Blood Amyloid-β Reduction Following Chongnoi-tang Treatment in Alzheimer’s Spectrum Conditions: A Retrospective Pilot Observational Study

Background/Objectives: Anti-amyloid immunotherapies reduce amyloid-β (Aβ) plaques but carry a 15–35% risk of amyloid-related imaging abnormalities (ARIA), particularly in APOE ε4/ε4 carriers. This preliminary observational study evaluated blood Aβ oligomer changes following treatment with the multi-component herbal formula Chongnoi-tang (CNT) and contextualized these findings against natural disease trajectories in National Alzheimer’s Coordinating Center (NACC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) reference cohorts. Methods: This retrospective pilot cohort included 16 patients with Alzheimer’s spectrum conditions treated with CNT. Blood Aβ oligomers were measured using the AlzOn Plus immunoassay. Primary analysis (n = 13) excluded cases with a ceiling-level baseline value, an intercurrent potentially confounding condition, or no true baseline measurement. Results: Mean blood Aβ oligomer levels decreased by 15.8% ± 13.4% at 6 months (median −20.6%; 95% CI −23.9% to −7.8%; Wilcoxon signed-rank test, p < 0.001; paired Cohen’s dz = 1.07). At each participant’s final available follow-up, all 13 primary-analysis patients had values below baseline. High-risk patients (n = 4) showed a mean 25.7% reduction. Baseline Aβ level and 6-month percent biomarker change exhibited an exploratory, non-significant inverse trend in the Pearson correlation (r = −0.489, p = 0.090) that was weaker and non-significant in the Spearman sensitivity analysis (ρ = −0.300, p = 0.320), consistent with regression to the mean and mathematical coupling as plausible contributors. Importantly, all four APOE ε4/ε4 homozygotes showed Aβ reductions without ARIA-like clinical events. Mini-Mental State Examination (MMSE) worsening occurred in 37.5% (3/8) of CNT-treated patients versus 42.9% (15/35) in propensity-matched NACC controls (p = 0.89); given the small sample, this comparison is inconclusive. Conclusions: In this small, uncontrolled pilot study, CNT was associated with blood Aβ reductions, which should be interpreted as a statistical association rather than confirmed evidence of a treatment effect; no treatment discontinuations due to adverse effects were documented in this small cohort, including among APOE ε4/ε4 carriers. These hypothesis-generating findings warrant further confirmation in prospective randomized controlled trials.