Alzheimer's disease (AD) has been reported to be associated with changes in inflammatory levels, although further research is needed. This study focused on identifying specific inflammatory biomarkers in peripheral blood that could differentiate patients with AD from healthy control subjects.
Objective
The primary objective was to determine whether a selection of peripheral blood inflammatory biomarkers could serve as a diagnostic tool for AD.
Methods
A multicenter study was conducted, comparing 39 patients with AD to 27 healthy controls. AD diagnosis was confirmed through a comprehensive evaluation, including the Mini-Mental State Examination and analysis of cerebrospinal fluid or positron emission tomography. Thirteen inflammatory markers were measured, and logistic regression analysis was used to assess their discriminatory potential. The relationship between the APOE genotype and biomarker levels was also examined.
Results
The analysis revealed that interleukin-8 (IL-8), platelet-derived growth factor (PDGF-AB/BB), and interleukin-12p40 (IL-12p40) were the most significant markers. IL-8 levels showed a strong correlation with disease status, being notably lower in AD patients compared to controls. Furthermore, the levels of these three markers were associated with the patient's amyloid-positive status of the APOE genotype.
Conclusions
These results suggest that reduced levels of IL-8 in the blood could be a promising biomarker for the diagnosis of AD. Additionally, inflammatory biomarkers such as IL-8 and IL-12p40 may be linked to the amyloid pathology of the APOE genotype in AD patients.
SperlingRAAisenPSBeckettLA, et al.Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011; 7: 280–292.
2.
KingEO’BrienJTDonaghyP, et al.Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias. J Neurol Neurosurg Psychiatry2018; 89: 339–345.
RaySBritschgiMHerbertC, et al.Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med2007; 13: 1359–1362.
5.
HampelHCaraciFCuelloAC, et al.A path toward precision medicine for neuroinflammatory mechanisms in Alzheimer’s disease. Front Immunol2020; 11: 456.
6.
MorganARTouchardSLeckeyC, et al.Inflammatory biomarkers in Alzheimer’s disease plasma. Alzheimers Dement2019; 15: 776–787.
7.
LaiKSPLiuCSRauA, et al.Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies. J Neurol Neurosurg Psychiatry2017; 88: 876–882.
8.
AkiyamaHBargerSBarnumS, et al.Inflammation and Alzheimer’s disease. Neurobiol Aging2000; 21: 383–421.
9.
DaniMWoodMMizoguchiR, et al.Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease. Brain2018; 141: 2740–2754.
10.
LengFEdisonP. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?Nat Rev Neurol2021; 17: 157–172.
11.
PascoalTABenedetALAshtonNJ, et al.Microglial activation and tau propagate jointly across Braak stages. Nat Med2021; 27: 1592–1599.
12.
SartyIMPicardCLabonteA, et al.Longitudinal association between CSF markers of Alzheimer Disease and inflammation in preclinical Alzheimer disease. Alzheimers Dement2025; 20: e087640.
13.
ParkJ-CHanS-HMook-JungI. Peripheral inflammatory biomarkers in Alzheimer’s disease: a brief review. BMB Rep2020; 53: 10–19.
14.
SwardfagerWLanctôtKRothenburgL, et al.A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry2010; 68: 930–941.
15.
ScarabinoDPeconiMBroggioE, et al.Relationship between proinflammatory cytokines (Il-1beta, Il-18) and leukocyte telomere length in mild cognitive impairment and Alzheimer’s disease. Exp Gerontol2020; 136: 110945.
16.
ChenXHuYCaoZ, et al.Cerebrospinal fluid inflammatory cytokine aberrations in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis: a systematic review and meta-analysis. Front Immunol2018; 9: 2122.
17.
AksnesMAassHCDTiimanA, et al.Serum amyloidogenic nanoplaques and cytokines in Alzheimer’s disease: pilot study in a small naturalistic memory clinic cohort. J Alzheimers Dis2022; 86: 1459–1470.
18.
BrosseronFKrauthausenMKummerM, et al.Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol2014; 50: 534–544.
19.
MottaCFinardiATonioloS, et al.Protective role of cerebrospinal fluid inflammatory cytokines in patients with amnestic mild cognitive impairment and early Alzheimer’s disease carrying apolipoprotein E4 genotype. J Alzheimers Dis2020; 76: 681–689.
20.
PetersenRCSmithGEWaringSC, et al.Mild cognitive impairment: clinical characterization and outcome. Arch Neurol1999; 56: 303–308.
