Criterion-Referenced Sex-Specific Six-Minute Walk Distance Cut-Offs for Staging Alzheimer's Disease

Background: Functional decline emerges early in Alzheimer's disease (AD) and may support clinical staging. However, criterion-referenced thresholds for interpreting the six-minute walk distance (6MWD) across AD stages are lacking. This study aims to derive sex-specific 6MWD cut-off values to differentiate mild cognitive impairment (MCI) from moderate AD dementia. Methods: In this cross-sectional study, 233 community-dwelling adults (128 women) were consecutively recruited from a neurology department and classified using IWG-2 criteria (MCI: MMSE ≥ 26; moderate AD dementia: MMSE 10-19). All participants completed a standardized 6 min walk test (6MWT) following American Thoracic Society guidelines. Receiver operating characteristic (ROC) analyses were performed overall and by sex, optimal thresholds were selected using Youden's index, and diagnostic indices such as area under the curve (AUC), sensitivity, specificity, 95% confidence intervals (CI), likelihood ratios (LR) and odds ratio (OR) were computed. Results: Overall, participants with moderate AD dementia exhibited substantially lower 6MWD values than those with MCI (313.7 ± 46.5 m vs. 461.2 ± 60.1 m, p < 0.001). The optimal overall threshold was 390 m, yielding an AUC of 0.97, sensitivity of 98.0%, and specificity of 79.4%. Sex-specific thresholds were 389 m in men (AUC = 0.96, sensitivity = 96.4%, specificity = 79.3%) and 367 m in women (AUC = 0.98, sensitivity = 97.8%, specificity = 87.7%). Conclusions: The 6MWD demonstrates strong discriminatory ability between MCI and moderate AD dementia in this sample. Sex-specific thresholds may support functional staging and monitoring but require internal and external validation before clinical implementation.