Reduced serum carboxymethyllysine is independently associated with Alzheimer's disease

INTRODUCTION: Advanced glycation end products accumulate in Alzheimer's disease (AD) brain, but the clinical significance of circulating N ε -(carboxymethyl)lysine (CML) remains uncertain. We evaluated serum CML as a complementary peripheral biomarker of AD. METHODS: This observational case-control study enrolled 101 patients with clinically diagnosed AD and 91 healthy controls. Serum CML was quantified in 191 participants. Multivariable logistic regression and receiver operating characteristic analyses assessed association and discrimination. A randomly selected subcohort underwent ultrasensitive measurement of amyloid-, tau-, glial-, and neuroaxonal-related biomarkers. RESULTS: Serum CML was lower in AD than controls (median 15.26 versus 23.72 ng/mL; P<0.001). In a complete-case model (n=178), each 1-ng/mL increase was associated with lower odds of AD (adjusted odds ratio 0.727, 95% confidence interval 0.656-0.804). CML alone yielded an area under the curve (AUC) of 0.883. Five-fold cross-validation yielded AUCs of 0.727 for a clinical model and 0.911 after adding CML. In the biomarker subcohort, AD showed lower Aβ42/Aβ40 and higher p-tau217; exploratory CML plus p-tau217 discrimination reached an AUC of 0.966 (n=60). DISCUSSION: Reduced serum CML was independently associated with clinically diagnosed AD and may reflect a systemic glycoxidative dimension complementary to canonical biomarkers. Its biological origins and clinical value require external, longitudinal, and biomarker-defined validation.