21.
CalsolaroVEdisonP. Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimers Dement2016; 12: 719–732.
22.
ChicoLSimonciniCLo GerfoA, et al.Oxidative stress and APO E polymorphisms in Alzheimer’s disease and in mild cognitive impairment. Free Radic Res2013; 47: 569–576.
23.
BaldacciFListaSMancaML, et al.Age and sex impact plasma NFL and t-tau trajectories in individuals with subjective memory complaints: a 3-year follow-up study. Alzheimers Res Ther2020; 12: 147.
24.
FerrettiMTIulitaMFCavedoE, et al.Sex differences in Alzheimer disease — the gateway to precision medicine. Nat Rev Neurol2018; 14: 457–469.
25.
DatoSDe RangoFCroccoP, et al.Sex- and APOE-specific genetic risk factors for late-onset Alzheimer’s disease: evidence from gene–gene interaction of longevity-related loci. Aging Cell2023; 22: e13938.
26.
ShenXNNiuLDWangYJ, et al.Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies. J Neurol Neurosurg Psychiatry2019; 90: 590–598.
27.
BrosseronFKrauthausenMKummerM, et al.Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol2014; 50: 534–544.
28.
GrossALWalkerKAMoghekarAR, et al.Plasma markers of inflammation linked to clinical progression and decline during preclinical AD. Front Aging Neurosci2019; 11: 229.
29.
DugganMRButlerLPengZ, et al.Plasma proteins related to inflammatory diet predict future cognitive impairment. Mol Psychiatry2023; 28: 1599–1609.
30.
TaoQAngTFADeCarliC, et al.Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers. JAMA Netw Open2018; 1: e183597.
31.
DarweeshSKLWoltersFJIkramMA, et al.Inflammatory markers and the risk of dementia and Alzheimer’s disease: a meta-analysis. Alzheimers Dement2018; 14: 1450–1459.
32.
KoyamaAO’BrienJWeuveJ, et al.The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: a meta-analysis. J Gerontol A Biol Sci Med Sci2013; 68: 433–440.
33.
LeeKSChungJHChoiTK, et al.Peripheral cytokines and chemokines in Alzheimer’s disease. Dement Geriatr Cogn Disord2009; 28: 281–287.
34.
ZhangJSokalIPeskindER, et al.CSF Multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol2008; 129: 526–529.
35.
ZulianiGGuerraGRanziniM, et al.High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia. Int J Geriatr Psychiatry2007; 22: 305–311.
36.
SwardfagerWLanctôtKRothenburgL, et al.A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry2010; 68: 930–941.
37.
AlsadanyMAShehataHHMohamadMI, et al.Histone deacetylases enzyme, copper, and IL-8 levels in patients with Alzheimer’s disease. Am J Alzheimers Dis Other Demen2013; 28: 54–61.
38.
KimSMSongJKimS, et al.Identification of peripheral inflammatory markers between normal control and Alzheimer’s disease. BMC Neurol2011; 11: 51.
39.
ShenX-NNiuL-DWangY-J, et al.Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies. J Neurol Neurosurg Psychiatry2019; 90: 590–598.
40.
CroxfordALKuligPBecherB. IL-12-and IL-23 in health and disease. Cytokine Growth Factor Rev2014; 25: 415–421.
41.
TrinchieriG. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol2003; 3: 133–146.
42.
MottaMImbesiRDi RosaM, et al.Altered plasma cytokine levels in Alzheimer’s disease: correlation with the disease progression. Immunol Lett2007; 114: 46–51.
43.
YangHSZhangCCarlyleBC, et al.Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults. Alzheimers Dement2022; 18: 645–653.
KocaSKirisISahinS, et al.Decreased levels of cytokines implicate altered immune response in plasma of moderate-stage Alzheimer’s disease patients. Neurosci Lett2022; 786: 136799.
46.
MagakiSMuellerCDicksonC, et al.Increased production of inflammatory cytokines in mild cognitive impairment. Exp Gerontol2007; 42: 233–240.
47.
LiuHSaffiGTVasefiMS, et al.Amyloid-β inhibits PDGFβ receptor activation and prevents PDGF-BB induced neuroprotection. Curr Alzheimer Res2018; 15: 618–627.
48.
MinersJSSchulzILoveS. Differing associations between aβ accumulation, hypoperfusion, blood–brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer’s disease. J Cereb Blood Flow Metab2018; 38: 103–115.
