RARE DISEASE
Frontotemporal dementia
Frontotemporal dementia
Frontotemporal dementia
Synonyms: FTD
Synonyms: FTD
Synonyms: FTD
Drug discovery
21
drugs
With orphan designations
Overview
Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive atrophy of the frontal and temporal lobes, leading to behavioral changes, language deficits, and/or motor dysfunction. It is distinguished from Alzheimer’s disease by earlier onset (typically 45–65 years), relative preservation of memory in early stages, and prominent personality or language alterations [1][2][6]. Subtypes include behavioral variant FTD, primary progressive aphasia, and motor disorders like corticobasal syndrome [1][11]. Neuropathology involves tau or TDP-43 protein accumulation [1][14].
Population
Affects ~15/100,000 people aged 45–64, with comparable prevalence to early-onset Alzheimer’s in this group [4][12].
Lifetime risk: 1 in 742; median survival ranges from 2.9 years (progressive supranuclear palsy) to 9.1 years (semantic variant FTD) [4][14].
Equal sex distribution, though behavioral variant FTD shows male predominance [12][17].
Burden
Leads to 6–11 years of dependency post-diagnosis, often requiring full-time care [7][17].
Economic strain: 40% of patients have familial forms, with 50% risk to offspring [17]; misdiagnosis delays average 3.6 years [7][9].
Caregiver stress peaks due to behavioral symptoms (apathy, impulsivity) and young onset disrupting work/family roles [6][16].
Therapies
Pharmacological: Off-label SSRIs (e.g., citalopram) for disinhibition/compulsions [3][8], low-dose antipsychotics (e.g., quetiapine) for agitation [8][18]. No disease-modifying therapies exist [2][10].
Non-pharmacological: Behavioral interventions, speech/occupational therapy, and caregiver education [3][18].
Research focus: Targeting tau/TDP-43 pathology and genetic variants (e.g., C9orf72) [5][14].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,992 drug discovery papers about Frontotemporal dementia, with 5 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,992 drug discovery papers about Frontotemporal dementia, with 5 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | Palmitoylethanolamide and Luteolin in Brain Aging and Cognitive Decline: Biological Rationale and Current Evidence.
Cognitive decline is closely associated with biological aging and with interconnected processes, including chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and cellular senescence. Nutraceutical strategies capable of modulating several of these pathways may represent a complementary approach to supporting cognitive health. This narrative review examines the biological rationale and available evidence regarding palmitoylethanolamide (PEA), luteolin, and their co-ultramicronized formulation (PEA-Lut) in cognitive impairment and dementia. Evidence from mechanistic studies, animal models, observational studies, and clinical trials was considered. PEA is an endogenous N-acylethanolamine with anti-inflammatory and neuroprotective properties, whereas luteolin exerts complementary antioxidant and anti-inflammatory effects. Co-ultramicronization may improve their physicochemical properties and biological activity. Preclinical studies suggest that PEA-Lut may attenuate glial activation, pro-inflammatory signaling, oxidative and nitrosative stress, and amyloid-β-induced cellular injury while supporting neurotrophic signaling and neuronal survival. Preliminary clinical findings have suggested possible benefits in stroke rehabilitation, frontotemporal dementia, and other neuroinflammatory conditions. However, human evidence specifically addressing mild cognitive impairment and Alzheimer's disease remains limited, heterogeneous, and largely derived from preclinical and small or non-randomized studies. PEA-Lut therefore represents a biologically plausible investigational nutraceutical approach, although available clinical safety data are limited to relatively small and heterogeneous populations and short observation periods. Adequately powered randomized controlled trials are needed to determine its clinical efficacy, optimal timing and dosage, and long-term safety in individuals at risk of dementia.
2026-09-25 | Intrinsically disordered proteins and liquid-liquid phase separation: Molecular grammar, condensate physiology, and disease-relevant phase transitions.
Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins constitute a substantial and functionally critical fraction of the eukaryotic proteome. Through multivalent, low-affinity interactions encoded in their low-complexity domains (LCDs), IDPs drive liquid-liquid phase separation (LLPS)-a physicochemical process that produces membraneless biomolecular condensates serving as dynamic reaction hubs within cells. Recent advances have substantially refined the conceptual framework governing condensate biophysics: the phase separation coupled to percolation (PSCP) model now recognizes that condensates are viscoelastic network fluids arising from the synergy between density transitions and connectivity (percolation) transitions, rather than simple LLPS alone. This updated mechanistic understanding, combined with proteome-wide computational tools and AI-driven prediction models, is rapidly transforming the field. Physiologically, condensates regulate transcription at super-enhancers, modulate RNA metabolism in stress granules, and orchestrate ribosome biogenesis in the nucleolus. Pathologically, aberrant liquid-to-solid transitions of disease-associated IDPs-including TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia, tau in Alzheimer's disease, and α-synuclein in Parkinson's disease-represent a convergent pathomechanism across neurodegenerative proteinopathies. Post-translational modifications, particularly phosphorylation, arginine methylation, and ubiquitination, function as a dynamic regulatory code controlling condensate assembly and dissolution. The emerging paradigm of condensate-modifying therapeutics (c-mods) identifies biomolecular condensates as druggable entities and proposes four mechanistic strategies-dissolvers, inducers, localizers, and morphers-to restore normal phase behavior in disease. This review integrates the most current molecular, cellular, and biomedical insights into IDP-driven phase separation, highlighting open questions and translational opportunities.
2026-09-19 | TBK1 overexpression reduces neuronal loss in the P497S UBQLN2 mouse model of ALS/FTD.
Missense mutations in UBQLN2 are linked to dominant inheritance of amyotrophic lateral sclerosis (ALS) which is frequently accompanied by frontotemporal dementia (FTD). The encoded UBQLN2 protein functions to maintain proteostasis, collapse of which is increasingly being realized as the cause of many neurodegenerative diseases. During investigations of our UBQLN2 mouse models of ALS/FTD, we observed a significant decline in Tank-binding kinase 1 (TBK1) protein in end-stage mice. The decline could be significant, as haploinsufficiency of TBK1 expression is linked to ALS/FTD. To determine whether the reduction in TBK1 levels is responsible for driving pathogenesis, we crossed P497S UBQLN2 transgenic (Tg) mice with BacTBK1 Tg mice that overexpress TBK1 and analyzed the progeny for signs of pathology. The analysis revealed that double transgenic mice had a significant reduction in neurodegeneration in both the brain and spinal cord (SC) compared to P497S single-Tg mice. Double immunofluorescence staining of P497S mouse tissue revealed TBK1 colocalizes with UBQLN2 aggregates in spinal motor neurons. Biochemical extraction studies of mouse brain tissue revealed increased enrichment of TBK1 along with wild type and mutant UBQLN2 proteins in detergent-insoluble material, suggesting TBK1 gets sequestered by UBQLN2 aggregates. GST-pulldown assays revealed that UBQLN2 binds directly with TBK1, but paradoxically the P497S mutation was found to reduce TBK1 binding. Turnover studies indicated that loss of UBQLN2 destabilizes TBK1, providing another route for its reduction. These findings lead us to propose that efforts directed toward increasing TBK1 expression may provide a therapeutic approach for treating ALS/FTD caused by UBQLN2 mutations.
2026-09-15 | Sigma-1 Receptor Stimulation Rescues FTD/ALS Mutant TDP43-Induced Disruption of the VAPB-PTPIP51 ER-Mitochondria Tethering Proteins via Inhibition of GSK3β.
Signalling between the ER and mitochondria regulates a number of key cellular functions that are damaged in frontotemporal dementia and related amyotrophic lateral sclerosis (FTD/ALS). This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER-mitochondria "tethering" proteins. A number of studies have shown that mutant genes which cause familial FTD/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3β. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER-mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER-mitochondria Ca2+ delivery. We also show that these effects involve inhibition of the kinase GSK3β, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer's disease, also stimulates VAPB-PTPIP51 binding via GSK3β inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER-mitochondria signalling in FTD/ALS.
2026-09-11 | Behavioral and psychological symptoms of dementia and its relationship with caregiver burden: A cross-sectional study of inpatients with dementia in a tertiary center.
Behavioral and psychological symptoms of dementia (BPSD) is commonly associated with caregiver distress, and often a reason for short-term or long-term care. Very few studies have examined the pattern of the BPSD and caregiver burden in an Indian tertiary care inpatient setting. Our study aimed to understand the pattern of BPSD, particularly its individual domains, in different types of dementia, and its relationship with caregiver distress and burden in a geriatric inpatient setting. One hundred inpatients with dementia and their informal primary caregivers participated in a cross-sectional, semi-structured interview using validated tools to assess the types and severity of BPSD and the relationship with caregiver burden. All inpatients had one or more BPSD, as expected, with a median of 7 (1QR 5-8). Night-time behavioral disturbances (79%), irritability (78%), and apathy (74%) were the most common ones. In Alzheimer's dementia (AD), night-time behavioral disturbances (80%), irritability/lability (74.3%), and agitation/aggression (68.6%) were the most observed. Apathy (84.4%) was the most common BPSD in frontotemporal dementia (FTD), followed by irritability (80%), aberrant motor behavior (71.2%), and night-time behavioral disturbances (71.2%). Caregiver distress varied across different BPSD, with irritability (10%), agitation (8%), and aberrant motor behavior (7%) associated with the highest levels of distress in our study. Worsening cognitive impairment was not associated with increased burden. An individually tailored management approach targeting specific BPSD symptoms, with equal focus on both the patient and the caregiver, is key.
oligonucleotides
2026-09-26 | Decoding MAPT Exon 10 Mis-Splicing in FTDP-17: From Pathogenic Mechanisms and Experimental Models to Molecular Therapies.
Frontotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is a rare, early-onset, autosomal-dominant neurodegenerative tauopathy caused by mutations in the Microtubule-Associated Protein Tau (MAPT) gene. A subset of these mutations selectively disrupts the normal alternative splicing of MAPT exon 10, altering the physiological ratio of 3-Repeat (3R) and 4-Repeat (4R) tau isoforms; this imbalance, driving pathological tau aggregation and progressive neurodegeneration, is a pathogenic hallmark of FTDP-17. This review explores the molecular mechanisms regulating exon 10 splicing, focusing on how exonic and intronic splicing mutations destabilise mRNA structures or alter splicing factor binding, and discusses how these changes can cause disease symptoms in experimental models. It describes different research methods for studying splicing issues, including minigene reporters, cell lines, human induced pluripotent stem cell (iPSC)-derived neurons, brain organoids and mouse models that naturally express only 4R tau. It also covers potential therapeutic approaches applicable to restoring the normal 3R/4R tau ratio. These include Antisense Oligonucleotides (ASOs), RNA interference (siRNA), Small-Molecule Splicing modulators (SMCs), Spliceosome-Mediated RNA trans-splicing (SMaRT), CRISPR-based transcript engineering, genome editing and RNA stem-loop binders. Additionally, the review highlights recent Phase 2 trial results, including the Diranersen (BIIB080) tau-lowering ASO, the development of MAPT-targeted RNA therapies, new tau-PET and plasma p-tau biomarkers, and innovative strategies to deliver CNS treatments, including non-invasive approaches. By integrating advances in RNA biology, disease modelling and targeted therapies, the review outlines potential future strategies for treating FTDP-17 and other tau-related disorders.
2026-09-24 | AUG-Dependent Translation of Antisense Repeat Transcripts Contributes to Dipeptide Repeat Protein Production in C9ORF72 Expansion Carriers.
A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Bidirectional transcription of the repeat expansion generates sense and antisense RNAs that are translated into dipeptide repeat (DPR) proteins, but the mechanisms of translation initiation remain incompletely understood. Here, we used CRISPR-Cas9 genome editing and steric-blocking antisense oligonucleotides (ASOs) to investigate the role of AUG codons within the antisense repeat RNA. Deletion of an AUG-containing region upstream of the antisense repeats markedly reduced poly(GP) production without affecting antisense RNA levels, demonstrating that this sequence is required for efficient poly(GP) synthesis. We further found that unspliced sense transcripts containing the repeat expansion likely serve as templates for poly(GA) and poly(GR) production in motor neurons. Finally, ASOs targeting the antisense AUG-containing region reduced poly(PR) and poly(GP) levels without altering repeat RNA abundance, supporting a role for AUG-dependent translation of the antisense repeat RNA. These findings provide new insights into the mechanisms of DPR production and suggest that translation-blocking ASOs may represent a therapeutic strategy for C9ORF72-associated ALS/FTD.
2026-09-08 | Decoding Frontotemporal Dementia: Genes, Proteins and Prospects for Precision Medicine.
Frontotemporal Dementia is an umbrella term for several neurodegenerative disorders that have a similar presentation pattern, which is accompanied by neural damage and brain tissue loss in the frontal and temporal regions. Recent studies have observed that the heterogeneity of Frontotemporal Dementia (FTD) is reflected in clinical features, genetics, and molecular perspectives. Specifically, the major forms of pathology in FTD are linked to abnormal protein accumulation, which includes tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Moreover, genetic research on FTD has identified vital mutations in MAPT (Microtubule-associated protein Tau), GRN (Progranulin Gene), and C9ORF72 genes (Chromosome 9 open reading frame genes). Recent developments in neuroimaging, biomarker levels in body fluids, and molecular profiling have increased diagnostic precision, enabling earlier detection of disease subtypes. Neurofilament light chain (NfL), progranulin, and several other biomarkers, together with novel neuroimaging approaches, are currently being applied for disease classification, prognosis, and disease treatment monitoring. These developments have accelerated the application of precision medicine for FTD, including antisense oligonucleotides, progranulin-restorative drugs, tau-specific therapies, and gene therapy. Despite advances in elucidating the biology of FTD, no disease-modifying therapies have yet been developed, and treatments remain symptomatic until now. Undoubtedly, there are many challenges when taking into account variable presentation, overlapping pathologies, and the lack of robust biomarkers. The aim of this paper is to provide an in-depth analysis of the epidemiology, clinical features, molecular pathologies, biomarkers, and potential therapeutic approaches concerning FTD, with a particular emphasis on the growing role of precision medicine. Omics technologies, biomarker- based patient stratification, and hypothesis-driven clinical trials are undoubtedly essential steps towards personalized therapy for FTD.
2026-08-13 | The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.
The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA-tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.
2026-06-25 | Clinical and literature insights into the frontotemporal dementia and motor neuron disease spectrum.
Frontotemporal dementia represents a heterogeneous group of neurodegenerative disorders primarily affecting the frontal and temporal lobes. The overlap between FTD and motor neuron disease is increasingly recognized, presenting a complex clinical syndrome characterized by progressive cognitive, behavioral, and motor decline. We describe a 69-year-old patient with a 4-year history of excessive ambulation. Over the last year, behavioral changes including disorganized conduct, irritability, spitting, and cold water foot immersion developed. The patient experienced compelling auditory hallucinations driving her to walk continuously for up to 10 h per day. Four months prior to admission, gait impairment with frequent falls, along with hyperorality developed. Neurological examination revealed asymmetric mild weakness, marked muscle atrophy of facial and limb muscles, hyperreflexia, and impaired postural control. Brain MRI showed diffuse cerebral atrophy; electrophysiological studies indicated probable motor neuron disease; and TRODAT SPECT demonstrated impaired presynaptic dopaminergic function bilaterally, consistent with parkinsonism. Final diagnosis was frontotemporal dementia with probable motor neuron disease. A review of the literature highlights the clinical, radiological, and molecular features of FTD-MND overlap, emphasizing the role of TDP-43 pathology, C9orf72 mutations, and the need for multidisciplinary management. Current strategies are symptomatic, though novel therapies such as antisense oligonucleotides and biomarkers like neurofilament light chain (NfL) show promise. This case highlights the diagnostic complexity of FTD with MND overlap syndrome, emphasizing the need for comprehensive clinical, neuroimaging, and electrophysiological evaluation. Multimodal treatment approaches focusing on behavioral symptoms and functional support are essential for optimizing patient outcomes.
proteins
2026-09-26 | Comparative Analysis of Plasma Biomarkers of Alzheimer's Disease and Frontotemporal Dementia: The Dual Role of Soluble Fractalkine as a Biomarker of Frontotemporal Dementia and Its Neuroprotective Effects in Cortical Neurons "In Vitro".
Frontotemporal lobar degeneration (FTD) and Alzheimer's disease (AD) are proteinopathies characterized by the abnormal accumulation and aggregation of specific proteins like Aβ-42 deposits, p-tau accumulation, and abnormal cytosolic aggregation of TAR DNA-binding protein 43 (TDP-43) in FTD patients. Recently, the identification of neuroinflammatory mediators as predictors of cognitive decline has gained attention. We have compared several plasma biomarkers of cognitive impairment between AD and FTD patients using Enzyme-Linked Immunosorbent Assay (ELISA) (pg/mL), including CX3CR1 and soluble fractalkine (sFK, also termed CX3CL1), TDP-43, neurofilament light chain M (NfL M), p-tau217, and GFAP (glial fibrillary acidic protein). Chemokines are HIV-1 co-receptors that facilitate the spread of HIV-1 infection and induce apoptosis in the brain. Whilst these chemokines promote neuronal survival and regulate neuron-glia interactions, they also contribute to neurodegeneration. Fractalkine, also known as CX3CL1, is a delta chemokine that binds to its CX3CR1 chemokine receptor. As a membrane isoform, fractalkine can be released in a soluble form by damaged neurons under either inflammatory and/or excitotoxic conditions; since neuroinflammation contributes to neurodegeneration and dementia, we compared these CX3CR1/sFK delta chemokine levels in seropositive patients (with suppressed viral loads) and without neurodegeneration to age-matched controls. This was done in order to study whether inflammation could upregulate these chemokines in the absence of cognitive impairment. To our knowledge, this is the first study showing that increased plasma levels of CX3CR1 and soluble fractalkine could be associated with FTD pathology as compared to control subjects (without neurodegeneration). However, peripheral NfL M, GFAP, and p-tau217 levels did not differ between AD and FTD patients. Post-mortem analysis of human FTD brains revealed anatomical changes, including hippocampal involution and tau deposits. Given that soluble fractalkine can contribute to cognitive impairment while also exerting protective effects against brain insults, we did an additional (independent experiment) in cortical neurons in vitro under LPS-induced neurotoxicity. We confirmed that adding recombinant fractalkine for 24 h prevented lipopolysaccharide (LPS)-induced apoptosis in cortical neurons at 7 days in vitro (DIV); moreover, twenty-four hours after LPS treatment, sFK prevented neuronal apoptosis by decreasing caspase-3 activity and exerted neuroprotective effects against inflammation. Our findings suggest that fractalkine mitigates LPS-induced neuronal injury by limiting apoptosis and inflammatory responses. Furthermore, our findings suggest for the first time that elevated circulating sFK levels may indirectly be associated with FTD pathology as compared to healthy controls. However, sFK could also reflect compensatory protective responses to neuronal injury.
