Evidence that iron accelerates Alzheimer's pathology: a CSF biomarker study

Objective To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF beta-amyloid (A beta) and tau. Methods Mixed-effects models of CSF A beta(1-42) and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and A beta(1-42) for up to 5 years. Results In subjects with biomarker-confirmed Alzheimer's pathology, high CSF ferritin (> 6.2 ng/mL) was associated with accelerated depreciation of CSF A beta(1-42) (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or A beta(1-42) in subjects with low baseline pathology. In simulation modelling of the natural history of A beta deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF A beta from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF A beta over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical A beta levels to the average level of Alzheimer's subjects from 18.8 to 10.8 years. Conclusions Iron might facilitate A beta deposition in Alzheimer's and accelerate the disease process.