Alzheimer’s disease-related cerebrospinal fluid Biomarkers in Amyotrophic Lateral Sclerosis: Real-World Associations with Disease Status, Cognition and Tofersen Response

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 (Aβ ₄₀ , Aβ ₄₂ ), tau proteins, and neurofilaments are clinically established biomarkers in 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 incompletely understood.

Methods

In this retrospective study, we analyzed clinical and CSF biomarker data from patients with ALS, AD, Huntington’s disease (HD), and other disease controls from real-world clinical settings. The dataset comprised Aβ ₄₀ , Aβ ₄₂ , total tau (t-Tau), phosphorylated tau181 (pTau181), phosphorylated neurofilament heavy chain (pNfH), and relevant serum markers as well as clinical and cognitive status measurements. Additionally, longitudinal CSF sampling over one year was evaluated in three ALS patients receiving tofersen treatment.

Results

In this real-world cohort, AD-related CSF biomarkers demonstrated no diagnostic value for distinguishing ALS from other neurodegenerative conditions. However, Aβ ₄₀ , Aβ ₄₂ , 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 Aβ ₄₂ /Aβ ₄₀ 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.

Discussion

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.

Graphical Abstract