Sex-Specific Genetic Architecture of ALS: Evidence of a Female Protective Effect? Maurizio Grassano, Francesca Palumbo, Gabriele Mora, Salvatore Gallone, Giovanni De Marco, et al. Annals of Neurology, 2026 Background Amyotrophic lateral sclerosis (ALS) shows sex differences in incidence and age of onset, yet the underlying biological mechanisms remain poorly understood. Methods We investigated sex‐specific genetic architecture in an Italian ALS cohort with whole‐genome sequencing (1,333 ALS cases, 755 controls). We performed a sex‐stratified burden analysis of rare variants in ALS‐associated genes and compared the proportions of male and female ALS patients carrying pathogenic or rare damaging variants. Key findings were replicated in the AnswerALS cohort ( n = 723). Gene‐specific sex ratios and familial history for C9ORF72 , SOD1 , and TARDBP were examined in an expanded dataset of 2,301 Italian ALS patients. Results Sex‐stratified burden testing revealed that rare variants in ALS genes were enriched in female cases versus controls (odds ratio [OR] 5.47, 95% confidence interval [CI] 1.60–34.29) but not in male cases. Female ALS patients more frequently carried rare damaging variants compared to males (23.2% vs 18.3%; OR 1.38, 95% CI 1.05–1.81), a finding that was replicated in the AnswerALS cohort (18.9% vs 12.4%; OR 1.58, 95% CI 1.10–2.26). Gene‐level analyses of TARDBP carriers revealed a male predominance (2.1:1), yet a higher rate of familial history among females (40.4% vs 24.5%; OR 2.13, 95% CI 1.03–4.39). Interpretation Females with ALS exhibited a higher overall burden of rare damaging variants, suggesting sex‐related differences in genetic liability. Gene‐level analyses indicate that the influence of sex varies across ALS genes, particularly TARDBP . These findings help explain epidemiological patterns and have implications for the identification of sex‐linked protective mechanisms. ANN NEUROL 2026
MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis Paolo V Fioretti, Anna Barbieri, Alice Migazzi, Davide Bressan, Maurizio Grassano, et al. Brain, 2026 Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis and frontotemporal dementia with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice and patient-derived cells modelling TDP-43, SOD1 and C9ORF72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioural abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived extracellular vesicles that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.
The Epidemiology of Primary Lateral Sclerosis: Results from a Population-Based Cohort Rosario Vasta, Enrico Matteoni, Giorgio Pellegrino, Antonio Canosa, Umberto Manera, et al. Annals of Neurology, 2026 Objective In this population‐based study, we described the epidemiology of primary lateral sclerosis (PLS) in northern Italy and compared the clinical characteristics of patients with PLS to those with predominant upper motor neuron (PUMN) involvement and classic amyotrophic lateral sclerosis (ALS). Methods Patients from the PARALS registry diagnosed with probable or definite PLS between 2007 and 2021 were included. Crude annual incidence rates were calculated, along with age‐ and sex‐specific rates. A survival analysis was performed to identify prognostic factors at diagnosis. Covariates included sex, age at onset, site of onset, diagnostic delay, forced vital capacity (FVC), change in ALS Functional Rating Scale (ΔFRS), and change in body mass index (ΔBMI). Results A total of 57 PLS patients (2.7%) were included, with a crude incidence rate of 0.084 per 100,000 person‐years. Compared to PUMN and classic ALS, PLS patients were younger (median onset age 63.5 years, interquartile range [IQR] 54.9–70.4) and predominantly female (male‐to‐female ratio 0.58). Bulbar onset occurred in 11 cases (19.3%), all of whom later developed spinal symptoms. At censoring, 38 patients (66.7%) were still alive (median survival 8.3 years, IQR 5.7–12.3), corresponding to a point prevalence of 0.89 per 100,000. Survival was significantly associated with age at onset (hazard ratio [HR] 1.17, 95% confidence interval [CI]: 1.05–1.33, p = 0.001), male sex (HR 4.41, 95% CI: 1.24–15.6, p = 0.02), and FVC at diagnosis (HR 0.95, 95% CI: 0.93–0.98, p = 0.006). Interpretation PLS was confirmed to be rarer than other ALS phenotypes. Patients had a higher age at onset than previously reported and a female predominance. Sex, age at onset, and respiratory function were key prognostic factors. ANN NEUROL 2025
