CSF Glucose-6-Phosphate Isomerase Is a Tau-Related Biomarker Associated with Neurodegeneration and Cognitive Impairment in Alzheimer's Disease.

Skeletal diseases are closely linked to Alzheimer's disease (AD) in terms of epidemiology and pathogenesis. Glucose-6-phosphate isomerase (GPI), a critical enzyme in the glycolytic pathway that participates in various skeletal disorders, has unclear effects on AD pathological progression in humans. This cross-sectional study included 601 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) [260 (43.3%) women; 288 (47.9%) APOE ε4 carriers]. The cohort comprised 151 cognitively normal (CN) participants [mean age 74.7 (5.9) years] and 450 cognitively impaired (CI) participants [mean age 72.8 (7.8) years]. We assessed CSF GPI levels, AD biomarkers (CSF β-amyloid [Aβ]42, phosphorylated Tau [p-Tau]181), magnetic resonance imaging-based neurodegenerative changes, and cognitive function. Associations between CSF GPI levels and AD pathology, neurodegeneration, and cognition were evaluated using linear regression models. Mediation models were employed to investigate the potential mechanism of how CSF GPI affects AD pathology. Findings were validated in two independent external cohorts using autopsy-confirmed Braak staging (n = 419; mean age 84.1 [6.6] years; 195 [46.5%] women) and cross-platform validation (n = 36). Among the total cohort (N = 601), CSF GPI levels were significantly elevated among participants with tau pathology (T+ group), regardless of Aβ status, and correlated positively with CSF p-Tau181 but not with Aβ42. Higher CSF GPI levels were also associated with downstream events of tau pathology, including reduced hippocampal volume and worse cognitive performance. Mediation analyses revealed that CSF GPI partially mediated tau pathology's effects on hippocampal volume reduction and cognitive impairment. Moreover, CSF GPI exhibited excellent diagnostic accuracy in distinguishing tau-positive/negative (T+/-) participants (area under the curve [AUC] = 0.833), with even higher accuracy when combined with demographic indicators (AUC = 0.862). In the external cohort, we used Braak staging of neuropathologies found at autopsy to indicate tau pathology and validated its positive association with CSF GPI levels (p < 0.001), with cross-platform validation demonstrating strong concordance of GPI measurements between different analytical methods (r = 0.817, p < 0.001). CSF GPI shows associations with tau pathology independent of amyloid status and may partially mediate relationships between tau pathological changes and neurodegeneration. These findings indicate that CSF GPI may serve as a potential biomarker reflecting tau-related pathological processes. However, further validation studies are required to establish its utility for clinical diagnostic evaluation or therapeutic monitoring.