Increased PCSK9 cerebrospinal fluid concentrations in Alzheimer's disease

Background: 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 protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial. Objective: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with 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. AD patients showed the typical CSF neurobiomarker pattern (decreased Aβ₄₂ and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test. Results: 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.