Spatial clustering of amyotrophic lateral sclerosis in Sardinia, Italy: The contribution of age, sex, and genetic factors

Abstract

Introduction/AimsSeveral microgeographic clusters of higher/lower incidence of amyotrophic lateral sclerosis (ALS) have been identified worldwide. Differences in the distribution of local factors were proposed to explain the excess ALS risk, whereas the contribution of known genetic/epigenetic factors remains unclear. The aim is to identify restricted areas of higher risk in Sardinia and to assess whether age, sex, and the most common causative genetic mutations in Sardinia (C9orf72 and TARDBP mutations) contributed to the variation in the ALS risk.MethodsWe performed an ad hoc analysis of the 10‐y population‐based incident cohort of ALS cases from a recent study of a large Sardinian area. Cluster analysis was performed by age‐ and sex‐adjusted Kulldorff's spatial scan statistic.ResultsWe identified a statistically significant cluster of higher ALS incidence in a relatively large area including 34 municipalities and >100,000 individuals. The investigated genetic mutations were more frequent in the cluster area than outside. Regardless of the genetic mutations, the excess of ALS risk was significantly associated with either sex or with age ≥ 65 y. Finally, an additive interaction between older age and male sex contributed to the excess of ALS risk in the cluster area but not outside.DiscussionOur analysis demonstrated that known genetic factors, age, and sex may contribute to microgeographic variation in ALS incidence. The significant additive interaction between older age and male sex we found in the high‐incidence cluster could suggest the presence of a third factor connecting the analyzed risk factors.

The role of statins in amyotrophic lateral sclerosis: protective or not?

“…Genetic alterations, together with environmental factors, promote the development of ALS (Motataianu et al, 2022 ). ALS below the age of 70 is more common in men by 20%, but sex differences are not observed above the age of 70 years (Borghero et al, 2023 ). ALS neuropathology is characterized by neuronal lesions located in the brain motor cortex for the upper motor neurons, the brain stem, and spinal cord for the lower motor neurons (Del Tredici and Braak, 2022 ).…”