CSF ferritin in the clinicopathological progression of Alzheimer’s disease and associations with APOE and inflammation biomarkers

Abstract

BackgroundA putative role for iron in driving Alzheimer’s disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ42/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.MethodsFerritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ42/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort.ResultsIn both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%–40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-.ConclusionsCSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“… 180 The authors suggested that this may indicate a role for iron‐induced neuroinflammation. CSF ferritin levels increased across the AD continuum, 181 and higher CSF ferritin was associated with worse cognition, 181 , 182 worse CSF p‐tau181, 181 , 182 and with other inflammatory proteins 181 but not Aβ. 181 , 182 The association between CSF ferritin and p‐tau181 was mediated by APOE .…”

“…CSF ferritin levels increased across the AD continuum, 181 and higher CSF ferritin was associated with worse cognition, 181 , 182 worse CSF p‐tau181, 181 , 182 and with other inflammatory proteins 181 but not Aβ. 181 , 182 The association between CSF ferritin and p‐tau181 was mediated by APOE . 182 The contribution of iron metabolism to AD disease progression appears to be a complex process involving microglial activation, p‐tau, and APOE .…”

“… 181 , 182 The association between CSF ferritin and p‐tau181 was mediated by APOE . 182 The contribution of iron metabolism to AD disease progression appears to be a complex process involving microglial activation, p‐tau, and APOE .…”

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

“…In general, dysregulated iron metabolism is associated with cognitive disorders, including memory and attention disorders, and anemia or, at least, an iron deficiency [ 36 , 37 ]. Ferritin levels in the cerebrospinal fluid are associated with inflammation markers, phospho-tau, and apolipoprotein E levels [ 38 ]. Amyloid precursor protein and tau have been reported to have physiological roles in neuronal iron homeostasis [ 39 , 40 ].…”

The Role of Cellular Defense Systems of Ferroptosis in Parkinson’s Disease and Alzheimer’s Disease

“…Over the past decade, a large body of evidence has shown that ferroptosis plays an important role in a variety of diseases, including neurological disorders, cancer, metabolic disorders, and cardiovascular diseases [ 17 , 18 , 19 ]. Recently, there has also been increased focus on the role of ferroptosis in neurological disorders, with studies suggesting that ferroptosis is implicated in the pathogenesis of a variety of neurodegenerative disorders, including PD, AD, amyotrophic lateral sclerosis (ALS), and strokes, including acute ischemic stroke (AIS), spontaneous intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH).…”