Increased PCSK9 cerebrospinal fluid concentrations in Alzheimer’s disease

Objectives: Alzheimer’s disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease firstly described to target hepatic low-density lipoprotein receptor (LDLr) and to mediate its degradation. Such effect leads to increased plasma LDL cholesterol levels. However, PCSK9 has several extrahepatic effects. It was firstly identified in the brain and recently it was detectable in the CSF of healthy subjects without the typical diurnal pattern of plasma PCSK9, indicating a different regulation in the two body compartments. In neurons, PCSK9 has been shown to degrade LDLr as well as other apoE-binding receptors such as the very low-density lipoprotein receptor (VLDLr), the LDL receptor–related protein 1 (LRP1) and the apolipoprotein E receptor 2 (apoER2); these proteins are involved in the internalization of the cholesterol transported within CSF by particles similar to plasma HDL. Thus, PCSK9 modified activity might in principle be involved in the derangement of brain cholesterol trafficking, in lipoprotein homeostasis and in AD pathogenesis. In this work, we measured PCSK9 in CSF of AD patients to establish whether PCSK9 levels alterations occur in AD and looked for a correlation between PCSK9 values and CSF total apoE and apoE4. Methods: CSF from AD (n = 30) and from age and sex-matched non-AD patients (n = 30) was collected by lumbar puncture for routine diagnosis. CSF PCSK9, total apoE, and apoE4 levels were measured by ELISA. Results: AD patients showed the typical CSF neurobiomarker pattern (decreased A42 and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test. PCSK9 levels in CSF were higher in AD than in non-AD subjects (+1.45 fold; p = 0.0049). CSF total apoE concentrations did not differ between the two groups, while apoE4 levels were higher in AD subjects (+3.34 fold; p = 0.0068). Considering all samples, a significant positive correlation was found between PCSK9 and apoE4 (r = 0.4409; p = 0.0006). PCSK9 levels were higher in APOE ε4 carriers, reaching statistical significance in the AD group (+1.45 fold; p = 0.0454). Conclusion: These results report for the first time an alteration of CSF PCSK9 levels in AD and suggest a pathophysiological link between PCSK9, apoE4, and AD.