2026-09-24 | Protecting Against Cytoplasmic Protein Aggregates With Cytoplasmic PML Variants.
Cytoplasmic protein aggregation is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and certain forms of motor neuron disease. Recent evidence indicates that promyelocytic leukemia protein (PML) and engineered PML-derived variants can act as versatile aggregate-remodeling factors. In particular, cytoplasmically redirected PML variants recognize pathological cytoplasmic inclusions and promote their clearance. Here, we describe a protocol to generate and validate two engineered cytoplasmic PML variants: full-length mPML, which is redirected to the cytoplasm by disruption of its nuclear localization sequence, and the truncated mPMLΔRBC variant, which lacks the RING, B-box, and coiled-coil domain but retains aggregate-reducing activity. The protocol integrates fluorescence-based imaging, bimolecular fluorescence complementation, detergent-soluble/insoluble fractionation, and validation in primary rat cortical neurons. This workflow provides a practical platform for assessing cytoplasmic aggregate burden and for comparing the aggregate-remodeling activities of PML-derived constructs. It can also be adapted to other disease-associated aggregation-prone proteins, including TDP-43, SOD1, FUS, tau, polyGA, and polyQ-expanded proteins. Key features • Describes the generation and validation of two complementary cytoplasmic PML variants: full-length mPML and truncated mPMLΔRBC. • Provides fluorescence-based and BiFC-based assays to visualize pathological cytoplasmic protein assemblies. • Includes detergent-soluble/insoluble fractionation for biochemical assessment of aggregate burden. • Establishes a primary rat cortical neuron workflow to evaluate the effect of mPML on TDP-43-CTF aggregates. • Can be adapted to other aggregation-prone proteins and additional PML-derived aggregate-remodeling candidates.
2026-08-27 | Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.
In neurodegenerative diseases such as frontotemporal dementia and amyotrophic lateral sclerosis, pathological forms of proteins such as Tau and TDP-43 accumulate within large heterogeneous inclusions inside cells. Current strategies to eliminate such aberrant protein species in patients encounter three main challenges: crossing the blood-brain barrier and plasma membrane, specifically recognizing pathological forms of proteins, and engaging mechanisms to eliminate large entities. Here we fuse LC3A, a central protein in the recruitment of substrates into autophagosomes, to cytoplasm-stable antibodies. These engineered autophagy receptors, targeting Tau or TDP-43, are delivered using small extracellular vesicles and reduce pathology in models, including Tau P301S adult primary mouse neurons, TDP-43G298S iPSC-derived motor neurons and after intravenous injection in Tau P301S mice. Similarly, adeno-associated-virus-mediated delivery in TDP-43ΔNLS mice enhances clearance of pathological TDP-43. This targeted degradation strategy allows delivery into the brain while capitalizing on the specificity of antibodies and the ability of autophagy to degrade large intracellular entities.
2026-08-19 | Carboxyl-terminal blockade of sortilin binding enhances progranulin gene therapy in a mouse model of frontotemporal dementia.
Frontotemporal dementia is commonly caused by loss-of-function mutations in the progranulin gene. Potential therapies for this disorder have entered clinical trials, including progranulin gene therapy and drugs that reduce progranulin interactions with sortilin. Both approaches ameliorate functional and pathological abnormalities in mouse models of progranulin insufficiency. Here, we investigated whether modifying the progranulin carboxyl terminus to block sortilin interactions would improve the efficacy of progranulin gene therapy. We compared the effects of treating progranulin-deficient mice with gene therapy vectors expressing progranulin with intact sortilin interactions, progranulin with the carboxyl terminus blocked to reduce sortilin interactions, or GFP control. We found that expressing carboxyl-terminally blocked progranulin generated higher levels of progranulin both at the injection site and in more distant regions. Carboxyl-terminally blocked progranulin was also more effective at ameliorating microgliosis, microglial lipofuscinosis, microglial morphology changes, and lipid abnormalities including ganglioside accumulation and loss of bis(monoacylglycero)phosphate lipids. Behavioral abnormalities detected in progranulin-deficient mice using an unbiased machine learning analysis were absent after treatment with carboxyl-terminally blocked progranulin but not corrected by unblocked progranulin. Last, only carboxyl-terminally blocked progranulin reduced plasma neurofilament light chain, a biomarker of axonal damage, in progranulin-deficient mice. These results demonstrate that modifying the progranulin cargo to block sortilin interactions may be important for increasing the effectiveness of progranulin gene therapy.
2026-06-17 | Novel Compounds as TREM2 Modulators for Treating Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Nasu-Hakola Disease.
Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Nasu-Hakola disease, and processes for preparing such compounds.
gene therapies
2026-07-03 | ADAR2-Mediated RNA Editing Promotes TDP-43 Nuclear Export and Alters RNA Binding.
TAR DNA binding protein - 43 (TDP-43) nuclear loss is a pathological hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and related neurodegenerative disorders. While the consequences of TDP-43 dysfunction have been well-characterized, the mechanisms driving TDP-43 mislocalization remain poorly understood. Previous observations of altered localization and function of the adenosine-to-inosine (A-to-I) RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) in ALS/FTD tissue prompted us to investigate whether dysregulated RNA editing contributes to pathological TDP-43 nucleocytoplasmic trafficking. TDP-43 cytoplasmic mislocalization was assessed following ADAR2 and TDP-43 co-overexpression in HEK293T cells and a Drosophila model co-overexpressing human TDP-43 and dADAR in motor neurons. We further evaluated TDP-43 mislocalization through both HeLa cell assays and interspecies heterokaryon assays. Next, we assessed TDP-43 binding to A-to-I edited RNA oligomers through electrophoretic mobility shift assays (EMSAs), and investigated inosine-containing RNAs in vivo via TDP-43 RNA immunoprecipitation followed by sequencing (RIP-seq) datasets from human TDP-43-expressing Drosophila . Finally, RNAseq and enhanced cross-linking and immunoprecipitation (eCLIP-seq) were performed in SH-SY5Y cells overexpressing three ADAR2 variants with differing editing activity to identify editing-related transcriptional alterations and RNAs differentially bound to TDP-43. ADAR2 overexpression reduced the nucleocytoplasmic (N:C) ratio of TDP-43 in HEK293T cells in a ADAR2 catalytic activity- and TDP-43 RNA-binding capacity-dependent manner. Drosophila motor neurons overexpressing dADAR also exhibited decreased nuclear TDP-43. Interspecies heterokaryons and permeabilized HeLa cell assays demonstrated that catalytically active ADAR2 and synthetic inosine-containing RNA oligomers, respectively, enhance nuclear export of endogenous TDP-43. EMSAs revealed preferential binding of TDP-43 to inosine-containing RNAs relative to unedited RNAs, and analysis of Drosophila RIP-seq datasets demonstrated enrichment of edited transcripts within TDP-43-bound RNAs. Finally, RNAseq and eCLIP-seq analyses identified editing-dependent alterations in gene expression and TDP-43 RNA-binding profiles in SH-SY5Y cells overexpressing active ADAR2 variants. Together, our findings identify A-to-I RNA editing as a previously unrecognized regulator of TDP-43 localization and RNA interactions. These results support a model where altered RNA editing modifies TDP-43-RNA interactions, promoting increased nuclear export of TDP-43. Broadly, our work highlights RNA editing dysregulation as a potential contributor to early pathogenic mechanisms underlying TDP-43 proteinopathies.
2026-05-26 | Systemic delivery of synapsin-promoted caveolin-1 overexpression ameliorates pathological TDP-43-induced cognitive decline and neurodegenerative changes.
Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy. AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43A315T mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue. SynCav1 exerted robust neuroprotective effects on cognition. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling. These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a "neuron-centric" candidate for treating TDP-43-related neurodegeneration.
2026-05-19 | Protective TMEM106B-rs3173615 delays age at onset in GRN mutation carriers.
One of the major causative genes involved in Frontotemporal dementia (FTD) is Granulin (GRN), encoding for Progranulin (PGRN). GRN mutation carriers show a substantial heterogeneity with high variability in age at onset and pathological presentation, even within the same family or identical mutations, suggesting the presence of additional genetic factors. Single nucleotide polymorphisms in the Transmembrane protein 106B (TMEM106B) locus were identified as a genetic risk-associated factor for FTD. The top variant identified was the non-coding rs1990622, with the major allele (T) associated with an increased risk to develop FTD, while subjects with the minor allele (C) were less likely to develop disease, suggesting a protective effect. In this study, we investigate in a large Italian cohort of GRN mutation carriers, how the coding variant TMEM106B-rs3173615, in linkage disequilibrium with rs1990622, modulates age at onset, survival, and PGRN levels, including, up to date, the highest sample size of homozygous protective allele carriers. Genetic screening for TMEM106B-rs3173615 was performed on a total of 187 GRN mutation carriers, comprising 131 FTD patients and 56 pre-symptomatic subjects. Individuals with the protective genotype (GG) had a risk of FTD onset reduced by 80%, with a median age at onset of 77 years compared to a median age at onset of 63 years for individuals without the protective genotype. TMEM106B-rs3173615 acts as a genetic modifier of age at onset in the presence of GRN mutations and could be considered in clinical practice to optimize risk stratification for FTD.
