Associations of circulating C-reactive proteins, APOE e4, and brain markers for Alzheimer's disease in healthy samples across the lifespan

The apolipoprotein E gene e4 allele (APOE e4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer's disease (AD). Paradoxically, APOE e4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE e4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20-81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37-72 years of age), the developmental ABCD study (N = 10 283; 9-11 years of age), and a middle-aged sample (N = 339; 40-65 years of age). Hippocampal volume, brain amyloid-ll (All) plaque levels, cerebrospinal fluid (CSF) levels of All and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE e4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both e4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE e4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE e4 was associated with high All plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF All42 (FDR-corrected p = 6.9x10-2), and lower ratios of All42 to All40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF All42 to All40 (p = 0.03, FDR-corrected p = 0.4). APOE e4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. Conclusion: The inverse correlation between APOE epsilon 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOE epsilon 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD.