Free Water Elevation in Alzheimer’s Disease: Influence of Amyloid-Beta Deposition Beyond Brain Cell Loss

BACKGROUND: To investigate whether amyloid-beta (Aβ) deposition in Alzheimer's disease (AD) increases free water (FW) before cell loss, we examined regional Aβ levels, volume, and FW of the posterior cingulate cortex (PCC) and medial and inferior temporal cortex (MITC) across AD stages. METHODS: Aβ, volume, and FW in PCC and MITC were compared between normal cognition (NC), preclinical AD, prodromal AD, and dementia due to Alzheimer's disease (DEMAD) groups. Multiple linear regression was used to analyze the effect of Aβ and volume on FW. RESULTS: Continuous increases were observed in the regional standardized uptake value ratio of ¹⁸F-Florbetaben (SUVR) and regional volume loss in all regions of interest. Also, there was a consistent rise in the MITC FW. However, in PCC volume, only DEMAD showed a significant decrease. In the context of multiple linear regression, the study found that both SUVR and volume were significant predictors of FW in the MITC. However, in PCC, only SUVR was able to predict FW without considering volume. CONCLUSION: This study demonstrated that after Aβ deposition in AD, an increase in FW can occur not only due to brain cell loss but also through other Aβ-induced mechanisms, even in cases where brain cell loss has not yet occurred.