Baseline plasma C1q and C3 as potential biomarkers for lecanemab efficacy and ARIA risk in early Alzheimer's disease

Abstract INTRODUCTION The classical complement cascade has been implicated in amyloid beta (Aβ) clearance and in the pathogenesis of amyloid‐related imaging abnormalities (ARIA) during anti‐amyloid monoclonal antibody therapy. Clinically accessible peripheral biomarkers of this cascade remain uncharacterized in real‐world cohorts.

Methods

We conducted a retrospective, hypothesis‐generating cohort study of 62 patients with early Alzheimer's disease initiating lecanemab. ARIA risk was evaluated in the safety cohort (N = 62), and absolute amyloid reduction at week 26 was evaluated in the efficacy cohort with paired baseline and 26‐week amyloid positron emission tomography (N = 34). Associations of baseline plasma C1q, C3, and apolipoprotein E ε4 (APOE ε4) carrier status with these outcomes were examined using Firth's penalized logistic regression and bootstrap linear regression (2000 iterations), with prespecified sensitivity analyses. Within‐subject changes in C3 (N = 30) and C1q (N = 19) were assessed by paired Wilcoxon test.

Results

Lower baseline C3 was nominally associated with higher ARIA risk (odds ratio [OR] per 1 SD = 0.44, 95% CI: 0.15 to 0.97, p = 0.040, uncorrected), and this association persisted in international normalized ratio (INR)‐adjusted and simplified models. C3 ≤ 25th percentile (≤99 mg/dL) showed a trend (OR: 4.78, 95% CI: 0.98 to 26.34, p = 0.052). In the efficacy cohort, higher baseline C1q was associated with smaller amyloid reduction (β = −6.86, 95% CI: −12.19 to −3.06, p = 0.002); carriers of at least one APOE ε4 allele, a status that in this cohort jointly reflects genotype and dose‐titration, showed less amyloid reduction (β = −19.50, 95% CI −31.57 to −8.40, p < 0.001). Within‐subject changes in C1q and C3 were not significant (p = 0.248 and 0.114, respectively).

Discussion

Lower baseline C3 was consistently associated with ARIA risk across sensitivity analyses and higher baseline C1q with smaller amyloid reduction at week 26. Findings are exploratory given the limited single‐center sample.