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

Abstract

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 Alzheimers disease (AD). The preclinical stage of AD, when amyloid-{beta} (A{beta}) starts to accumulate before cognitive decline, provides a critical window for disease modification. In humans, decreases in cerebrospinal fluid (CSF) A{beta}42 and the A{beta}42/A{beta}40 ratio in preclinical AD are considered to reflect the preferential sequestration of aggregation-prone A{beta}42 into {beta}-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 A{beta}42 and the A{beta}42/A{beta}40 ratio decline with age in parallel with the progression of {beta}-sheet-rich A{beta} 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 A{beta}42/A{beta}40 ratio showed a negative correlation with {beta}-sheet-rich A{beta} deposition in the brain, whereas CSF A{beta}40 did not show a comparable association. In addition, the plasma A{beta}42/A{beta}40 ratio showed a positive correlation with the CSF A{beta}42/A{beta}40 ratio, suggesting that the plasma A{beta}42/A{beta}40 ratio may also reflect brain A{beta} deposition in this model. The strength of these correlations differed by sex, suggesting that sex-dependent differences in the A{beta} kinetics in this model may influence how closely fluid biomarkers reflect pathological progression. These findings support the potential utility of fluid A{beta} as a pathology-linked, translatable biomarker in preclinical 5XFAD mice. Highlights- Fluid A{beta} biomarkers are associated with early A{beta} deposition in preclinical 5XFAD mice. - The CSF A{beta}42/A{beta}40 ratio negatively correlates with {beta}-sheet-rich brain A{beta} deposition. - The plasma A{beta}42/A{beta}40 ratio positively correlates with the CSF A{beta}42/A{beta}40 ratio. - Monthly profiling defines fluid A{beta} biomarker dynamics in preclinical 5XFAD mice. - Sex differences may affect biomarker-pathology relationships in these mice.