Abstract INTRODUCTION Although cerebrospinal fluid (CSF) biomarkers reflect neurodegeneration in Alzheimer's disease (AD), it remains unclear whether these biomarkers track neurodegeneration in early‐onset Alzheimer's disease (EOAD). METHODS In 80 EOAD patients, we examined correlations between eight CSF biomarker levels and cortical thickness decreases within the EOAD cortical atrophy signature. Significant correlations were then entered into a multiple regression analysis. We also examined contributions of EOAD atrophy and CSF biomarkers to cognitive impairment. RESULTS The levels of four CSF biomarkers correlated to EOAD signature atrophy. Stepwise regression analyses revealed that CSF neurofilament light chain (NfL) levels best predicted EOAD signature atrophy. Multiple regression showed EOAD signature atrophy combined with CSF NfL levels explained more variance in cognitive impairment than either factor alone. DISCUSSION Within EOAD patients, CSF NfL levels relate to the magnitude of cortical atrophy, and a combination of EOAD signature atrophy and CSF NfL levels most robustly predict cognitive impairment.
Improving the clinical trial landscape for patients with atypical variants of Alzheimer's disease: a call to action
Alzheimer's & Dementia | June 23, 2026 | Volume: 22 | Issue: 6 | Pages: No page available
Abstract Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non‐amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large‐scale clinical trials, which typically focus on late‐onset, sporadic amnestic‐predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid‐targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early‐onset amnestic and non‐amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome‐specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.