Characterization of Hair Metabolome in 5xFAD Mice and Patients with Alzheimer’s Disease Using Mass Spectrometry-Based Metabolomics

Hair
emerged as a biospecimen for long-term investigation
of endogenous
metabolic perturbations, reflecting the chemical composition circulating
in the blood over the past months. Despite its potential, the use
of human hair for metabolomics in Alzheimer’s disease (AD)
research remains limited. Here, we performed both untargeted and targeted
metabolomic approaches to profile the key metabolic pathways in the
hair of 5xFAD mice, a widely used AD mouse model. Furthermore, we
applied the discovered metabolites to human subjects. Hair samples
were collected from 6-month-old 5xFAD mice, a stage marked by widespread
accumulation of amyloid plaques in the brain, followed by sample preparation
and high-resolution mass spectrometry analysis. Forty-five discriminatory
metabolites were discovered in the hair of 6-month-old 5xFAD mice
compared to wild-type control mice. Enrichment analysis revealed three
key metabolic pathways: arachidonic acid metabolism, sphingolipid
metabolism, and alanine, aspartate, and glutamate metabolism. Among
these pathways, six metabolites demonstrated significant differences
in the hair of 2-month-old 5xFAD mice, a stage prior to the onset
of amyloid plaque deposition. These findings suggest their potential
involvement in the early stages of AD pathogenesis. When evaluating
45 discriminatory metabolites for distinguishing patients with AD
from nondemented controls, a combination of l-valine and
arachidonic acid significantly differentiated these two groups, achieving
a 0.88 area under the curve. Taken together, these findings highlight
the potential of hair metabolomics in identifying disease-specific
metabolic alterations and developing biomarkers for improving disease
detection and monitoring.