Association of human brain‐age with genetically predicted plasma levels of brain rejuvenating and aging factors identified in mice

Abstract Background Aging is the primary risk factor for Alzheimer’s disease. Experiments in mice have identified circulating proteins with an “aging/rejuvenating” effect on the brain. However, whether these proteins have an effect on the human brain remains unknown. Here, we leverage genetic data to study links between the predicted plasma levels of these proteins and human brain age. Methods This study includes 1,394 cognitively unimpaired individuals of the ALFA study. Plasma proteins with an effect on mice brain aging were identified through a systematic review [ Figure 1 ]. Summary statistics data of protein quantitative trait loci (pQTLs) associated to these proteins in human (inclusion threshold<5×10 −5 ) were acquired from a previous study (Pietzner et al.,2021), and used for computing protein genetic scores (pPRS). For each ALFA cohort participant, DeltaAge scores was calculated by subtracting chronological age from MRI‐based estimation of brain age (Cumplido et al.,2022). Positive values are interpreted as brain age older than chronological age, and viceversa . The associations between brain DeltaAge measurements and pPRSs were assessed through general linear regression models stratified by sex, amyloid‐β (Aβ) status (CSF‐Aβ42/40<0.071 [Milà‐Alomà et al.,2020]) and APOE‐ε4 carriership. Results were reported for nominal and group‐correction (two experimental aging groups) level of significance (p<0.05, p<0.025, respectively). All pQTLs included in the significant pPRS were functionally annotated and an enrichment analysis was performed. Results Genetically predicted plasma levels of CSF2, VCAM1, HP, GHRH and BGLAP were associated with negative values of brain DeltaAge, while KLOTHO with positive values. Results for GHRH (Aβ+ and APOE‐ε4 non‐carriers) and BGLAP ( APOE‐ε4 carriers) remained significant after p‐value correction, with an effect in agreement with their brain rejuvenation role as found in mice [ Figure 2 ]. Enrichment analysis found immune response and complement activation processes associated with negative values of DeltaAge [ Figure 3 ]. Conclusions These results show that plasma levels of the brain aging/rejuvenating proteins discovered in mice may also influence human brain aging. In particular, genetically predicted levels of two rejuvenating factors in mice (BGLAP and GHRH) were associated with a younger brain age than chronological age. Follow‐up analyses will include protein level measurements to unravel the molecular complexity of brain aging.