Associations among Angiotensin-Converting Enzyme, Neuroinflammation, and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Non-Dementia Adults

Recent studies have identified the angiotensin-converting enzyme (ACE) gene as a potential candidate influencing Alzheimer's disease (AD) risk. It is crucial to investigate the impact of ACE on AD pathology and its underlying mechanisms. A total of 450 non-demented participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with data on cerebrospinal fluid (CSF) ACE, AD core biomarkers and inflammation-related biomarkers were included. Multiple linear regression was used to assess the associations among CSF ACE, AD core biomarkers and inflammation-related biomarkers. And we used the mediation models to investigate the potential mechanisms through which ACE influenced AD pathology. The results of multiple linear regression were shown that CSF ACE was significantly correlated with CSF A beta(42), P-tau, T-tau (all P < 0.001), and inflammation-related biomarkers (soluble triggering receptor expressed on myeloid cells 2 [sTREM2], progranulin [PGRN], glial fibrillary acidic protein [GFAP], transforming growth factor [TGF]-beta 1, TGF-beta 2, TGF-beta 3, tumor necrosis factor [TNF]-R1, TNF-R2, TNF-alpha, interleukin [IL]-21, IL-6, IL-7, IL-9, IL-10, IL-12p40, vascular cell adhesion molecule-1 [VCAM-1], and intercellular adhesion molecule-1 [ICAM-1]) (all P < 0.05). In addition, the mediation analysis results showed that the association of CSF ACE and inflammation-related biomarkers (sTREM2, PGRN, TGF-beta 1, TGF-beta 2, TNFR1, IL-6, IL-7, IL-9, and VCAM-1) mediated the correlation of CSF A beta(42) with P-tau. Our findings show that CSF ACE and neuroinflammation are correlated and that their correlation mediates the link between A beta pathology and P-tau. This suggests ACE may play a significant role in the progression from A beta pathology to tau pathology.