Plasma and CSF Amyloid-β42 Predict Plasma Sortilin, Which Influences Cognitive Impairment via Mediation of Whole-Brain Volume: A 12-Month Longitudinal Study Across the Alzheimer’s Disease Spectrum

Sortilin, a type I transmembrane protein encoded by SORT1 and part of the VPS10-domain receptor family, is crucial for intracellular trafficking and APP processing in Alzheimer’s disease (AD). It promotes protective α-secretase cleavage to prevent Aβ formation and aids Aβ clearance. However, under certain conditions, sortilin can become neurotoxic, causing Aβ buildup, tau phosphorylation, protein misrouting, and apoptosis, which accelerate neuronal damage and cognitive decline. No longitudinal human studies have yet explored how plasma and CSF Aβ42 predict plasma sortilin across the AD spectrum or whether whole-brain volume mediates the relationship between plasma sortilin and cognitive impairment. This study aimed to clarify these relationships and assess plasma sortilin as an indicator of central and peripheral amyloid pathology in AD for future experimental research. The results showed that at baseline, CSF Aβ42 levels were significantly lower in mild cognitive impairment (MCI) and AD compared to controls, while plasma Aβ42 levels did not differ, and sortilin levels were significantly reduced in MCI versus controls but not between other groups. Over 12 months, plasma sortilin levels declined in cognitively normal (CN) individuals but increased in MCI and AD, plasma Aβ42 rose across all groups, and CSF Aβ42 decreased modestly, highlighting diagnosis-specific sortilin changes and differing plasma versus CSF Aβ42 dynamics. Solely in MCI, higher plasma and CSF Aβ42 independently predicted increased plasma sortilin levels over time, indicating both peripheral and central Aβ42 contribute to sortilin upregulation, but when both were elevated simultaneously, the sortilin increase was attenuated, suggesting a non-linear or compensatory response. At the 12-month time point, higher plasma sortilin levels were negatively associated with whole-brain volume in MCI. In contrast, higher plasma Aβ42 levels showed positive associations with whole-brain volume in both CN and MCI groups, while no such association was observed in AD. CSF Aβ42 was not significantly related to brain volume in any group. Notably, at the 12-month time point in MCI, higher plasma sortilin levels were associated with poorer cognitive performance indirectly via reduced whole-brain volume; this mediation effect was not observed in CN or AD groups. Thus, plasma and CSF Aβ42 levels predict plasma sortilin levels, which may contribute to brain volume reduction and subsequent cognitive impairment, highlighting sortilin as a potential mediator or early indicator of neurodegeneration in AD progression.