Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan

•The APOE ε4 allele and high circulating levels of C-reactive protein (CRP) are associated with the risk of Alzheimer’s disease.•Whereas APOE ε4 carriers show lower CRP levels than non-carriers in clinical samples of middle- and older- age, here we show that this APOE ε4-CRP relation also exists among subjects as young as 20 years old.•APOE ε4 and PGS for CRP only associate with low CRP ranges, and the higher the CRP levels, the less their variations were attributable to genetic variation.•Both APOE ε4 and high CRP levels are associated with small hippocampal volume, but only APOE ε4 shows association with other biomarkers for AD, and CRP levels do not. The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer’s disease (AD). Paradoxically, APOE ε4 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 ε4, 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-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ 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 ε4 consistently associates with low blood CRP levels across all age groups (p