Amyotrophic Lateral Sclerosis Prevalence Projection in 2040: A Less Rare Disease Rosario Vasta, Stefano Callegaro, Antonio Canosa, Umberto Manera, Maurizio Grassano, et al. Annals of Clinical and Translational Neurology, 2026 ObjectiveTo project ALS prevalence across multiple countries through 2040, accounting for both population aging and increased survival.MethodsData from the Piemonte and Valle d'Aosta ALS register (PARALS) was used to estimate the trends in incidence and prevalence from 2005 to 2019. Survival trends over this period were also assessed. The observed annual increase was then projected into future years up to 2040. Concurrently, the incidence for each future year was calculated using population projections. Finally, the prevalence rate for each year was estimated as the product of the projected incidence and the projected survival. We also estimated survival for fifteen countries by dividing prevalence by incidence, based on available data, and applied the same increase observed in PARALS to project prevalence in these countries up to 2040.ResultsUsing data from 3294 patients, we determined that ALS survival increased by 0.06 years annually from 2005 to 2019 in Piemonte and Valle d'Aosta. Considering changes in incidence due to population aging, the prevalence is projected to reach 15.72 per 100,000 population by 2040 in this area, while rising by a median of 24.9% across multiple countries worldwide. If a new drug could provide a 6‐month increase in survival starting in 2025, disease prevalence would rise by 37.8% by 2040. We provided a web interface so users can model different data and assumptions.InterpretationALS prevalence is projected to increase significantly over the next decades. This underscores the need for careful planning and allocation of public health resources.
Role of 2-[18F]FDG-PET as a biomarker of upper motor neuron involvement in amyotrophic lateral sclerosis Sara Cabras, Umberto Manera, Francesca Di Pede, Grazia Zocco, Rosario Vasta, et al. Journal of Neurology, 2025 Introduction Amyotrophic Lateral Sclerosis (ALS) affects upper (UMN) and lower (LMN) motor neurons. ALS diagnosis is challenging, especially in predominant LMN phenotypes. Electromyography can disclose LMN damage, while UMN involvement is detectable by clinical examination, with possible support of magnetic resonance imaging (MRI) and transcranial magnetic stimulation. Our aim was to investigate the role of 2-[ 18 F]FDG-PET as an UMN biomarker in ALS. Methods In our cross-sectional study, we created an UMN burden score. Performing a multiple regression analysis in SPM12, we evaluated the relationship between UMNBS and brain metabolism. We split ALS cohort based on the UMN burden score median value (group A—under median, group B—above median). We ran a full factorial analysis including group A and B and healthy controls, followed by group comparisons. Results We included 118 ALS patients (group A and B, N = 59), with a median UMN burden score of 9.50 and a left lateralization of UMN signs. We found a negative correlation between motor cortex metabolism and UMN burden score. Comparing each ALS group with healthy controls, we found relative hypometabolism in the left frontal lobe and relative bilateral, right-prevalent hypermetabolism of cerebellum and corticospinal tracts. The relative hypermetabolism in corticospinal tracts was more evident in the group with low UMN signs. Conclusions Motor cortex metabolism reflects UMN burden. Corticospinal tracts’ metabolic changes could provide information about UMN involvement even in patients with predominant LMN phenotype, suggesting a possible role of brain 2-[ 18 F]FDG-PET as an UMN biomarker in ALS patients.
