APOE‐ε4 carriership modifies the association of CCL11 and sVCAM1 plasma protein levels with cognitive performance in individuals at risk of Alzheimer's disease

Abstract Background In murine models, peripheral blood factors have been identified as having either a brain rejuvenating or ageing effect. However, it is unclear whether these blood factors have similar effects in humans. We aimed at testing the association between these blood factors and cognitive performance in cognitively unimpaired (CU) individuals at risk of Alzheimer’s disease (AD). Method We included 414 CU participants from the ALFA+ cohort [mean age: 61.1(±4.72), women:60.4%, APOE‐ε4 carriers:54.8%, and amyloid‐positive:34.2%]. A subset of participants (n=341) had longitudinal follow‐up [mean follow of 3.28 years (0.50)]. Amyloid positivity was determined by CSF‐Aβ42/40<0.071. Blood factors associated with an ageing effect [β2‐microglobulin(β2‐M), CCL2, CCL11, CCL19, Haptoglobin, sVCAM1] or rejuvenating effect (CSF2 and TIMP2) were measured using ELISA, MSD, or Simoa immunoassays. Through linear regression analyses we first tested the association between chronological age and each protein, correcting by sex. Then, we tested the association of each protein with baseline cognition and longitudinal cognitive changes at follow‐up, adjusting for age, sex and years of education. Cognitive data included the PACC score and domain‐specific composites (attention, episodic memory[EM] and executive function). The modifying effect of sex, APOE‐ε4 carriership, and amyloid status was also tested and significant interactions stratified. Result β2‐M and CCL11 significantly increased with chronological age (Figure 1). Only APOE‐ε4 carriership modified the association of age‐related blood factors CCL11 (p int =0.011) and sVCAM1 (p int =0.006) with cross‐sectional and longitudinal EM, respectively (Figure 2). In APOE‐ε4 non‐carriers, higher CCL11 was associated with better EM at baseline (β=0.105, p=0.025), while higher sVCAM1 was associated with better EM at follow‐up (β=0.076, p=0.010). Inversively, in APOE‐ε4 carriers, higher CCL11 was associated with worse EM at baseline (β=‐0.104, p=0.014), and higher sVCAM1 was associated with worse EM at follow‐up (β=‐0.073, p=0.014). Conclusion We observe an association between higher CCL11 and sVCAM1 and worse cognition in APOE‐ε4 carriers. This may suggest that the APOE‐ε4 carriers are more susceptible to the ageing effect of these blood factors.