Alzheimer's & dementia (New York, N. Y.) · 2026
Baseline plasma C1q and C3 as potential biomarkers for lecanemab efficacy and ARIA risk in early Alzheimer's disease.
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Byeon Gihwan, Lee Jung-Won, Kim Suhyung, Um Yoo Hyun, Wang Sheng-Min, Ha Seunggyun, Park Sonya Youngju, Shin Ilah, Jang Jinhee, Lee Chang Uk, Lim Hyun Kook, Kang Dong Woo
Аннотация
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.
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.