Fluid amyloid-β (Aβ) biomarkers reflect early β-sheet-rich Aβ deposition during the preclinical stage in Alzheimer’s disease model 5XFAD mice

Early detection of disease progression using clinically-relevant biomarkers in animal models is important for mechanistic studies and for developing therapeutics in neurodegenerative diseases including Alzheimer’s disease (AD). The preclinical stage of AD, when amyloid-β (Aβ) starts to accumulate before cognitive decline, provides a critical window for disease modification. In humans, decreases in cerebrospinal fluid (CSF) Aβ ₄₂ and the Aβ ₄₂ /Aβ ₄₀ ratio in preclinical AD are considered to reflect the preferential sequestration of aggregation-prone Aβ ₄₂ into β-sheet-rich deposition in the brain, with corresponding changes being detectable in plasma. However, the extent to which these biomarker-pathology relationships are recapitulated in AD model mice remains incompletely defined. Here we show that CSF and plasma Aβ ₄₂ and the Aβ ₄₂ /Aβ ₄₀ ratio decline with age in parallel with the progression of β-sheet-rich Aβ deposition in preclinical 5XFAD mice, one of the most widely used AD mouse models, as assessed through monthly profiling of these biomarkers. Notably, the CSF Aβ ₄₂ /Aβ ₄₀ ratio showed a negative correlation with β-sheet-rich Aβ deposition in the brain, whereas CSF Aβ ₄₀ did not show a comparable association. In addition, the plasma Aβ ₄₂ /Aβ ₄₀ ratio showed a positive correlation with the CSF Aβ ₄₂ /Aβ ₄₀ ratio, suggesting that the plasma Aβ ₄₂ /Aβ ₄₀ ratio may also reflect brain Aβ deposition in this model. The strength of these correlations differed by sex, suggesting that sex-dependent differences in the Aβ kinetics in this model may influence how closely fluid biomarkers reflect pathological progression. These findings support the potential utility of fluid Aβ as a pathology-linked, translatable biomarker in preclinical 5XFAD mice.