Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous <i>APOE</i> ɛ4 Carriers
Qiushan Tao, Ting Fang Alvin Ang, Samia C. Akhter‐Khan, Indira Swetha Itchapurapu, Ronald Killiany, Xiaoling Zhang, Andrew E. Budson, Katherine W. Turk, Lee E. Goldstein, Jesse Mez, Michael L. Alosco, Wei Qiao Qiu, for the Alzheimer's Disease Neuroimaging Initiative
Abstract
<h3>Background and Objectives</h3> Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer disease (AD) risk only in <i>APOE</i> ε4 allele carriers; the objective of this study was to examine the interactive effects of plasma CRP and <i>APOE</i> genotype on cognition and AD biomarkers. <h3>Methods</h3> Data from the Alzheimer9s Disease Neuroimaging Initiative (ADNI) study were analyzed, including <i>APOE</i> 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 (Aβ<sub>42</sub>), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and <i>APOE</i> on cognitive and biomarker outcomes. <h3>Results</h3> Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had 1, and 70 (12.4%) had 2 <i>APOE ε</i>4 alleles. Among only participants who had 2 <i>APOE</i> ε4 alleles, elevated CRP was associated with lower MMSE score at baseline (<i>β</i> [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 <i>APOE</i> ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (β = 11.21, SE 3.37, <i>p</i> < 0.001) and p-Tau (β = +2.74, SE 1.14, <i>p</i> < 0.01). Among those who had no <i>APOE</i> ε4 alleles, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at the 12-month follow-up. <h3>Discussion</h3> CRP released during peripheral inflammation could be a mediator in <i>APOE</i> ε4–related AD neurodegeneration and serve as a drug target for AD.