Cerebrospinal fluid ferritin levels predict brain hypometabolism in people with underlying β-amyloid pathology.

β-Amyloid pathology is elevated in ~30% of cognitively normal people over 65, and is associated with accelerated neurodegeneration in the pre-clinical stages of Alzheimer's disease. Recent findings reveal that brain iron might also act to propel neurodegeneration in people with underlying amyloid pathology. Here, repeated PET scans of fluorodeoxyglucose (FDG) were used as a biomarker for brain hypometabolism and a downstream biomarker of neurodegeneration to investigate whether levels of ferritin in the cerebrospinal fluid (CSF; a reporter of brain iron load) are associated with prodromal disease progression of people with high β-amyloid pathology determined by established cut-off values in CSF t-tau/Aβ ratio. Nineteen cognitively normal participants with low t-tau/Aβ, and 71 participants with high t-tau/Aβ who were cognitively normal or had mild cognitive impairment were included as participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. These subjects had repeated FDG-PET scans at 6-month intervals for 2 years, and yearly intervals for up to a further 3 years. In mixed-effects linear models of FDG signal, baseline CSF ferritin was associated with an accelerated decline in FDG PET in high t-tau/Aβ participants (β[SE] = -0.066 [0.017]; P = .0002), but not in people with low t-tau/Aβ (-0.029 [0.049]; P = .554). These data implicate iron as a contributing factor to neurodegeneration associated with β-amyloid pathology, and highlight CSF ferritin as a complementary prognostic biomarker to the t-tau/Aβ ratio that predicts near-term risk for disease progression.