Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous APOE {varepsilon}4 Carriers

Background and Objectives

Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer disease (AD) risk only in APOE 4 allele carriers; the objective of this study was to examine the interactive effects of plasma CRP and APOE genotype on cognition and AD biomarkers.


Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study were analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., mild cognitive impairment and dementia due to AD); Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Dementia Staging Instrument scores; CSF concentrations of β-amyloid 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.


Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had 1, and 70 (12.4%) had 2 APOE 4 alleles. Among only participants who had 2 APOE 4 alleles, elevated CRP was associated with lower MMSE score at baseline (β [95% confidence interval] –0.52 [–1.01, –0.12]) and 12-month follow-up (β –1.09 [–1.88, –0.17]) after adjustment for sex, age, and education. The interaction of 2 APOE 4 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 4 alleles, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at the 12-month follow-up.


CRP released during peripheral inflammation could be a mediator in APOE 4–related AD neurodegeneration and serve as a drug target for AD.

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