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

Ayton, Scott ; Janelidze, Shorena LU ; Kalinowski, Pawel ; Palmqvist, Sebastian LU orcid ; Belaidi, Abdel Ali ; Stomrud, Erik LU orcid ; Roberts, Anne ; Roberts, Blaine ; Hansson, Oskar LU orcid and Bush, Ashley Ian (2023) In Journal of Neurology, Neurosurgery and Psychiatry 94(3). p.211-219
Abstract

Background: A 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.... (More)

Background: A 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. Methods: Ferritin, 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. Results: In 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-. Conclusions: CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alzheimer's disease, iron deposition
in
Journal of Neurology, Neurosurgery and Psychiatry
volume
94
issue
3
pages
211 - 219
publisher
BMJ Publishing Group
external identifiers
  • pmid:36357168
  • scopus:85143546313
ISSN
0022-3050
DOI
10.1136/jnnp-2022-330052
language
English
LU publication?
yes
id
8b8d491f-57c8-4a4d-8b68-93f00f14173e
date added to LUP
2023-01-20 15:48:17
date last changed
2024-04-18 18:22:33
@article{8b8d491f-57c8-4a4d-8b68-93f00f14173e,
  abstract     = {{<p>Background: A 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. Methods: Ferritin, 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. Results: In 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-. Conclusions: CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.</p>}},
  author       = {{Ayton, Scott and Janelidze, Shorena and Kalinowski, Pawel and Palmqvist, Sebastian and Belaidi, Abdel Ali and Stomrud, Erik and Roberts, Anne and Roberts, Blaine and Hansson, Oskar and Bush, Ashley Ian}},
  issn         = {{0022-3050}},
  keywords     = {{alzheimer's disease; iron deposition}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{211--219}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{Journal of Neurology, Neurosurgery and Psychiatry}},
  title        = {{CSF ferritin in the clinicopathological progression of Alzheimer's disease and associations with APOE and inflammation biomarkers}},
  url          = {{http://dx.doi.org/10.1136/jnnp-2022-330052}},
  doi          = {{10.1136/jnnp-2022-330052}},
  volume       = {{94}},
  year         = {{2023}},
}