospective cohort data indicate that pTau217 differentiates AD patients from psychiatric patients, with an excellent AUC value in receiver operating characteristic analysis. Our study supports the use of pTau217 rather than pTau181 as a minimally invasive tool to differentiate AD from non-neurodegenerative diseases (e.g., psychiatric disorders). Further studies are needed to determine the nature of pTau217 in iNPH.

BACKGROUND:The socioeconomic burden of early onset dementia (EOD) defined as disease onset before the age of 65 years, is substantial due to its widespread disabling effects in relatively young individuals. While dementia is widely recognised as a major contributor to mortality among the elderly, only a limited number of studies have assessed survival and factors associated with prognosis specifically in EOD. METHODS:A population-based cohort study, encompassing all incident EOD cases from two defined regions in Finland. The survival and all-cause mortality rates in EOD and its subtypes were evaluated from January 2010 to December 2021. All visits at the dementia outpatient clinics were reviewed and manually re-assessed (n=12 490), resulting in 794 validated EOD cases of Alzheimer's disease (AD), frontotemporal dementia (FTD), alpha-synucleinopathy (α-SYNU) and other EOD spectra. Region-, age- and sex-matched control groups without neurodegenerative diseases were created from nonselective general population data registers (1:10 case to control ratio, 7930 controls in total). RESULTS:The median survival for EOD was 8.7 years, with the shortest survival in the FTD (6.9 years) and α-SYNU groups (7.0 years), followed by the AD group (9.9 years). Compared with controls, mortality was significantly higher in the total EOD group (HR=6.56, 95% CI=5.56-7.74, p<0.001). Among the dementia subtypes, FTD spectrum patients had the highest all-cause mortality risk compared with controls (HR=13.75, 95% CI=10.25-18.43, p<0.001). Male sex, older age, several comorbidities and lower level of education were associated with increased mortality, but these were not EOD-specific. CONCLUSION:EOD diagnosis significantly deteriorates patients' survival, with significant variation between different diagnostic groups and in relation to patients' demographic factors.

C9orf72 hexanucleotide repeat expansion (C9-HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). However, approximately half of the FTD patients are sporadic without a clear genetic background. To compare characteristics of microglia from different FTD subtypes, we generated induced pluripotent stem cell-derived microglia (iMG) from sporadic and C9-HRE-carrying behavioral variant FTD (bvFTD) patients and healthy controls. C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins. All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG. Additionally, C9-HRE iMG showed significantly increased LC3BII/I conversion after bafilomycin A1 treatment and altered phagocytic activity. The gene expression profile of C9-HRE iMG only modestly differed from the control iMG, but was greatly different from the sporadic bvFTD patient iMG. Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time.

Long C9orf72 hexanucleotide repeat expansions (C9-HRE) are the most common genetic cause of frontotemporal dementia (FTD), a group of neurodegenerative syndromes leading to cognitive dysfunction and frontal and temporal atrophy. FTD is a potential comorbidity of idiopathic normal pressure hydrocephalus (iNPH) and carrying the C9-HRE can modify the age-of-onset in iNPH patients. While intermediate-length C9-HRE (<30 repeats) are often considered non-pathogenic, the exact pathological cutoff is unclear. In this study, we assessed whether skin fibroblasts from iNPH patients carrying intermediate C9-HRE display C9-HRE-associated pathological hallmarks and changes in cellular function. C9-HRE-associated RNA foci, present in the long (>60 repeats) C9-HRE carrier fibroblasts, were not detected in those of the intermediate carriers. The number of p62-positive puncta was significantly increased in long but not intermediate C9-HRE carrier fibroblasts, in line with p62-positive intracellular inclusions observed in a brain biopsy from the patient. Induction of autophagy did not suggest any defects in the intermediate carrier fibroblasts. Fibroblasts from the intermediate C9-HRE carriers showed upregulated glycolytic activity, possibly to counteract the slightly reduced mitochondrial respiration. This could not be observed in the long C9-HRE carrier fibroblasts. In conclusion, these data suggest that while the long C9-HRE leads to more severe cellular pathologies than intermediate C9-HRE, the latter might predispose cells to deficits in specific cellular functions, such as energy metabolism.

