Therapeutic time window of disease-modifying therapy for early Alzheimer's disease

IntroductionRecently approved disease-modifying therapies (DMT) for early Alzheimer's disease (AD), including lecanemab and donanemab, require patients to meet specific eligibility criteria for treatment. These criteria define a limited "therapeutic time window," after which patients become ineligible as the disease advances. Understanding factors influencing this window may help clinicians optimize patient management and reduce lost treatment opportunities. MethodsWe analyzed longitudinal data from two observational cohorts, the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). At each visit, individuals were deemed eligible if they were amyloid-positive and had a Mini-Mental State Examination (MMSE) score of 22-30 (lecanemab) or 20-30 (donanemab), plus a Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1. We then applied survival analyses and Cox proportional hazards models to estimate time-to-ineligibility based on baseline cognitive status. ResultsAcross both datasets, higher baseline CDR-GS and MMSE were associated with a lower risk of becoming ineligible (pooled hazard ratio of 1.601 for CDR-GS of 1 vs. 0.5, and pooled hazard ratio of 0.660 per 1-point increase in MMSE score above the lower limit of eligibility). The estimated 75% survival time for patients with baseline CDR-GS 0.5 was over 12 months, suggesting only 25% would become ineligible within 12 months. For those with CDR-GS 1, the estimated 50% survival time was approximately 12 months, depending on the data, indicating that half might become ineligible within 1 year. DiscussionWe quantitatively outlined the duration of the therapeutic time window for early AD patients who qualify for lecanemab or donanemab, which is significantly influenced by baseline CDR-GS and MMSE scores. These findings will support more proactive patient management, ensuring timely evaluations and prioritization of patients at higher risk of ineligibility, particularly where DMT access is limited. Highlights We examined the "therapeutic time window" eligibility for disease-modifying therapy. Longitudinal data from National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to quantify eligibility duration. Higher Clinical Dementia Rating-Global Score (CDR-GS) or lower Mini-Mental State Examination (MMSE) at baseline were associated with shorter window length. Our results will help optimize the management of the wait time for disease-modifying therapies (DMT) treatment.