Cognitive Reserve in Amyotrophic Lateral Sclerosis: A 2-[18F]FDG-PET Study on Sex-Related Differences Antonio Canosa, Stefano Callegaro, Umberto Manera, Rosario Vasta, Sara Cabras, et al. European Journal of Neurology, 2025 Background Cognitive reserve (CR) applies to ALS‐related cognitive impairment and education is a CR proxy. The influence of sex on CR in ALS is unclear. Methods We compared brain 2‐[ 18 F]FDG‐PET metabolism of male (m‐ALS, n = 95) and female (f‐ALS, n = 95) patients, matched for age, education, onset, and King's stage, with no significant difference in ECAS scores. In each group, clusters showing a negative/positive correlation with education were used as seed regions in an interregional correlation analysis (IRCA) to evaluate connectivity. We identified the seed regions including age, onset, King's stage and ECAS as covariates. Results M‐ALS showed a relative hypometabolism compared to f‐ALS in bilateral frontotemporal regions. In f‐ALS brain metabolism positively correlated with education in the left fusiform gyrus, cerebellum and pons. The IRCA showed a positive correlation of the seed region with the cerebellum, pons, right fusiform gyrus and cuneus, and the left precuneus, and a negative correlation with the frontal lobes and caudate nuclei. In m‐ALS brain metabolism negatively correlated with education in the left frontotemporal and insular cortices. The IRCA showed a positive correlation of the seed region with bilateral frontotemporal and cingulate cortices, and the right parietal cortex, and a negative correlation with bilateral cerebellum and motor cortex, and the left lingual gyrus. Conclusions M‐ALS showed relative frontotemporal hypometabolism compared to f‐ALS, suggesting a male prevalence of CR. In m‐ALS the negative correlation of education with left frontotemporal and insular metabolism supports the CR hypothesis. In f‐ALS the positive correlation of cerebellar metabolism with education suggests compensatory mechanisms, also supported by the IRCA.
A plasma proteomics-based candidate biomarker panel predictive of amyotrophic lateral sclerosis Ruth Chia, Ruin Moaddel, Justin Y. Kwan, Memoona Rasheed, Paola Ruffo, et al. Nature Medicine, 2025 Identifying a reliable biomarker for amyotrophic lateral sclerosis (ALS) is crucial for clinical practice. Here, in this cross-sectional study, we used the Olink Explore 3072 platform to investigate plasma proteomics as a biomarker tool for this neurodegenerative condition. Thirty-three proteins were differentially abundant in the plasma of patients with ALS (n = 183) versus controls (n = 309). We replicated our findings in an independent cohort (n = 48 patients with ALS and n = 75 controls). We then applied machine learning to create a model that diagnosed ALS with high accuracy (area under the curve, 98.3%). By analyzing plasma samples from individuals before ALS symptoms emerged, we estimated the age of clinical onset and showed that the disease process—impacting skeletal muscle, nerves and energy metabolism—occurs years before symptoms appear. Our research suggests that plasma proteins can be a biomarker for this fatal disease and offers molecular insights into its prodromal phase.
What is amyotrophic lateral sclerosis prevalence? Rosario Vasta, Cristina Moglia, Umberto Manera, Antonio Canosa, Maurizio Grassano, et al. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis PV Fioretti, A Barbieri, A Migazzi, D Bressan, M Grassano, L Donini, ... Brain 149 (5), 1604-1622 , 2026 2026 Citations: 2
Machine learning model based on plasma proteomics for the identification of Parkinson’s disease B Adewale, R Chia, R Moaddel, N Landeck, M Rasheed, C Alba, P Reho, ... Brain, awag140 , 2026 2026
Genetic analysis of neurodegenerative diseases M Grassano, AB Schindler, BJ Traynor, SW Scholz The Journal of Clinical Investigation 136 (7) , 2026 2026 Citations: 1
Brain metabolic connectivity in ALS due to C9ORF72 hexanucleotide expansion: a [18F] FDG-PET study A Canosa, S Callegaro, U Manera, R Vasta, S Cabras, F Di Pede, ... European Journal of Nuclear Medicine and Molecular Imaging 53 (4), 2786-2798 , 2026 2026