2026-05-18 | Arrayed dual-gRNA CRISPR screening platform for C9orf72 repeat expansion excision in patient iPSCs.
An intronic hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of both frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). We have previously demonstrated that CRISPR-Cas9 excision of the repeat expansion in patient iPSCs reverts pathological hallmarks of C9-FTD/ALS. Here, we aim to identify efficient and safe gRNAs for CRISPR-spCas9 dual-gRNA excision of the C9-repeat expansion. Utilizing novel ddPCR and single-molecule sequencing assays, we screened 120 gRNA pairs, comparing 64 bi-allelic, intronic excisions of the repeat region to 56 allele-specific excisions of the mutant allele in patient iPSCs, ranking them by efficiency. Bi-allelic excisions of the intronic repeat region were more efficient than excisions of the mutant allele. Single gRNA indel rates can nominate likely efficient gRNA pairs, but these pairs must be tested empirically. The length of the repeat expansion did not impact excision efficiency; rather, the activity of individual gRNAs drove excision efficiencies. Using whole genome sequencing and INDUCE-seq, we found only one detectable off-target of those nominated by Cas-OFFinder and CHANGE-seq across 4 of the most efficient gRNAs. This study advances the development of targeted therapies for C9-FTD/ALS and establishes a framework for dual-gRNA screening in patient iPSCs applicable to other repeat expansions.
2026-04-29 | Humanized mice carrying a pathogenic GRN deletion as a pre-clinical platform for targeted gene therapies in frontotemporal dementia.
Frontotemporal dementia (FTD) is an early onset dementia characterized by neuropathology and changes to patient behaviour. Haploinsufficiency of the gene progranulin (GRN) is a major cause of FTD, for which there are no effective therapies. Corrective gene therapies that restore GRN expression are of clinical interest, but current in vivo systems have limitations. We developed a novel strain of mice expressing a human GRN transgene bearing a four base pair deletion in exon 5 (GRNc.388_391delCAGT) that causes FTD. Characterization of mice expressing the mutant transgene (GRNmEx5) indicates that GRNmEx5 is expressed at low levels and retains partial function. The GRNmEx5 protein partially rescues progranulin nullizygous-associated neuropathology and transcriptomic dysfunction. Following characterization, we sought to determine if mice expressing GRNmEx5 in the absence of mouse progranulin (Grn-/-; GRNmEx5 mice) could enable pre-clinical gene therapy development. Using CRISPR/Cas9 with lipid nanoparticle delivery, we achieved 8.5% correction of GRNc.388_391delCAGT in target cells in Grn-/-; GRNmEx5 mice, demonstrating both effective in vivo homology-directed repair and the utility of Grn-/-; GRNmEx5 mice for developing novel progranulin-associated FTD therapies. The Grn-/-; GRNmEx5 model provides insight into progranulin biology, increases our understanding of a pathogenic variant that causes FTD, and facilitates the development of GRN gene therapies.
other
2026-09-03 | Context-dependent roles of osteopontin in aging-related neurological disorders.
Osteopontin (encoded by secreted phosphoprotein 1) is a multifunctional matricellular phosphoglycoprotein that has emerged as an important mediator in the aging nervous system. During aging, osteopontin interacts with microglial priming, vascular remodeling, myelin repair, and innate immune responses and is consistently implicated in major late-life neurological disorders. However, its biological effects are highly context dependent. Depending on its cellular source, proteolytic processing, receptor interactions, anatomical distribution, and disease stage, osteopontin may either exacerbate chronic neuroinflammation and tissue injury or promote phagocytic clearance, neuronal survival, remyelination, neuroplasticity, and tissue repair. This review critically synthesizes studies indexed in PubMed and Google Scholar through 3 April 2026 on the role of osteopontin in brain aging, Alzheimer's disease and related dementias, Parkinson's disease and Lewy body disorders, cerebrovascular disease, vascular cognitive impairment, cerebral small vessel disease, and amyotrophic lateral sclerosis. In Alzheimer's disease, cerebrospinal fluid and plasma osteopontin concentrations increase from the prodromal to symptomatic stages, whereas microglial or perivascular secreted phosphoprotein 1 expression correlates with amyloid pathology, synaptic remodeling, and cognitive decline. However, under specific conditions, osteopontin also enhances macrophage-mediated amyloid-beta clearance. In stroke, elevated circulating osteopontin predicts poor clinical outcomes, whereas experimental studies demonstrate that appropriately timed exogenous osteopontin, regulatory T cell-derived osteopontin, and osteopontin-mediated autophagic and reparative pathways promote white-matter repair, peri-infarct plasticity, and blood-brain barrier integrity. Evidence from Parkinson's disease, Lewy body disease, frontotemporal dementia, and amyotrophic lateral sclerosis further supports the role of osteopontin as both a candidate biomarker and a regulator of selective neuronal vulnerability. Rather than being uniformly detrimental or protective, osteopontin should be regarded as a context-dependent regulator of age-related neuroimmune remodeling. This perspective reconciles seemingly conflicting findings and supports the development of therapeutic strategies that are tailored to disease stage, protein fragment, and cell type rather than broadly targeting osteopontin.
2026-08-02 | Plasma proteomics reveals molecular overlap between physical activity and dementia risk.
Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer's disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer's disease and Parkinson's disease (Stanford Alzheimer's Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer's disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 'hub' protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.
2026-07-16 | Biparatopic affibody engineering enables high-affinity sortilin blockade and progranulin elevation.
Loss-of-function mutations in the gene encoding progranulin (PGRN) are a common cause of frontotemporal dementia, leading to markedly decreased PGRN levels. A potential therapeutic strategy is therefore to increase extracellular PGRN by blocking sortilin-mediated PGRN clearance. Here, we describe the systematic design and optimization of small biparatopic sortilin-binding proteins based on the non-immunoglobulin affibody scaffold. Two anti-sortilin affibody molecules were genetically fused into a panel of heterodimeric constructs exploring multiple domain orientations, linker lengths, and helix truncations. In total, ten distinct dimer variants were generated and evaluated for binding and functional activity. Optimization of domain arrangement and truncations yielded constructs exhibiting subnanomolar sortilin affinities, corresponding to up to an approximately 45-fold improvement over the strongest monomeric affibody and pronounced avidity effects. In a PGRN clearance assay, the lead 18.6-kDa dimer efficiently increased extracellular PGRN levels with an EC50 value of 0.32 nM and produced substantially greater PGRN fold changes than monomeric constructs. This PGRN elevation was accompanied by marked reductions in both cell surface and total sortilin levels, consistent with effective receptor blockade and modulation. Together, these results demonstrate how systematic combination and geometric optimization of two individually moderate-affinity binders can generate a highly potent biparatopic inhibitor, as well as illustrating the versatility of compact and modular affibody molecules as building blocks in therapeutic protein design. Given the growing amount of evidence implicating sortilin in neurodegeneration, inflammation, and cancer, biparatopic affibody-based inhibitors may enable exploration of this pathway in diverse biological contexts, both as research tools and as starting points for drug development.
2026-05-04 | Plasma Autoantibodies Against Neurodegeneration-Related Antigens in Dementia and Elevated Chi3Li Autoantibodies in Mild Cognitive Impairment.
Systemic autoimmunity plays an important role in pathogenesis of neurodegenerative diseases. The objective of our study was to explore the seroprevalence of naturally occurring autoantibodies (Aabs) targeting a panel of 14 antigens broadly involved in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, frontotemporal dementia, and vascular dementia. Commonly associated proteins with underlying neuronal pathology of the brain include amyloid-beta (Aβ), tau, alpha-synuclein (α-syn), TDP-43, and FUS. Proteins associated with glial and astrocytic involvement-TREM2 and Chi3Li; proteins related to myelin damage and axonal degeneration-light neurofilaments (NFL), myelin basic protein (MBP); synaptic loss reflected by neurogranin (NRGN), a marker of neuronal injury-neuron specific enolase (NSE); and markers of disturbed calcium homeostasis-VSNL1 and neuroinflammation-MCP-1. Presence and levels of plasma IgG against these antigens were examined using enzyme-linked immunosorbent assay (ELISA) method in patients with dementia, patients with mild cognitive impairment (MCI), and healthy age-matched controls. Aabs against all selected antigens were detected across all groups, including healthy control, with varied seroprevalence levels. For the first time, we report the presence of anti-FUS, anti-TREM2, anti-NRGN, anti-VSNL1, anti-NSE, and anti-MCP1 Aabs. Elevated anti-Chi3Li Aabs in individuals with MCI indicate a disease-associated immune signature linked to early neurodegenerative processes. Overall, these results provide evidence of systemic immune activation accompanying neurodegeneration, underscore the complexity of immune involvement, and highlight the importance of targeting multiple pathological pathways in future immunomodulatory strategies.
2026-04-15 | Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice.
Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge, in part because tau lacks well-defined druggable sites and accumulates as heterogeneous intracellular aggregates that are difficult to access and clear. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance through the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In neurons derived from patients with frontotemporal dementia (FTD) and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 promoted autophagy-lysosome-mediated tau degradation. It readily crossed the blood-brain barrier and improved motor function in JNPL3 tauopathy mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.
small molecules
2026-09-26 | Palmitoylethanolamide and Luteolin in Brain Aging and Cognitive Decline: Biological Rationale and Current Evidence.
