LAUSR

Dr. Tao et al. examined the interactive effects of plasma C-reactive protein (CRP) APOE genotype on cognition and Alzheimer disease (AD) biomarkers in 566 participants from the Alzheimer Disease Neuroimaging Initiative. Elevated CRP was associated with lower Mini-Mental State Examination scores at baseline and the 12-month follow-up only in participants with 2 APOE ε4 alleles. Furthermore, the interaction of 2 APOE ε4 alleles and elevated CRP was associated with increased CSF levels of total tau and phospho-tau. In a reader response, Dr. Royall cites their prior work that demonstrated CRP's mediation effect on the association of APOE with prospectively measured dementia severity in the Texas Alzheimer's Research and Care Consortium. Dr. Royall also posits that the elevated plasma CRP levels in ε4 homozygotes may reflect the residual influence of APOE-independent processes, given that CRP levels are observed to fall as a function of increasing APOE ε4 burden in several cohorts. Responding to these comments, the authors suggest that these drops in CRP levels may relate to cerebrovascular deposition of CRP in ε4 homozygotes, citing interesting evidence from a mouse model. This discussion highlights our evolving understanding of the role of inflammatory markers in the pathophysiology of AD, which may become another focus of therapeutic targets in the future.