The Epidemiology of Primary Lateral Sclerosis: Results from a Population‐Based Cohort R Vasta, E Matteoni, G Pellegrino, A Canosa, U Manera, F Palumbo, ... Annals of Neurology 99 (3), 606-613 , 2026 2026 Citations: 1
Sex‐Specific Genetic Architecture of ALS: Evidence of a Female Protective Effect? M Grassano, F Palumbo, G Mora, S Gallone, G De Marco, I Merulla, ... Annals of Neurology , 2026 2026
Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis TM Miller, ME Cudkowicz, PJ Shaw, A Genge, G Sobue, RC Bucelli, ... JAMA neurology 83 (2), 115-125 , 2026 2026 Citations: 10
Amyotrophic lateral sclerosis prevalence projection in 2040: a less rare disease R Vasta, S Callegaro, A Canosa, U Manera, M Grassano, F Palumbo, ... Annals of Clinical and Translational Neurology 13 (2), 379-386 , 2026 2026 Citations: 3
Role of 2-[ 18 F]FDG-PET as a biomarker of upper motor neuron involvement in amyotrophic lateral sclerosis S Cabras, U Manera, F Di Pede, G Zocco, R Vasta, A Novara, E Minerva, ... Journal of Neurology 272 (12), 766 , 2025 2025 Citations: 1
Cognitive Reserve in Amyotrophic Lateral Sclerosis: A 2‐[ 18 F]FDG‐PET Study on Sex‐Related Differences A Canosa, S Callegaro, U Manera, R Vasta, S Cabras, F Di Pede, ... European Journal of Neurology 32 (11), e70412 , 2025 2025
Genetic Variants Associated With Neurodegenerative Disorders in Patients With Amyotrophic Lateral Sclerosis and Phenotypic Variability M Grassano, E Koumantakis, FF Palumbo, M Brunetti, G De Marco, ... Neurology 105 (8), e214180 , 2025 2025
Proteomics Identifies a Panel of Plasma Proteins That Can Be Used as a Diagnostic Biomarker of ALS R Chia, R Moaddel, J Kwan, M Rasheed, P Ruffo, N Landeck, P Reho, ... MUSCLE & NERVE 72, S97-S97 , 2025 2025
A plasma proteomics-based candidate biomarker panel predictive of amyotrophic lateral sclerosis R Chia, R Moaddel, JY Kwan, M Rasheed, P Ruffo, N Landeck, P Reho, ... Nature medicine 31 (10), 3440-3450 , 2025 2025 Citations: 27
Lifetime Physical Activity as an Environmental Modifier of ALS Phenotype M Grassano, C Moglia, A Calvo, A Chia ANNALS OF NEUROLOGY 98 , 2025 2025
Whole genome sequencing analysis in primary lateral sclerosis (PLS) patients reveals mutations in neurological diseases-causing genes A Manini, A Brusati, M Grassano, G Scacciatella, S Peverelli, J Spagliardi, ... Journal of Neurology 272 (9), 587 , 2025 2025 Citations: 3
Exploring the phenotypic fingerprints of ANXA11 variants in ALS: a population-based study in an European cohort F Palumbo, B Iazzolino, C Moglia, U Manera, E Matteoni, S Cabras, ... Journal of Neurology 272 (8), 524 , 2025 2025 Citations: 1
Phosphatemia is an independent prognostic Factor in amyotrophic lateral sclerosis R Vasta, E Koumantakis, A Canosa, U Manera, M Grassano, F Palumbo, ... Annals of Neurology 98 (2), 286-293 , 2025 2025 Citations: 3
Another brick in our knowledge of ALS causes: a population-based study of residential clustering S Callegaro, U Manera, A Canosa, M Grassano, F Palumbo, S Cabras, ... Journal of Neurology, Neurosurgery & Psychiatry 96 (8), 821-822 , 2025 2025
KIF5A p.Pro986Leu Risk Variant and Accelerated Progression of Amyotrophic Lateral Sclerosis A Manini, R Vasta, A Brusati, F Scheveger, S Peverelli, A Maranzano, ... Annals of Clinical and Translational Neurology 12 (7), 1499-1503 , 2025 2025 Citations: 2
FUS mislocalization rewires a cortical gene network to drive cognitive and behavioral impairment in ALS R Cassel, F Lorenc, A Bombardier, C De Tapia, S Dieterle, CG Roque, ... medRxiv , 2025 2025 Citations: 4
MOST CITED SCHOLAR PUBLICATIONS
Genome-wide analyses identify KIF5A as a novel ALS gene A Nicolas, KP Kenna, AE Renton, N Ticozzi, F Faghri, R Chia, ... Neuron 97 (6), 1267-1288 , 2018 2018 Citations: 800
Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology W Van Rheenen, RAA Van Der Spek, MK Bakker, JJFA Van Vugt, PJ Hop, ... Nature genetics 53 (12), 1636-1648 , 2021 2021 Citations: 594
Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture R Chia, MS Sabir, S Bandres-Ciga, S Saez-Atienzar, RH Reynolds, ... Nature genetics 53 (3), 294-303 , 2021 2021 Citations: 443
ALS phenotype is influenced by age, sex, and genetics: a population-based study A Chiò, C Moglia, A Canosa, U Manera, F D'Ovidio, R Vasta, M Grassano, ... Neurology 94 (8), e802-e810 , 2020 2020 Citations: 224
Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis S Bandres‐Ciga, AJ Noyce, G Hemani, A Nicolas, A Calvo, G Mora, ... Annals of neurology 85 (4), 470-481 , 2019 2019 Citations: 205
Early weight loss in amyotrophic lateral sclerosis: outcome relevance and clinical correlates in a population-based cohort C Moglia, A Calvo, M Grassano, A Canosa, U Manera, F D'Ovidio, ... Journal of Neurology, Neurosurgery & Psychiatry 90 (6), 666-673 , 2019 2019 Citations: 133
Secular trends of amyotrophic lateral sclerosis: the Piemonte and Valle d’Aosta register A Chiò, G Mora, C Moglia, U Manera, A Canosa, S Cammarosano, A Ilardi, ... JAMA neurology 74 (9), 1097-1104 , 2017 2017 Citations: 132
Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS PJ Hop, RAJ Zwamborn, E Hannon, GL Shireby, MF Nabais, EM Walker, ... Science translational medicine 14 (633), eabj0264 , 2022 2022 Citations: 106
Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis JO Johnson, R Chia, DE Miller, R Li, R Kumaran, Y Abramzon, ... JAMA neurology 78 (10), 1236-1248 , 2021 2021 Citations: 96
Systematic evaluation of genetic mutations in ALS: a population-based study M Grassano, A Calvo, C Moglia, L Sbaiz, M Brunetti, M Barberis, F Casale, ... Journal of Neurology, Neurosurgery & Psychiatry 93 (11), 1190-1193 , 2022 2022 Citations: 74
Identifying and predicting amyotrophic lateral sclerosis clinical subgroups: a population-based machine-learning study F Faghri, F Brunn, A Dadu, A Chiò, A Calvo, C Moglia, A Canosa, ... The Lancet Digital Health 4 (5), e359-e369 , 2022 2022 Citations: 71
Integrative genetic analysis illuminates ALS heritability and identifies risk genes S Megat, N Mora, J Sanogo, O Roman, A Catanese, NO Alami, ... Nature communications 14 (1), 342 , 2023 2023 Citations: 57
Sex differences in amyotrophic lateral sclerosis survival and progression: a multidimensional analysis M Grassano, C Moglia, F Palumbo, E Koumantakis, P Cugnasco, ... Annals of Neurology 96 (1), 159-169 , 2024 2024 Citations: 56
Mutational analysis of known ALS genes in an Italian population-based cohort M Grassano, A Calvo, C Moglia, M Brunetti, M Barberis, L Sbaiz, ... Neurology 96 (4), e600-e609 , 2021 2021 Citations: 48
Telemedicine for patients with amyotrophic lateral sclerosis during COVID-19 pandemic: an Italian ALS referral center experience R Vasta, C Moglia, F D’Ovidio, F Di Pede, F De Mattei, S Cabras, L Peotta, ... Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 22 (3-4), 308-311 , 2021 2021 Citations: 47
Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study C Moglia, A Calvo, A Canosa, D Bertuzzo, P Cugnasco, L Solero, ... Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 18 (7-8), 590-597 , 2017 2017 Citations: 43
The interplay among education, brain metabolism, and cognitive impairment suggests a role of cognitive reserve in amyotrophic lateral sclerosis A Canosa, F Palumbo, B Iazzolino, L Peotta, F Di Pede, U Manera, ... Neurobiology of Aging 98, 205-213 , 2021 2021 Citations: 42
Effects of intracellular calcium accumulation on proteins encoded by the major genes underlying amyotrophic lateral sclerosis G De Marco, A Lomartire, U Manera, A Canosa, M Grassano, F Casale, ... Scientific Reports 12 (1), 395 , 2022 2022 Citations: 40
Differential Neuropsychological Profile of Patients With Amyotrophic Lateral Sclerosis With and Without C9orf72 Mutation B Iazzolino, L Peotta, JP Zucchetti, A Canosa, U Manera, R Vasta, ... Neurology 96 (1), e141-e152 , 2021 2021 Citations: 37
Phenotype analysis of fused in sarcoma mutations in amyotrophic lateral sclerosis M Grassano, G Brodini, G De Marco, F Casale, G Fuda, P Salamone, ... Neurology: Genetics 8 (5), e200011 , 2022 2022 Citations: 36