Cognitive decline is closely associated with biological aging and with interconnected processes, including chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and cellular senescence. Nutraceutical strategies capable of modulating several of these pathways may represent a complementary approach to supporting cognitive health. This narrative review examines the biological rationale and available evidence regarding palmitoylethanolamide (PEA), luteolin, and their co-ultramicronized formulation (PEA-Lut) in cognitive impairment and dementia. Evidence from mechanistic studies, animal models, observational studies, and clinical trials was considered. PEA is an endogenous N-acylethanolamine with anti-inflammatory and neuroprotective properties, whereas luteolin exerts complementary antioxidant and anti-inflammatory effects. Co-ultramicronization may improve their physicochemical properties and biological activity. Preclinical studies suggest that PEA-Lut may attenuate glial activation, pro-inflammatory signaling, oxidative and nitrosative stress, and amyloid-β-induced cellular injury while supporting neurotrophic signaling and neuronal survival. Preliminary clinical findings have suggested possible benefits in stroke rehabilitation, frontotemporal dementia, and other neuroinflammatory conditions. However, human evidence specifically addressing mild cognitive impairment and Alzheimer's disease remains limited, heterogeneous, and largely derived from preclinical and small or non-randomized studies. PEA-Lut therefore represents a biologically plausible investigational nutraceutical approach, although available clinical safety data are limited to relatively small and heterogeneous populations and short observation periods. Adequately powered randomized controlled trials are needed to determine its clinical efficacy, optimal timing and dosage, and long-term safety in individuals at risk of dementia.
2026-09-25 | Intrinsically disordered proteins and liquid-liquid phase separation: Molecular grammar, condensate physiology, and disease-relevant phase transitions.
Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins constitute a substantial and functionally critical fraction of the eukaryotic proteome. Through multivalent, low-affinity interactions encoded in their low-complexity domains (LCDs), IDPs drive liquid-liquid phase separation (LLPS)-a physicochemical process that produces membraneless biomolecular condensates serving as dynamic reaction hubs within cells. Recent advances have substantially refined the conceptual framework governing condensate biophysics: the phase separation coupled to percolation (PSCP) model now recognizes that condensates are viscoelastic network fluids arising from the synergy between density transitions and connectivity (percolation) transitions, rather than simple LLPS alone. This updated mechanistic understanding, combined with proteome-wide computational tools and AI-driven prediction models, is rapidly transforming the field. Physiologically, condensates regulate transcription at super-enhancers, modulate RNA metabolism in stress granules, and orchestrate ribosome biogenesis in the nucleolus. Pathologically, aberrant liquid-to-solid transitions of disease-associated IDPs-including TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia, tau in Alzheimer's disease, and α-synuclein in Parkinson's disease-represent a convergent pathomechanism across neurodegenerative proteinopathies. Post-translational modifications, particularly phosphorylation, arginine methylation, and ubiquitination, function as a dynamic regulatory code controlling condensate assembly and dissolution. The emerging paradigm of condensate-modifying therapeutics (c-mods) identifies biomolecular condensates as druggable entities and proposes four mechanistic strategies-dissolvers, inducers, localizers, and morphers-to restore normal phase behavior in disease. This review integrates the most current molecular, cellular, and biomedical insights into IDP-driven phase separation, highlighting open questions and translational opportunities.
2026-09-19 | TBK1 overexpression reduces neuronal loss in the P497S UBQLN2 mouse model of ALS/FTD.
Missense mutations in UBQLN2 are linked to dominant inheritance of amyotrophic lateral sclerosis (ALS) which is frequently accompanied by frontotemporal dementia (FTD). The encoded UBQLN2 protein functions to maintain proteostasis, collapse of which is increasingly being realized as the cause of many neurodegenerative diseases. During investigations of our UBQLN2 mouse models of ALS/FTD, we observed a significant decline in Tank-binding kinase 1 (TBK1) protein in end-stage mice. The decline could be significant, as haploinsufficiency of TBK1 expression is linked to ALS/FTD. To determine whether the reduction in TBK1 levels is responsible for driving pathogenesis, we crossed P497S UBQLN2 transgenic (Tg) mice with BacTBK1 Tg mice that overexpress TBK1 and analyzed the progeny for signs of pathology. The analysis revealed that double transgenic mice had a significant reduction in neurodegeneration in both the brain and spinal cord (SC) compared to P497S single-Tg mice. Double immunofluorescence staining of P497S mouse tissue revealed TBK1 colocalizes with UBQLN2 aggregates in spinal motor neurons. Biochemical extraction studies of mouse brain tissue revealed increased enrichment of TBK1 along with wild type and mutant UBQLN2 proteins in detergent-insoluble material, suggesting TBK1 gets sequestered by UBQLN2 aggregates. GST-pulldown assays revealed that UBQLN2 binds directly with TBK1, but paradoxically the P497S mutation was found to reduce TBK1 binding. Turnover studies indicated that loss of UBQLN2 destabilizes TBK1, providing another route for its reduction. These findings lead us to propose that efforts directed toward increasing TBK1 expression may provide a therapeutic approach for treating ALS/FTD caused by UBQLN2 mutations.
2026-09-15 | Sigma-1 Receptor Stimulation Rescues FTD/ALS Mutant TDP43-Induced Disruption of the VAPB-PTPIP51 ER-Mitochondria Tethering Proteins via Inhibition of GSK3β.
Signalling between the ER and mitochondria regulates a number of key cellular functions that are damaged in frontotemporal dementia and related amyotrophic lateral sclerosis (FTD/ALS). This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER-mitochondria "tethering" proteins. A number of studies have shown that mutant genes which cause familial FTD/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3β. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER-mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER-mitochondria Ca2+ delivery. We also show that these effects involve inhibition of the kinase GSK3β, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer's disease, also stimulates VAPB-PTPIP51 binding via GSK3β inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER-mitochondria signalling in FTD/ALS.
2026-09-11 | Behavioral and psychological symptoms of dementia and its relationship with caregiver burden: A cross-sectional study of inpatients with dementia in a tertiary center.
Behavioral and psychological symptoms of dementia (BPSD) is commonly associated with caregiver distress, and often a reason for short-term or long-term care. Very few studies have examined the pattern of the BPSD and caregiver burden in an Indian tertiary care inpatient setting. Our study aimed to understand the pattern of BPSD, particularly its individual domains, in different types of dementia, and its relationship with caregiver distress and burden in a geriatric inpatient setting. One hundred inpatients with dementia and their informal primary caregivers participated in a cross-sectional, semi-structured interview using validated tools to assess the types and severity of BPSD and the relationship with caregiver burden. All inpatients had one or more BPSD, as expected, with a median of 7 (1QR 5-8). Night-time behavioral disturbances (79%), irritability (78%), and apathy (74%) were the most common ones. In Alzheimer's dementia (AD), night-time behavioral disturbances (80%), irritability/lability (74.3%), and agitation/aggression (68.6%) were the most observed. Apathy (84.4%) was the most common BPSD in frontotemporal dementia (FTD), followed by irritability (80%), aberrant motor behavior (71.2%), and night-time behavioral disturbances (71.2%). Caregiver distress varied across different BPSD, with irritability (10%), agitation (8%), and aberrant motor behavior (7%) associated with the highest levels of distress in our study. Worsening cognitive impairment was not associated with increased burden. An individually tailored management approach targeting specific BPSD symptoms, with equal focus on both the patient and the caregiver, is key.
oligonucleotides
2026-09-26 | Decoding MAPT Exon 10 Mis-Splicing in FTDP-17: From Pathogenic Mechanisms and Experimental Models to Molecular Therapies.
Frontotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is a rare, early-onset, autosomal-dominant neurodegenerative tauopathy caused by mutations in the Microtubule-Associated Protein Tau (MAPT) gene. A subset of these mutations selectively disrupts the normal alternative splicing of MAPT exon 10, altering the physiological ratio of 3-Repeat (3R) and 4-Repeat (4R) tau isoforms; this imbalance, driving pathological tau aggregation and progressive neurodegeneration, is a pathogenic hallmark of FTDP-17. This review explores the molecular mechanisms regulating exon 10 splicing, focusing on how exonic and intronic splicing mutations destabilise mRNA structures or alter splicing factor binding, and discusses how these changes can cause disease symptoms in experimental models. It describes different research methods for studying splicing issues, including minigene reporters, cell lines, human induced pluripotent stem cell (iPSC)-derived neurons, brain organoids and mouse models that naturally express only 4R tau. It also covers potential therapeutic approaches applicable to restoring the normal 3R/4R tau ratio. These include Antisense Oligonucleotides (ASOs), RNA interference (siRNA), Small-Molecule Splicing modulators (SMCs), Spliceosome-Mediated RNA trans-splicing (SMaRT), CRISPR-based transcript engineering, genome editing and RNA stem-loop binders. Additionally, the review highlights recent Phase 2 trial results, including the Diranersen (BIIB080) tau-lowering ASO, the development of MAPT-targeted RNA therapies, new tau-PET and plasma p-tau biomarkers, and innovative strategies to deliver CNS treatments, including non-invasive approaches. By integrating advances in RNA biology, disease modelling and targeted therapies, the review outlines potential future strategies for treating FTDP-17 and other tau-related disorders.
2026-09-24 | AUG-Dependent Translation of Antisense Repeat Transcripts Contributes to Dipeptide Repeat Protein Production in C9ORF72 Expansion Carriers.
