CSF Alzheimer's Disease Biomarkers in Relation to Functional Status and Tofersen Treatment Response in ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons but also frequently involving cognitive impairment. Cerebrospinal fluid (CSF) measurements of β amyloid peptides (Aβ40, Aβ42), tau proteins, and neurofilaments are clinically established biomarkers in neurodegenerative disorders such as Alzheimer's disease (AD). Emerging evidence suggests that AD-related pathological changes and AD-related biomarkers may appear in ALS, yet their diagnostic and prognostic significance remains unclear. In this retrospective study, we analyzed clinical and CSF biomarker data from patients with ALS, AD, Huntington's disease (HD), and other disease controls recruited in a real-world clinical setting. The dataset comprised Aβ40, Aβ42, total tau (t-Tau), phosphorylated tau181 (pTau181), phosphorylated neurofilament heavy chain (pNfH), and relevant serum markers. Additionally, longitudinal CSF sampling over one year was evaluated in three ALS patients receiving tofersen treatment. In this real-world cohort, AD-related CSF biomarkers demonstrated no diagnostic value for distinguishing ALS from other neurodegenerative conditions. However, Aβ40, Aβ42, and pTau181 levels correlated positively with ALS Functional Rating Scale (ALSFRS-R) global score and serum Creatine Kinase MB (CK-MB) concentrations. At the same time, a higher Aβ42/Aβ40 ratio was associated with better memory performance on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). In tofersen-treated cases, AD-related biomarkers gradually declined during follow-up. These findings suggest that elevated CSF AD-associated biomarkers in ALS may reflect preserved functional and cognitive status and exhibited parallel declines during follow-up in three tofersen-treated patients, supporting their further prospective evaluation as exploratory markers of therapeutic responsiveness.