Background Ignite is an iPad-based cognitive assessment app designed to enhance the sensitivity of detecting early cognitive changes in presymptomatic frontotemporal dementia (FTD). It is intended for use as a remote outcome measure in future clinical trials. Before use in clinical trials, it is essential to establish the app’s sensitivity for detecting cognitive impairment and to evaluate its performance relative to established clinical measures. Methods A total of 569 participants from the Genetic FTD Initiative who completed Ignite during their annual research visit were included. Each participant also underwent a clinical assessment and a standard neuropsychological battery. Ignite scores were z-scored against a normative sample, and cognitive composite scores were calculated across distinct domains. Disease stage was defined using the CDR+NACC-FTLD global score including neuropsychiatric and motor components (CDR+NACC-FTLD-NM), where 0 = asymptomatic (N = 190), 0.5 = prodromal (N = 110), 1 = mildly symptomatic (N = 27) and ≥ 2 = moderately/severely symptomatic (N = 42). Linear regressions (adjusting for age, sex, and education) compared Ignite scores between healthy non-carriers (N = 200) and mutation carriers stratified by disease stage, with further analyses also conducted by genetic group ( C9orf72 , MAPT , and GRN ). Receiver operating characteristic (ROC) analyses were used to compare Ignite with standard neuropsychological composites. Results Ignite detected significant cognitive impairment in all symptomatic mutation carriers (CDR = 1 and CDR ≥ 2) across all six cognitive domains compared with non-carriers ( p < 0.001). Prodromal mutation carriers (CDR = 0.5) showed impairments in all domains except social cognition, while asymptomatic carriers (CDR = 0) demonstrated reduced performance in executive function, social cognition, and calculation ( p < 0.05). C9orf72 mutation carriers showed the earliest and broadest deficits across all cognitive domains, MAPT carriers exhibited pronounced impairments in semantic knowledge and social cognition, and GRN carriers demonstrated marked deficits in executive function and processing speed, particularly at symptomatic stages. ROC analyses demonstrated similarly good discrimination for Ignite and GENFI neuropsychology between symptomatic carriers and non-carriers across all cognitive domains (AUCs 0.91–0.92 for Ignite vs 0.89–0.93 for GENFI). Discrimination at the prodromal stage was lower for both measures, though Ignite showed higher AUCs across all domains (0.58–0.70 vs 0.55–0.64). Conclusions Ignite is a sensitive digital cognitive assessment capable of detecting early cognitive changes in genetic FTD and demonstrates improved discrimination compared with standard neuropsychological measures at milder disease severity. Its sensitivity to disease stage and gene-specific profiles, supports its potential utility as a scalable remote outcome measure for FTD clinical trials.

Frontotemporal dementia (FTD) is an important group of neurodegenerative diseases causing early onset dementia. While FTD is mostly sporadic, a common cause of genetic FTD is the C9orf72 hexanucleotide repeat expansion (C9exp). To date, no imaging biomarkers have been identified for differentiating between sporadic and hereditary cases. In this study, we focused on MRI-based neuroanatomical comparisons between FTD subtypes bvFTD and nfvPPA, as well as the C9exp status, to identify potential imaging biomarkers. Fifty-six patients with FTD (43 bvFTD and 13 nfvPPA) underwent clinical evaluation and magnetic resonance imaging (MRI) at 1,5T and 3,0T The genetically analysed subgroup consisted of 13 C9exp -positive and 22 C9exp -negative cases. cNeuro® cMRI software was used for comprehensive voxel-based morphometry (VBM) analyses of the MRI images for multiple brain regions, structures and their volumes. Our results show that orbitofrontal volumes, particularly of the right anterior and posterior orbital gyri, demonstrate high sensitivity (90,9-100%) and specificity (76,9%) in differentiating C9exp cases from sporadic FTD. Furthermore, we elucidated and corroborated several statistically significant volumetric differences in multiple brain regions between the FTD subtypes of bvFTD and nfvPPA, such as asymmetrical, right-sided atrophy in the former. This is the first demonstration that C9exp-positive FTD cases can be reliably differentiated from sporadic cases based solely on MRI atrophy patterns. Furthermore, we corroborate several diagnostically significant volumetric differences in brain regions between bvFTD and nfvPPA variants, providing evidence that advanced brain morphometry techniques constitute a valuable tool for identifying even more FTD subtypes.