A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Bidirectional transcription of the repeat expansion generates sense and antisense RNAs that are translated into dipeptide repeat (DPR) proteins, but the mechanisms of translation initiation remain incompletely understood. Here, we used CRISPR-Cas9 genome editing and steric-blocking antisense oligonucleotides (ASOs) to investigate the role of AUG codons within the antisense repeat RNA. Deletion of an AUG-containing region upstream of the antisense repeats markedly reduced poly(GP) production without affecting antisense RNA levels, demonstrating that this sequence is required for efficient poly(GP) synthesis. We further found that unspliced sense transcripts containing the repeat expansion likely serve as templates for poly(GA) and poly(GR) production in motor neurons. Finally, ASOs targeting the antisense AUG-containing region reduced poly(PR) and poly(GP) levels without altering repeat RNA abundance, supporting a role for AUG-dependent translation of the antisense repeat RNA. These findings provide new insights into the mechanisms of DPR production and suggest that translation-blocking ASOs may represent a therapeutic strategy for C9ORF72-associated ALS/FTD.
2026-09-08 | Decoding Frontotemporal Dementia: Genes, Proteins and Prospects for Precision Medicine.
Frontotemporal Dementia is an umbrella term for several neurodegenerative disorders that have a similar presentation pattern, which is accompanied by neural damage and brain tissue loss in the frontal and temporal regions. Recent studies have observed that the heterogeneity of Frontotemporal Dementia (FTD) is reflected in clinical features, genetics, and molecular perspectives. Specifically, the major forms of pathology in FTD are linked to abnormal protein accumulation, which includes tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Moreover, genetic research on FTD has identified vital mutations in MAPT (Microtubule-associated protein Tau), GRN (Progranulin Gene), and C9ORF72 genes (Chromosome 9 open reading frame genes). Recent developments in neuroimaging, biomarker levels in body fluids, and molecular profiling have increased diagnostic precision, enabling earlier detection of disease subtypes. Neurofilament light chain (NfL), progranulin, and several other biomarkers, together with novel neuroimaging approaches, are currently being applied for disease classification, prognosis, and disease treatment monitoring. These developments have accelerated the application of precision medicine for FTD, including antisense oligonucleotides, progranulin-restorative drugs, tau-specific therapies, and gene therapy. Despite advances in elucidating the biology of FTD, no disease-modifying therapies have yet been developed, and treatments remain symptomatic until now. Undoubtedly, there are many challenges when taking into account variable presentation, overlapping pathologies, and the lack of robust biomarkers. The aim of this paper is to provide an in-depth analysis of the epidemiology, clinical features, molecular pathologies, biomarkers, and potential therapeutic approaches concerning FTD, with a particular emphasis on the growing role of precision medicine. Omics technologies, biomarker- based patient stratification, and hypothesis-driven clinical trials are undoubtedly essential steps towards personalized therapy for FTD.
2026-08-13 | The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.
The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA-tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.
2026-06-25 | Clinical and literature insights into the frontotemporal dementia and motor neuron disease spectrum.
Frontotemporal dementia represents a heterogeneous group of neurodegenerative disorders primarily affecting the frontal and temporal lobes. The overlap between FTD and motor neuron disease is increasingly recognized, presenting a complex clinical syndrome characterized by progressive cognitive, behavioral, and motor decline. We describe a 69-year-old patient with a 4-year history of excessive ambulation. Over the last year, behavioral changes including disorganized conduct, irritability, spitting, and cold water foot immersion developed. The patient experienced compelling auditory hallucinations driving her to walk continuously for up to 10 h per day. Four months prior to admission, gait impairment with frequent falls, along with hyperorality developed. Neurological examination revealed asymmetric mild weakness, marked muscle atrophy of facial and limb muscles, hyperreflexia, and impaired postural control. Brain MRI showed diffuse cerebral atrophy; electrophysiological studies indicated probable motor neuron disease; and TRODAT SPECT demonstrated impaired presynaptic dopaminergic function bilaterally, consistent with parkinsonism. Final diagnosis was frontotemporal dementia with probable motor neuron disease. A review of the literature highlights the clinical, radiological, and molecular features of FTD-MND overlap, emphasizing the role of TDP-43 pathology, C9orf72 mutations, and the need for multidisciplinary management. Current strategies are symptomatic, though novel therapies such as antisense oligonucleotides and biomarkers like neurofilament light chain (NfL) show promise. This case highlights the diagnostic complexity of FTD with MND overlap syndrome, emphasizing the need for comprehensive clinical, neuroimaging, and electrophysiological evaluation. Multimodal treatment approaches focusing on behavioral symptoms and functional support are essential for optimizing patient outcomes.
proteins
2026-09-26 | Comparative Analysis of Plasma Biomarkers of Alzheimer's Disease and Frontotemporal Dementia: The Dual Role of Soluble Fractalkine as a Biomarker of Frontotemporal Dementia and Its Neuroprotective Effects in Cortical Neurons "In Vitro".
Frontotemporal lobar degeneration (FTD) and Alzheimer's disease (AD) are proteinopathies characterized by the abnormal accumulation and aggregation of specific proteins like Aβ-42 deposits, p-tau accumulation, and abnormal cytosolic aggregation of TAR DNA-binding protein 43 (TDP-43) in FTD patients. Recently, the identification of neuroinflammatory mediators as predictors of cognitive decline has gained attention. We have compared several plasma biomarkers of cognitive impairment between AD and FTD patients using Enzyme-Linked Immunosorbent Assay (ELISA) (pg/mL), including CX3CR1 and soluble fractalkine (sFK, also termed CX3CL1), TDP-43, neurofilament light chain M (NfL M), p-tau217, and GFAP (glial fibrillary acidic protein). Chemokines are HIV-1 co-receptors that facilitate the spread of HIV-1 infection and induce apoptosis in the brain. Whilst these chemokines promote neuronal survival and regulate neuron-glia interactions, they also contribute to neurodegeneration. Fractalkine, also known as CX3CL1, is a delta chemokine that binds to its CX3CR1 chemokine receptor. As a membrane isoform, fractalkine can be released in a soluble form by damaged neurons under either inflammatory and/or excitotoxic conditions; since neuroinflammation contributes to neurodegeneration and dementia, we compared these CX3CR1/sFK delta chemokine levels in seropositive patients (with suppressed viral loads) and without neurodegeneration to age-matched controls. This was done in order to study whether inflammation could upregulate these chemokines in the absence of cognitive impairment. To our knowledge, this is the first study showing that increased plasma levels of CX3CR1 and soluble fractalkine could be associated with FTD pathology as compared to control subjects (without neurodegeneration). However, peripheral NfL M, GFAP, and p-tau217 levels did not differ between AD and FTD patients. Post-mortem analysis of human FTD brains revealed anatomical changes, including hippocampal involution and tau deposits. Given that soluble fractalkine can contribute to cognitive impairment while also exerting protective effects against brain insults, we did an additional (independent experiment) in cortical neurons in vitro under LPS-induced neurotoxicity. We confirmed that adding recombinant fractalkine for 24 h prevented lipopolysaccharide (LPS)-induced apoptosis in cortical neurons at 7 days in vitro (DIV); moreover, twenty-four hours after LPS treatment, sFK prevented neuronal apoptosis by decreasing caspase-3 activity and exerted neuroprotective effects against inflammation. Our findings suggest that fractalkine mitigates LPS-induced neuronal injury by limiting apoptosis and inflammatory responses. Furthermore, our findings suggest for the first time that elevated circulating sFK levels may indirectly be associated with FTD pathology as compared to healthy controls. However, sFK could also reflect compensatory protective responses to neuronal injury.
2026-09-24 | Protecting Against Cytoplasmic Protein Aggregates With Cytoplasmic PML Variants.
Cytoplasmic protein aggregation is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and certain forms of motor neuron disease. Recent evidence indicates that promyelocytic leukemia protein (PML) and engineered PML-derived variants can act as versatile aggregate-remodeling factors. In particular, cytoplasmically redirected PML variants recognize pathological cytoplasmic inclusions and promote their clearance. Here, we describe a protocol to generate and validate two engineered cytoplasmic PML variants: full-length mPML, which is redirected to the cytoplasm by disruption of its nuclear localization sequence, and the truncated mPMLΔRBC variant, which lacks the RING, B-box, and coiled-coil domain but retains aggregate-reducing activity. The protocol integrates fluorescence-based imaging, bimolecular fluorescence complementation, detergent-soluble/insoluble fractionation, and validation in primary rat cortical neurons. This workflow provides a practical platform for assessing cytoplasmic aggregate burden and for comparing the aggregate-remodeling activities of PML-derived constructs. It can also be adapted to other disease-associated aggregation-prone proteins, including TDP-43, SOD1, FUS, tau, polyGA, and polyQ-expanded proteins. Key features • Describes the generation and validation of two complementary cytoplasmic PML variants: full-length mPML and truncated mPMLΔRBC. • Provides fluorescence-based and BiFC-based assays to visualize pathological cytoplasmic protein assemblies. • Includes detergent-soluble/insoluble fractionation for biochemical assessment of aggregate burden. • Establishes a primary rat cortical neuron workflow to evaluate the effect of mPML on TDP-43-CTF aggregates. • Can be adapted to other aggregation-prone proteins and additional PML-derived aggregate-remodeling candidates.
2026-08-27 | Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.
