Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous APOE ɛ4 Carriers

Abstract

OBJECTIVE:Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer’s disease (AD) risk only in apoliprotein E4 genotype (APOE ε4) allele carriers. The objective of this study was to examine the interactive effects of plasma CRP and apoliprotein E (APOE) genotype on cognition and AD biomarkers.METHODS:Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study was analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., MCI and dementia due to AD); Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) Dementia Staging Instrument; cerebral spinal fluid (CSF) concentrations of amyloid-β peptide (Aβ42), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and APOE on cognitive and biomarker outcomes.RESULTS:Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had one, and 70 (12.4%) had two APOE ε4 alleles. Only among participants who had two APOE ε4 alleles, elevated CRP was associated with lower MMSE at baseline [β (95%CI): -0.52 ( -1.01, -0.12)] and 12-month follow-up [β (95%CI): -1.09 (-1.88, -0.17)] after adjusting for sex, age and education. The interaction of two APOE ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (β = +11.21, SE = 3.37, p < 0.001) and p-Tau (β = +2.74, SE = 1.14, p < 0.01). Among those who had no APOE ε4 allele, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at 12-month follow-up.CONCLUSIONS:CRP released during peripheral inflammation could be a mediator in APOE ε4 related AD neurodegeneration and serve as a drug target for AD.

Monomeric C‐reactive protein induces the cellular pathology of Alzheimer's disease

“…This study extends our previous research 3, 4 by investigating if and how proinflammatory isoform of CRP, for example, mCRP, 6 , 7 , 8 can contribute to the cellular pathology of AD. Results showed that mCRP induced Aβ42 secretion and phosphorylated tau (p‐tau) production in primary neurons in a dose‐, time‐, and APOE genotype ( APOE ε4 > APOE ε3 > APOE ε2)‐dependent pattern.…”

“…These cellular pathologies are consistent and parallel with the interactive effects of APOE ε4 and CRP for AD risk 3 and AD brain biomarkers in humans. 4 …”

“… 2 Our study used the data from the Framingham Heart Study (FHS) offspring cohort and found that chronically elevated C‐reactive protein (CRP) impacts the risk of AD only in APOE ε4, but not in APOE ε3 and APOE ε2, carriers; 3 another study showed that CRP is associated with the biomarkers of tauopathy in cerebrospinal fluid (CSF) only in APOE ε4/ε4 carriers. 4 However, it is unclear whether CRP is directly involved in cellular AD pathogenesis in the presence of APOE ε4. As APOE ε4 leads to blood–brain barrier (BBB) dysfunction and leakage, 5 it is possible that the leaked peripheral inflammatory factors like CRP directly act on neuronal cells in the brain.…”

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

“…C-reactive protein (CRP) is an acute-phase protein, the level of which rises during inflammation; however, evidence for its use as an AD biomarker remains inconclusive. Indeed, while some studies indicate that blood CRP levels correlate with Mini-Mental State Examination (MMSE) score, other results suggest that this is valid only among APOEε4 homozygote AD patients [ 88 , 89 ]. Still, no association with cognitive decline has been reported from independent data, leaving CRP as a debatable biomarker [ 90 , 91 ].…”

Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks

“…Another group of genes (MAP2, METAP2, NFE2L2, SELP, SST, and VEGFA) was down-regulated by hypoglycemia and also downregulated in AD. A number of analyzed genes were suggested as potential targets for AD treatment, including ADIPOQ [83], AQP4 [84], CCL2 [85], CRP [86], EIF2AK3 [87], EPO [88], IGF1 [89], IGF1R [90,91], IGF2 [92,93], IGFBP2 [94], IL6 [95], NFE2L2 [96,97], NOS1 [98], NPY [99,100], PARK7 [101], SERPINE1 [102], SIRT1 [103], SIRT6 [81,104], SLC2A1 [105,106], TNF [107,108], VEGF and VEGFR [109]. The role of these molecules in hypoglycemia-induced brain dysfunction needs further research.…”