BACKGROUND AND OBJECTIVES:Early-onset dementia (EOD), affecting individuals younger than 65 years, imposes a substantial socioeconomic burden. However, evidence on long-term income trajectories and productivity loss across EOD subtypes remains limited. The aim of this study was to evaluate income trajectories and societal productivity loss in individuals with different EOD subtypes. METHODS:This retrospective, population-based longitudinal cohort study included all patients with EOD from Kuopio University Hospital and Oulu University Hospital referral area between January 2010 and December 2021. Diagnoses were re-validated through clinical data review. For each study case, 10 randomly selected matched controls were used. Demographics, education, and comorbidities were obtained from national registers. Annual gross income was retrieved from Statistics Finland tax records. The Human Capital Approach was used to calculate productivity losses, in effect by estimating the annual income difference relative to controls using a generalized estimating equation regression model, with panel data spanning 15 years before diagnosis and the year of diagnosis. RESULTS:The EOD cohort comprised 793 patients (50.4% women; mean age 59.6 years): 421 with Alzheimer disease (AD), 179 with frontotemporal dementia (FTD) spectrum disorders, 46 with α-synucleinopathies (α-SYNUs), and 147 with other EOD etiologies. Compared with 7,926 age-matched and sex-matched controls, patients with EOD showed substantial and progressively increasing productivity loss up to 15 years before diagnosis, with cumulative losses of €74,577 (46,423-102,732) per patient. In the AD group, productivity loss emerged 6 years before diagnosis (€2,767; 95% CI 18-5,515; p = 0.024) and reached €11,431 at diagnosis (95% CI 8,676-14,184; p < 0.001). In the FTD group, loss appeared 11 years before diagnosis (€4,799; 95% CI 433-9,166; p = 0.031) and increased to €16,116 at diagnosis (95% CI 11,671-20,561; p < 0.001). In the α-SYNU group, differences were variable and significant only at diagnosis (€11,284; 95% CI 2,574-19,993; p < 0.011). In the "other EOD" group (predominantly vascular and mixed dementias), productivity loss remained consistently high across the follow-up (e.g., €8,744 at diagnosis; p < 0.001). DISCUSSION:This large-scale longitudinal study demonstrates significant productivity loss up to 15 years before EOD diagnosis, with variation across dementia subtypes. Earlier recognition and targeted interventions are needed in the future to mitigate the substantial socioeconomic burden of EOD. TRIAL REGISTRATION INFORMATION:This study is part of DEGE-RWD-research project (protocol registered to ClinicalTrials.gov: NCT06209515), coordinated by Neurocenter Finland.

BACKGROUND:What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation. METHODS:In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method. FINDINGS:Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6·94 years (95% CI 6·59-7·80) from symptom onset. The median survival estimate for patients with GRN mutations was 6·63 years (6·08-7·98), for patients with a C9orf72 expansion was 7·04 years (6·45-8·77), and for patients with MAPT mutations was 8·56 years (7·06-13·50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level. INTERPRETATION:Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed. FUNDING:Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.

This study explores how legal experts and physicians ensure the autonomy of individuals with dementia when assessing the need for legal guardianship and appointing guardians. Through interviews with 20 legal experts and 30 physicians, and thematic analysis, the research identified key analytical groups. Legal experts focus on (1) Ascertaining the individual’s views and (2) Minimising interference with autonomy. Physicians emphasise (1) ascertaining the individual’s views, (2) Supporting the realisation of autonomy and (3) Providing accurate information on the legal process. The study found that legal experts strongly respect autonomy, sometimes even deviating from strict legal requirements to ensure that individuals with dementia are heard and their opinions considered during court proceedings. Although physicians generally stress the patient’s autonomy, they prioritise protecting the individual more than legal experts.

Brain disorders characterized by progressive neurodegeneration, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), represent an increasing medical and societal challenge. While genome‑wide studies have uncovered numerous susceptibility loci, these efforts have largely focused on common variants and leave a substantial portion of genetic liability unresolved. Variants of low frequency, often associated with stronger biological effects, remain insufficiently characterized, particularly in heterogeneous populations. Genetically isolated populations offer an effective strategy to overcome these limitations. Finland, shaped by historical demographic events, harbors a distinctive spectrum of enriched rare variants that can facilitate gene discovery. The FinnGen initiative capitalizes on this setting by combining extensive genotyping with nationwide health registry data through a coordinated network of Finnish biobanks. With half a million participants analyzed, FinnGen supports highly powered analyses across a broad array of clinical outcomes and registry data. Recent comprehensive analyses have reported thousands of significant genotype-phenotype associations, including novel protein‑altering variants. Importantly, the FinnGen cohort structure favors older individuals and hospital‑derived samples, increasing representation of brain disorders, such as AD and idiopathic normal pressure hydrocephalus (iNPH), a disorder frequently accompanied by AD‑like pathological features. In this expert review, we summarize FinnGen‑based investigations relevant to neurodegenerative diseases and iNPH, highlighting insights into genetic susceptibility, disease overlap, and protective factors, and discuss how integration with recall studies as well as biomarker and clinical data accelerates translational applications in brain disorders.