In neurodegenerative diseases such as frontotemporal dementia and amyotrophic lateral sclerosis, pathological forms of proteins such as Tau and TDP-43 accumulate within large heterogeneous inclusions inside cells. Current strategies to eliminate such aberrant protein species in patients encounter three main challenges: crossing the blood-brain barrier and plasma membrane, specifically recognizing pathological forms of proteins, and engaging mechanisms to eliminate large entities. Here we fuse LC3A, a central protein in the recruitment of substrates into autophagosomes, to cytoplasm-stable antibodies. These engineered autophagy receptors, targeting Tau or TDP-43, are delivered using small extracellular vesicles and reduce pathology in models, including Tau P301S adult primary mouse neurons, TDP-43G298S iPSC-derived motor neurons and after intravenous injection in Tau P301S mice. Similarly, adeno-associated-virus-mediated delivery in TDP-43ΔNLS mice enhances clearance of pathological TDP-43. This targeted degradation strategy allows delivery into the brain while capitalizing on the specificity of antibodies and the ability of autophagy to degrade large intracellular entities.
2026-08-19 | Carboxyl-terminal blockade of sortilin binding enhances progranulin gene therapy in a mouse model of frontotemporal dementia.
Frontotemporal dementia is commonly caused by loss-of-function mutations in the progranulin gene. Potential therapies for this disorder have entered clinical trials, including progranulin gene therapy and drugs that reduce progranulin interactions with sortilin. Both approaches ameliorate functional and pathological abnormalities in mouse models of progranulin insufficiency. Here, we investigated whether modifying the progranulin carboxyl terminus to block sortilin interactions would improve the efficacy of progranulin gene therapy. We compared the effects of treating progranulin-deficient mice with gene therapy vectors expressing progranulin with intact sortilin interactions, progranulin with the carboxyl terminus blocked to reduce sortilin interactions, or GFP control. We found that expressing carboxyl-terminally blocked progranulin generated higher levels of progranulin both at the injection site and in more distant regions. Carboxyl-terminally blocked progranulin was also more effective at ameliorating microgliosis, microglial lipofuscinosis, microglial morphology changes, and lipid abnormalities including ganglioside accumulation and loss of bis(monoacylglycero)phosphate lipids. Behavioral abnormalities detected in progranulin-deficient mice using an unbiased machine learning analysis were absent after treatment with carboxyl-terminally blocked progranulin but not corrected by unblocked progranulin. Last, only carboxyl-terminally blocked progranulin reduced plasma neurofilament light chain, a biomarker of axonal damage, in progranulin-deficient mice. These results demonstrate that modifying the progranulin cargo to block sortilin interactions may be important for increasing the effectiveness of progranulin gene therapy.
2026-06-17 | Novel Compounds as TREM2 Modulators for Treating Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Nasu-Hakola Disease.
Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Nasu-Hakola disease, and processes for preparing such compounds.
gene therapies
2026-07-03 | ADAR2-Mediated RNA Editing Promotes TDP-43 Nuclear Export and Alters RNA Binding.
TAR DNA binding protein - 43 (TDP-43) nuclear loss is a pathological hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and related neurodegenerative disorders. While the consequences of TDP-43 dysfunction have been well-characterized, the mechanisms driving TDP-43 mislocalization remain poorly understood. Previous observations of altered localization and function of the adenosine-to-inosine (A-to-I) RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) in ALS/FTD tissue prompted us to investigate whether dysregulated RNA editing contributes to pathological TDP-43 nucleocytoplasmic trafficking. TDP-43 cytoplasmic mislocalization was assessed following ADAR2 and TDP-43 co-overexpression in HEK293T cells and a Drosophila model co-overexpressing human TDP-43 and dADAR in motor neurons. We further evaluated TDP-43 mislocalization through both HeLa cell assays and interspecies heterokaryon assays. Next, we assessed TDP-43 binding to A-to-I edited RNA oligomers through electrophoretic mobility shift assays (EMSAs), and investigated inosine-containing RNAs in vivo via TDP-43 RNA immunoprecipitation followed by sequencing (RIP-seq) datasets from human TDP-43-expressing Drosophila . Finally, RNAseq and enhanced cross-linking and immunoprecipitation (eCLIP-seq) were performed in SH-SY5Y cells overexpressing three ADAR2 variants with differing editing activity to identify editing-related transcriptional alterations and RNAs differentially bound to TDP-43. ADAR2 overexpression reduced the nucleocytoplasmic (N:C) ratio of TDP-43 in HEK293T cells in a ADAR2 catalytic activity- and TDP-43 RNA-binding capacity-dependent manner. Drosophila motor neurons overexpressing dADAR also exhibited decreased nuclear TDP-43. Interspecies heterokaryons and permeabilized HeLa cell assays demonstrated that catalytically active ADAR2 and synthetic inosine-containing RNA oligomers, respectively, enhance nuclear export of endogenous TDP-43. EMSAs revealed preferential binding of TDP-43 to inosine-containing RNAs relative to unedited RNAs, and analysis of Drosophila RIP-seq datasets demonstrated enrichment of edited transcripts within TDP-43-bound RNAs. Finally, RNAseq and eCLIP-seq analyses identified editing-dependent alterations in gene expression and TDP-43 RNA-binding profiles in SH-SY5Y cells overexpressing active ADAR2 variants. Together, our findings identify A-to-I RNA editing as a previously unrecognized regulator of TDP-43 localization and RNA interactions. These results support a model where altered RNA editing modifies TDP-43-RNA interactions, promoting increased nuclear export of TDP-43. Broadly, our work highlights RNA editing dysregulation as a potential contributor to early pathogenic mechanisms underlying TDP-43 proteinopathies.
2026-05-26 | Systemic delivery of synapsin-promoted caveolin-1 overexpression ameliorates pathological TDP-43-induced cognitive decline and neurodegenerative changes.
Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy. AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43A315T mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue. SynCav1 exerted robust neuroprotective effects on cognition. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling. These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a "neuron-centric" candidate for treating TDP-43-related neurodegeneration.
2026-05-19 | Protective TMEM106B-rs3173615 delays age at onset in GRN mutation carriers.
One of the major causative genes involved in Frontotemporal dementia (FTD) is Granulin (GRN), encoding for Progranulin (PGRN). GRN mutation carriers show a substantial heterogeneity with high variability in age at onset and pathological presentation, even within the same family or identical mutations, suggesting the presence of additional genetic factors. Single nucleotide polymorphisms in the Transmembrane protein 106B (TMEM106B) locus were identified as a genetic risk-associated factor for FTD. The top variant identified was the non-coding rs1990622, with the major allele (T) associated with an increased risk to develop FTD, while subjects with the minor allele (C) were less likely to develop disease, suggesting a protective effect. In this study, we investigate in a large Italian cohort of GRN mutation carriers, how the coding variant TMEM106B-rs3173615, in linkage disequilibrium with rs1990622, modulates age at onset, survival, and PGRN levels, including, up to date, the highest sample size of homozygous protective allele carriers. Genetic screening for TMEM106B-rs3173615 was performed on a total of 187 GRN mutation carriers, comprising 131 FTD patients and 56 pre-symptomatic subjects. Individuals with the protective genotype (GG) had a risk of FTD onset reduced by 80%, with a median age at onset of 77 years compared to a median age at onset of 63 years for individuals without the protective genotype. TMEM106B-rs3173615 acts as a genetic modifier of age at onset in the presence of GRN mutations and could be considered in clinical practice to optimize risk stratification for FTD.
2026-05-18 | Arrayed dual-gRNA CRISPR screening platform for C9orf72 repeat expansion excision in patient iPSCs.
An intronic hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of both frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). We have previously demonstrated that CRISPR-Cas9 excision of the repeat expansion in patient iPSCs reverts pathological hallmarks of C9-FTD/ALS. Here, we aim to identify efficient and safe gRNAs for CRISPR-spCas9 dual-gRNA excision of the C9-repeat expansion. Utilizing novel ddPCR and single-molecule sequencing assays, we screened 120 gRNA pairs, comparing 64 bi-allelic, intronic excisions of the repeat region to 56 allele-specific excisions of the mutant allele in patient iPSCs, ranking them by efficiency. Bi-allelic excisions of the intronic repeat region were more efficient than excisions of the mutant allele. Single gRNA indel rates can nominate likely efficient gRNA pairs, but these pairs must be tested empirically. The length of the repeat expansion did not impact excision efficiency; rather, the activity of individual gRNAs drove excision efficiencies. Using whole genome sequencing and INDUCE-seq, we found only one detectable off-target of those nominated by Cas-OFFinder and CHANGE-seq across 4 of the most efficient gRNAs. This study advances the development of targeted therapies for C9-FTD/ALS and establishes a framework for dual-gRNA screening in patient iPSCs applicable to other repeat expansions.
2026-04-29 | Humanized mice carrying a pathogenic GRN deletion as a pre-clinical platform for targeted gene therapies in frontotemporal dementia.
Frontotemporal dementia (FTD) is an early onset dementia characterized by neuropathology and changes to patient behaviour. Haploinsufficiency of the gene progranulin (GRN) is a major cause of FTD, for which there are no effective therapies. Corrective gene therapies that restore GRN expression are of clinical interest, but current in vivo systems have limitations. We developed a novel strain of mice expressing a human GRN transgene bearing a four base pair deletion in exon 5 (GRNc.388_391delCAGT) that causes FTD. Characterization of mice expressing the mutant transgene (GRNmEx5) indicates that GRNmEx5 is expressed at low levels and retains partial function. The GRNmEx5 protein partially rescues progranulin nullizygous-associated neuropathology and transcriptomic dysfunction. Following characterization, we sought to determine if mice expressing GRNmEx5 in the absence of mouse progranulin (Grn-/-; GRNmEx5 mice) could enable pre-clinical gene therapy development. Using CRISPR/Cas9 with lipid nanoparticle delivery, we achieved 8.5% correction of GRNc.388_391delCAGT in target cells in Grn-/-; GRNmEx5 mice, demonstrating both effective in vivo homology-directed repair and the utility of Grn-/-; GRNmEx5 mice for developing novel progranulin-associated FTD therapies. The Grn-/-; GRNmEx5 model provides insight into progranulin biology, increases our understanding of a pathogenic variant that causes FTD, and facilitates the development of GRN gene therapies.
other
2026-09-03 | Context-dependent roles of osteopontin in aging-related neurological disorders.
