A population based study to analyse amyotrophic lateral sclerosis as a multi-step process

Abstract

Recent studies suggest that Amyotrophic Lateral Sclerosis (ALS) follows a multistep process. We evaluated this hypothesis in a well-defined ALS population in Palermo, Sicily, almost entirely followed by our ALS Clinical Center. Incident data from the ALS Center (2014-2023) were analyzed, including both sporadic and familial ALS forms of the disease. To evaluate the multistep process, we regressed the natural log of age-specific incidence against the natural log of patient age We identified 216 ALS patients. We obtained a slope of 5 (r² = 0.93); the 95% CI ranged from 2.51 to 7.60, remaining relatively wide due to the small sample size, with a p-value of 0.008. The slope estimate was consistent with a 6-step process. In the Palermo ALS population, the multistep analysis confirms a process consistent with a 6-step model. This data, obtained in a relatively homogeneous population, further highlights the probability of strict interaction between environmental and genetic variables in the disease. Our data offer insights into the complexity of the mechanisms involved in the pathogenesis of the disease, particularly during its asymptomatic phase. This study supports the hypothesis that a single therapeutic silver bullet would probably be insufficient to arrest or slow the disease's progression.

Fig. 1

ALS patients diagnosed/referred at the ALS Clinical Research Center in Palermo in 2014–2023. a) Number of patients by age. b). Crude incidence rates by age.

Fig. 2

Log incidence vs. log age in the ALS population province of Palermo, Sicily Island geographical area. The graph shows a good fit with a straight line with r2 = 0.93 consistent with the multistep model. The slope estimate is 5 (CI 95% 2.51–7.60; p = 0.008), suggesting that six steps are needed to trigger the onset of the disease.