Objective: Topical data on causes of death and death certificate (DC) accuracy in patients with amyotrophic lateral sclerosis (ALS) are constantly needed. Methods: Data on a previously published ALS cohort from North Karelia in easternmost Finland was updated by extracting DC information from the electronic health records. Results: Death certificate data were available for 91% of the deceased. In all cases, ALS had been coded as a cause of death. In four cases, it had been inserted as a contributory cause of death. In three cases, ALS was indicated but incorrect coding was used. Three of the four cases in which ALS had not been deemed the underlying or immediate cause of death were cardiovascular deaths. One or more contributory causes of death had been recorded in 28% of DCs (54% of these were cardiovascular disorders), although comorbidities had not always been coded in the DC. In individual cases, the death had been sudden and unexpected, resembling a cardiovascular death, but this had not been coded. Conclusion: Finnish DC data remain a very reliable data source for ALS epidemiology, albeit with the caveat that data need to be obtained rigorously. Comorbidities are incompletely recorded as may be some immediate causes of death.

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.

BACKGROUND AND OBJECTIVES: Early-onset dementia (EOD), affecting individuals younger than 65 years, imposes a substantial socioeconomic burden. However, evidence on long-term income trajectories and productivity loss across EOD subtypes remains limited. The aim of this study was to evaluate income trajectories and societal productivity loss in individuals with different EOD subtypes. METHODS: This retrospective, population-based longitudinal cohort study included all patients with EOD from Kuopio University Hospital and Oulu University Hospital referral area between January 2010 and December 2021. Diagnoses were re-validated through clinical data review. For each study case, 10 randomly selected matched controls were used. Demographics, education, and comorbidities were obtained from national registers. Annual gross income was retrieved from Statistics Finland tax records. The Human Capital Approach was used to calculate productivity losses, in effect by estimating the annual income difference relative to controls using a generalized estimating equation regression model, with panel data spanning 15 years before diagnosis and the year of diagnosis. RESULTS: < 0.001). DISCUSSION: This large-scale longitudinal study demonstrates significant productivity loss up to 15 years before EOD diagnosis, with variation across dementia subtypes. Earlier recognition and targeted interventions are needed in the future to mitigate the substantial socioeconomic burden of EOD. TRIAL REGISTRATION INFORMATION: This study is part of DEGE-RWD-research project (protocol registered to ClinicalTrials.gov: NCT06209515), coordinated by Neurocenter Finland.

We report on the utility of speech-based digital endpoints measured during a Phase 1b study of VRG50635 in Amyotrophic Lateral Sclerosis (ALS). Fifty-four participants with ALS were enrolled and participated in an 8-week pretreatment run-in, followed by three 8-week dosing periods and an 8-week follow-up. They completed a speech assessment every two weeks in the clinic or at home. We observed moderate to high correlations between digital measures of speech timing and articulatory motor function, and the ALS Functional Rating Scale-Revised, slow vital capacity and plasma neurofilament light chain. Furthermore, speech measures can show functional decline before the ALSFRS-R does, while also capturing differences between participants with bulbar symptoms and those without. The results support the feasibility and utility of digital speech endpoints to study disease impact in ALS clinical trials.

Frontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with the C9orf72 repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such as C9orf72 haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased cytosolic accumulation of TDP-43 and p62/SQSTM1 and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene, NUPR2, potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.

INTRODUCTION:We aimed to investigate early differences in sociodemographic factors before the onset of Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular dementia (VaD), and mixed dementia (AD + VaD). METHODS:Lifetime sociodemographic factors were collected from Statistics Finland for 1238 AD, 274 FTD, 343 VaD, and 402 AD + VaD patients with a diagnosis and visit at Kuopio and Oulu University Hospitals between January 2010 and December 2021. Comparisons were performed between dementia groups and matched controls. RESULTS:All patient groups showed decreased employment status compared to controls already 10 years prior to diagnosis. In particular, individuals with early-onset FTD (EOFTD; 66.9% vs. 77.6%, p < 0.01) and early-onset VaD (EOVaD; 49.0% vs. 76.5%, p < 0.001) had significantly lower employment rates than controls. Similarly, 10 years prior to diagnosis the proportion of married individuals was lower in the VaD (60.1% vs. 65.2%, p < 0.05) and EOVaD (50.0% vs. 61.6%, p < 0.05) groups versus controls, while single status was more common in early-onset AD (EOAD; 23.2% vs. 17.0%, p < 0.01) versus controls. Patients with VaD and AD + VaD had lower levels of education than controls: basic education only in 51.9% of VaD (vs. 45.0%, p < 0.05) and 65.7% of AD + VaD (vs. 60.2%, p < 0.05). DISCUSSION:Our findings may aid in the early recognition or potential risk factor evaluation for different types of dementia. Screening cognitive symptoms in individuals with unexplained long-term unemployment may help detect prodromal dementia. HIGHLIGHTS:Employment rates were already reduced 10 years before the diagnosis of Alzheimer's disease, frontotemporal dementia, and vascular dementia. The association between education level and dementia risk appears to be subtype specific. Lower employment may serve as an early "social marker" of subtle cognitive decline. Social markers could help inform models predicting progression to cognitive impairment.