Osteopontin (encoded by secreted phosphoprotein 1) is a multifunctional matricellular phosphoglycoprotein that has emerged as an important mediator in the aging nervous system. During aging, osteopontin interacts with microglial priming, vascular remodeling, myelin repair, and innate immune responses and is consistently implicated in major late-life neurological disorders. However, its biological effects are highly context dependent. Depending on its cellular source, proteolytic processing, receptor interactions, anatomical distribution, and disease stage, osteopontin may either exacerbate chronic neuroinflammation and tissue injury or promote phagocytic clearance, neuronal survival, remyelination, neuroplasticity, and tissue repair. This review critically synthesizes studies indexed in PubMed and Google Scholar through 3 April 2026 on the role of osteopontin in brain aging, Alzheimer's disease and related dementias, Parkinson's disease and Lewy body disorders, cerebrovascular disease, vascular cognitive impairment, cerebral small vessel disease, and amyotrophic lateral sclerosis. In Alzheimer's disease, cerebrospinal fluid and plasma osteopontin concentrations increase from the prodromal to symptomatic stages, whereas microglial or perivascular secreted phosphoprotein 1 expression correlates with amyloid pathology, synaptic remodeling, and cognitive decline. However, under specific conditions, osteopontin also enhances macrophage-mediated amyloid-beta clearance. In stroke, elevated circulating osteopontin predicts poor clinical outcomes, whereas experimental studies demonstrate that appropriately timed exogenous osteopontin, regulatory T cell-derived osteopontin, and osteopontin-mediated autophagic and reparative pathways promote white-matter repair, peri-infarct plasticity, and blood-brain barrier integrity. Evidence from Parkinson's disease, Lewy body disease, frontotemporal dementia, and amyotrophic lateral sclerosis further supports the role of osteopontin as both a candidate biomarker and a regulator of selective neuronal vulnerability. Rather than being uniformly detrimental or protective, osteopontin should be regarded as a context-dependent regulator of age-related neuroimmune remodeling. This perspective reconciles seemingly conflicting findings and supports the development of therapeutic strategies that are tailored to disease stage, protein fragment, and cell type rather than broadly targeting osteopontin.
2026-08-02 | Plasma proteomics reveals molecular overlap between physical activity and dementia risk.
Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer's disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer's disease and Parkinson's disease (Stanford Alzheimer's Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer's disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 'hub' protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.
2026-07-16 | Biparatopic affibody engineering enables high-affinity sortilin blockade and progranulin elevation.
Loss-of-function mutations in the gene encoding progranulin (PGRN) are a common cause of frontotemporal dementia, leading to markedly decreased PGRN levels. A potential therapeutic strategy is therefore to increase extracellular PGRN by blocking sortilin-mediated PGRN clearance. Here, we describe the systematic design and optimization of small biparatopic sortilin-binding proteins based on the non-immunoglobulin affibody scaffold. Two anti-sortilin affibody molecules were genetically fused into a panel of heterodimeric constructs exploring multiple domain orientations, linker lengths, and helix truncations. In total, ten distinct dimer variants were generated and evaluated for binding and functional activity. Optimization of domain arrangement and truncations yielded constructs exhibiting subnanomolar sortilin affinities, corresponding to up to an approximately 45-fold improvement over the strongest monomeric affibody and pronounced avidity effects. In a PGRN clearance assay, the lead 18.6-kDa dimer efficiently increased extracellular PGRN levels with an EC50 value of 0.32 nM and produced substantially greater PGRN fold changes than monomeric constructs. This PGRN elevation was accompanied by marked reductions in both cell surface and total sortilin levels, consistent with effective receptor blockade and modulation. Together, these results demonstrate how systematic combination and geometric optimization of two individually moderate-affinity binders can generate a highly potent biparatopic inhibitor, as well as illustrating the versatility of compact and modular affibody molecules as building blocks in therapeutic protein design. Given the growing amount of evidence implicating sortilin in neurodegeneration, inflammation, and cancer, biparatopic affibody-based inhibitors may enable exploration of this pathway in diverse biological contexts, both as research tools and as starting points for drug development.
2026-05-04 | Plasma Autoantibodies Against Neurodegeneration-Related Antigens in Dementia and Elevated Chi3Li Autoantibodies in Mild Cognitive Impairment.
Systemic autoimmunity plays an important role in pathogenesis of neurodegenerative diseases. The objective of our study was to explore the seroprevalence of naturally occurring autoantibodies (Aabs) targeting a panel of 14 antigens broadly involved in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, frontotemporal dementia, and vascular dementia. Commonly associated proteins with underlying neuronal pathology of the brain include amyloid-beta (Aβ), tau, alpha-synuclein (α-syn), TDP-43, and FUS. Proteins associated with glial and astrocytic involvement-TREM2 and Chi3Li; proteins related to myelin damage and axonal degeneration-light neurofilaments (NFL), myelin basic protein (MBP); synaptic loss reflected by neurogranin (NRGN), a marker of neuronal injury-neuron specific enolase (NSE); and markers of disturbed calcium homeostasis-VSNL1 and neuroinflammation-MCP-1. Presence and levels of plasma IgG against these antigens were examined using enzyme-linked immunosorbent assay (ELISA) method in patients with dementia, patients with mild cognitive impairment (MCI), and healthy age-matched controls. Aabs against all selected antigens were detected across all groups, including healthy control, with varied seroprevalence levels. For the first time, we report the presence of anti-FUS, anti-TREM2, anti-NRGN, anti-VSNL1, anti-NSE, and anti-MCP1 Aabs. Elevated anti-Chi3Li Aabs in individuals with MCI indicate a disease-associated immune signature linked to early neurodegenerative processes. Overall, these results provide evidence of systemic immune activation accompanying neurodegeneration, underscore the complexity of immune involvement, and highlight the importance of targeting multiple pathological pathways in future immunomodulatory strategies.
2026-04-15 | Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice.
Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge, in part because tau lacks well-defined druggable sites and accumulates as heterogeneous intracellular aggregates that are difficult to access and clear. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance through the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In neurons derived from patients with frontotemporal dementia (FTD) and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 promoted autophagy-lysosome-mediated tau degradation. It readily crossed the blood-brain barrier and improved motor function in JNPL3 tauopathy mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
21 orphan drug designations for Frontotemporal dementia.
21 orphan drug designations for Frontotemporal dementia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
progranulin replacement therapy | gene therapies | FDA | Denali Therapeutics Inc. | |
neflamapimod | small molecules | FDA | EIP Pharma, LLC | |
Sodium selenate | small molecules | EMA | — | Monash University |
Rifampin | small molecules | FDA | — | Medilabo RFP, Inc. |
Autologous human bone marrow-derived haematopoietic and mesenchymal stem cells depleted of erythrocytes, monocytes and lymphocytes | cell therapies | EMA | — | Neuroplast B.V. |
Adeno-associated virus vector serotype 9 encoding the human GRN gene | gene therapies | EMA | Scendea (NL) B.V. | |
Recombinant AAV9 vector encoding the human progranulin (PGRN) gene | gene therapies | FDA | AviadoBio Ltd. | |
Latozinemab | antibodies | EMA | Glaxosmithkline Trading Services Limited | |
Adeno-associated virus vector serotype 1 containing the human GRN gene | gene therapies | EMA | Pharma Gateway AB | |
Non-replicating recombinant adeno-associated virus serotype 1 vector delivering human GRN gene encoding the protein progranulin | gene therapies | FDA | Passage Bio, Inc. | |
Adeno-associated viral vector serotype 9 expressing codon-optimized human GRN gene | gene therapies | EMA | PPD Bulgaria EOOD | |
Fasudil | small molecules | FDA | Woolsey Pharmaceuticals, Inc. | |
Non-replicating recombinant adeno-associated virus serotype 9 containing the progranulin gene | gene therapies | FDA | Prevail Therapeutics | |
recombinant human anti-human sortilin (SORT1) IgG1 G1m17,1 [or G1m (z,a)] kappa monoclonal antibody | antibodies | FDA | Alector, Inc. | |
hydromethylthionine mesylate | small molecules | FDA | Tau Rx Therapeutics Management Ltd. | |
recombinant human anti-human Sortilin (SORT1) monoclonal IgG1 G1m17,1 [or G1m (z,a)] kappa monoclonal antibody | antibodies | FDA | Alector | |
Isoindolin-1,3-Di Thione | small molecules | FDA | — | P2D, Inc. |
tolfenamic acid | small molecules | FDA | — | Nasser H. Zawia |
1-(2,8-Dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one | small molecules | FDA | — | Anavex Life Sciences Corp. |
peptide fraction derived from porcine brain protein | peptides | FDA | — | EVER Neuro Pharma GmbH |
Methylthioninium | small molecules | EMA | Pharma Gateway AB |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.