A novel evaluation of potential risk and prognostic factors for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Although the etiology of ALS is known to involve both genetic and environmental factors, the mechanisms underlying disease onset and progression are still not fully understood. Leveraging data from Swedish national and quality registers, we explored how cardiometabolic conditions, lifestyle factors, mental health and environmental exposures influence both the risk of developing ALS and the progression after diagnosis. Study 1 This nationwide study examined whether cardiometabolic diseases (CMDs) are associated with the risk and progression of motor neuron diseases (MNDs). We analyzed 1,463 MND patients diagnosed in Sweden between 2015 and 2023 and compared them with age- and sex-matched population controls (n = 7,311) as well as siblings (n = 2,002) and spouses (n = 1,220). Associations between prediagnostic CMDs and MND risk were assessed using conditional logistic regression, while disease progression and mortality were evaluated with joint longitudinal–survival models accounting for repeated ALSFRS-R measurements. Hierarchical clustering was used to identify clinical subgroups. Type 2 diabetes mellitus and hypercholesterolemia diagnosed more than one year before MND onset were associated with a lower risk of MND, with similar associations observed beyond five years before diagnosis. In contrast, after diagnosis, a history of cardiovascular disease, arrhythmia, heart failure, hypertension, or hypercholesterolemia was associated with higher mortality, independent of longitudinal functional decline. Cluster analysis identified a subgroup of older patients with worse functional status and a higher CMD burden at diagnosis, who experienced faster progression and shorter survival. Overall, while diabetes and hypercholesterolemia were linked to a reduced future risk of MND, most CMDs predicted poorer outcomes after diagnosis. Study 2 This study introduced the Swedish ALSrisc Study and investigated how lifestyle factors and medical conditions relate to the risk and progression of amyotrophic lateral sclerosis (ALS). We included 265 newly diagnosed ALS patients in Stockholm (2016–2022) and 207 ALS-free individuals (patients’ siblings and partners) as controls. Data on body mass index (BMI), smoking, head injury, diabetes, hypercholesterolemia, and hypertension were collected at recruitment, and patients were followed until death, invasive ventilation, or November 30, 2022. Higher BMI at recruitment and over the 30 years preceding diagnosis was associated with a lower risk of ALS, particularly among individuals diagnosed after age 65. Diabetes was also linked to reduced ALS risk, whereas hypercholesterolemia was associated with increased risk. After diagnosis, higher BMI predicted lower mortality, while heavy smoking, hypercholesterolemia, and hypertension were associated with poorer survival. Overall, higher BMI and diabetes were associated with lower ALS risk, whereas smoking and cardiometabolic conditions predicted worse outcomes after diagnosis. Study 3 We conducted a nationwide register-based case-control study in Sweden, including all ALS patients diagnosed between 2015-2023, from the Swedish Motor Neuron Disease Quality Registry. Each case was matched by age and sex with up to five population controls, as well as with full siblings and spouses. Patients were followed for a median of 1.33 years after diagnosis. Prediagnostic use of anxiolytics, hypnotics and sedatives, or antidepressants was defined as at least two prescriptions before ALS diagnosis. Conditional logistic regression models assessed associations between prediagnostic medication use and ALS risk, while disease progression and mortality were examined using joint longitudinal–survival models accounting for ALS Functional Rating Scale–Revised (ALSFRS-R) changes. Among 1,057 ALS patients and 5,281 population controls with a similar age and sex distribution across groups the use of psychiatric medications before diagnosis was consistently associated with a higher risk of ALS across multiple exposure periods. Anxiolytics and antidepressants were associated with increased risk when used several years earlier. Analyses using sibling and spouse controls largely supported these results, indicating limited influence of shared familial factors, although findings for hypnotics and sedatives were less consistent. Prediagnostic use of anxiolytics or antidepressants was also linked to shorter survival after diagnosis. All in all, prescribed use of psychiatric medications is associated with higher risk of ALS and poorer prognosis following diagnosis. Study 4 We investigated the association between metal mixtures and ALS risk and prognosis using high-resolution hair metal profiling and genetic data from the Swedish ALSrisc Study. Hair samples from 244 newly diagnosed ALS patients and 191 controls were analyzed to quantify daily deposition of 15 metals over the 34 days preceding sample collection. Metal concentrations were measured using laser ablation–inductively coupled plasma mass spectrometry and evaluated using lagged weighted quantile sum regression. Linear mixed-effects models compared temporal metal patterns between cases and controls. ALS polygenic risk scores were used to assess gene–environment interactions. Associations with survival were examined using Cox regression, while crosssectional and longitudinal relationships with functional status, cognition, depression, and anxiety were assessed using linear regression and mixedeffects models. ALS patients showed higher hair deposition of lithium in the days preceding diagnosis compared with controls. Overall metal mixture levels were elevated among ALS patients, particularly among those with spinal onset and higher genetic susceptibility. Magnesium, cobalt, calcium, phosphorus, lithium, cesium, and arsenic contributed most to the mixture effect. The metal mixture was not associated with survival or clinical measures at diagnosis or during follow-up. These findings underscore the relevance of metal mixtures and gene–environment interactions in ALS etiology. Taken together, these findings support the view that ALS arises from a multifactorial and highly interconnected network of biological and environmental influences, encompassing metabolic and cardiovascular profiles, mental health, lifestyle-related factors, genetic susceptibility, and environmental exposures. Rather than acting in isolation, these domains appear to converge across the life course to shape vulnerability to disease onset and progression. Integrating these dimensions may improve risk stratification, facilitate the identification of individuals at increased susceptibility, and refine our understanding of early and potentially preclinical disease mechanisms. List of scientific papers I. Chourpiliadis C, Lovik A, Seitz C, Hu Y, Wu J, Ljungman P, Press R, Samuelsson K, Ingre C, Fang F. Association between cardiometabolic diseases and the risk and progression of motor neuron diseases in Sweden: a population-based case-control study. Lancet Reg Health Eur. 2024 Dec 10;49:101173. PMID: 39759580. https://doi.org/10.1016/j.lanepe.2024.101173 II. Chourpiliadis C, Seitz C, Lovik A, Joyce EE, Pan L, Hu Y, Kläppe U, Samuelsson K, Press R, Ingre C, Fang F. Lifestyle and medical conditions in relation to ALS risk and progression – an introduction to the Swedish ALSrisc Study. J Neurol. 2024 Aug;271(8):5447-5459. Epub 2024 Jun 15. PMID: 38878106. https://doi.org/10.1007/s00415-024-12496-w III. Chourpiliadis C, Lovik A, Ingre C, Press R, Samuelsson K, Valdimarsdottir U, Fang F. Use of Common Psychiatric Medications and Risk and Prognosis of Amyotrophic Lateral Sclerosis. JAMA Netw Open. 2025 Jun 2;8(6):e2514437. PMID: 40465292. https://doi.org/10.1001/jamanetworkopen.2025.14437 IV. Chourpiliadis C, Midya V, Hou C, Seitz C, Lafitta J, Graff C, Lovikm A, Press R, Samulesson K, Kläppe U, Öijerstedt L, Ye W, Harris R, Mälarstig A, Ingre C, Arora M, Fang F. Metal co-exposure in relation to the risk and prognosis of amyotrophic lateral sclerosis – an analysis of the Swedish ALSrisc Study. [Manuscript]