Copper isotope shifts in biofluids track Alzheimer's pathology

INTRODUCTION Altered copper metabolism has been reported in Alzheimer's disease (AD), with post mortem brain tissue showing depletion of 65 Cu compared with 63 Cu. Whether such isotopic shifts can be detected in biofluids remains unknown. METHODS We analyzed copper isotope composition in human cerebrospinal fluid (CSF) and serum from AD patients and controls using multi‐collector inductively coupled plasma mass spectrometry (MC‐ICP‐MS) and single quadrupole inductively coupled plasma mass spectrometry (SQ‐ICP‐MS). Samples included 22 CSFs (10 AD, 12 controls), 54 sera (28 AD, 26 controls). RESULTS AD CSF was enriched in 65 Cu (+0.32‰, p = 0.02), correlating inversely with CSF amyloid beta (Aβ) 42/40 ratios. Serum from AD patients was depleted in 65 Cu (−0.23‰, p = 0.013), trending inversely with amyloid positron emission tomography burden. Serum and CSF δ 65 Cu diagnostically discriminate between AD and controls (area under the curve = 0.8, Youden's J ≈ 0.5 SD, p ≤ 0.0002). DISCUSSION Copper isotope excursions in brain parenchyma are mirrored in CSF and serum. These shifts reflect amyloid pathology and highlight isotopic copper analysis as a potential minimally invasive biomarker for AD.