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Cross-sectional associations of Kidney deficiency, Phlegm-stasis, and Heat-toxin syndrome patterns with disease severity in Alzheimer’s disease: an exploratory study

Year: 2026

Type: article

Abstract: Background Current Alzheimer’s diagnostics lack integration with Traditional Chinese Medicine’s syndrome differentiation framework, making it difficult to fully capture the clinical heterogeneity and multidimensional nature of the disease. Methods This cross-sectional study analyzed 236 AD patients stratified by CDR into early-stage ( n = 127), moderate ( n = 66), and severe ( n = 43) groups. Using the SHA-03-W1 diagnostic instrument and Tian Jinzhou Scale, patients were classified into three TCM syndrome patterns: Kidney essence deficiency ( n = 87), Phlegm-stasis obstructing the orifices ( n = 93), and Heat-toxin obstructing the collaterals ( n = 56). Data collected included demographics, cognitive scores (MMSE, MoCA), activities of daily living (ADL), and plasma biomarkers (GFAP, NfL, p-tau181, p-tau217, Aβ42/40). Statistical analyses involved intergroup comparisons (Chi-square and Kruskal-Wallis tests), Spearman correlation analysis between dementia severity/TCM patterns and clinical measures, logistic regression to examine factors associated with disease severity, and exploratory ROC analysis to describe discriminatory performance within this development sample. Results Across the three CDR-defined severity groups ( n = 236), MMSE, MoCA, ADL and estimated symptom duration differed significantly ( p < 0.05, q < 0.05). Dementia severity correlated strongly with MMSE ( r = −0.779), MoCA ( r = −0.785) and ADL ( r = 0.742) ( p < 0.001), and only weakly with estimated symptom duration ( r = 0.384, p < 0.001). TCM syndrome distribution patterns differed across severity stages, with kidney essence deficiency being most prevalent in the early-stage group (48%), Phlegm-stasis in the moderate group (54.5%), and Heat-toxin in the severe group (60.5%). In multivariable multinomial logistic regression (reference: early-stage AD), MMSE and ADL scores were associated with AD severity (MMSE: moderate vs. early, OR = 0.844, 95% CI 0.774–0.921; severe vs. early, OR = 0.485, 95% CI 0.351–0.671; ADL: moderate vs. early, OR = 1.128, 95% CI 1.065–1.196; severe vs. early, OR = 1.280, 95% CI 1.150–1.425; all p < 0.001). Among TCM syndrome elements, Heat-toxin was associated with both moderate and severe AD (Moderate vs. Early-stage: OR = 1.177, 95% CI 1.046–1.324, p = 0.007; Severe vs. Early-stage: OR = 1.498, 95% CI 1.205–1.861, p < 0.001) and Phlegm-stasis with moderate AD only (OR = 1.198, 95% CI 1.079–1.329, p = 0.001). In an exploratory ROC analysis, single indicators showed modest discriminatory performance for Heat-toxin syndrome, with CDR (AUC = 0.709) > ADL (AUC = 0.690) > MMSE (AUC = 0.683), whereas AUCs for Kidney deficiency (≤0.633) and Phlegm-stasis (≤0.581) were close to chance. In a sensitivity analysis excluding participants with CDR 0.5 ( n = 186), the cognitive, functional and Heat-toxin associations were essentially unchanged, but the Phlegm-stasis score was associated with both moderate and severe AD, with comparable effect sizes (Moderate vs. Early-stage: OR = 1.26, 95% CI 1.12–1.42, p < 0.001; Severe vs. Early-stage: OR = 1.25, 95% CI 1.02–1.54, p = 0.032), indicating that its restriction to moderate AD was not robust. Discussion In this cross-sectional single-center sample, TCM syndrome distributions and scores differed across concurrent CDR-defined severity groups, with kidney essence deficiency predominating in early-stage AD (48.0%), Phlegm-stasis in moderate AD (54.5%), and Heat-toxin in severe AD (60.5%). Heat-toxin scores were associated with greater concurrent cognitive and functional impairment, whereas plasma biomarkers showed limited and inconsistent associations. These findings do not establish temporal syndrome transitions or validated diagnostic utility outside this development sample, but provide hypothesis-generating evidence for future prospective investigations.

Source: Frontiers in Aging Neuroscience

DOI: 10.3389/fnagi.2026.1763273