The largest risk factor for neurodegenerative disease is age. Understanding the neurobiology of age will help identify transdiagnostic therapy targets. Heterochronic parabiosis studies (joining circulatory systems between animals of differing ages) have uncovered >dozen individual age-related blood factors that when systemically injected demonstrate “pro-aging” or “pro-youthful” effects on brain and cognitive outcomes in mouse models. However, the importance of these factors for aging humans is unclear. Further, each factor has been examined in isolation and the combinatorial benefit of these factors is unknown. We cross-referenced the heterochronic parabiosis literature for rejuvenation factors captured by the Somascan assay that were known to cross the blood-brain-barrier to identify five factors. We examined the clinical relevance of these rejuvenation factors in cerebrospinal fluid (CSF) of adults with autosomal dominant forms of frontotemporal dementia (FTD) and sporadic Alzheimer’s disease.

The discovery cohort included 100 adults carrying autosomal dominant FTD mutations (M_age=49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 noncarrier family members (M_age=52.6; 45% female) who completed baseline lumbar puncture with CSF analyzed on Somascan (version 4.0), and longitudinal (M_visits=3yrs, range 1-7yrs) neuropsychological evaluations, functional assessments (FTLD-NACC-CDR), and plasma analyzed for neurofilament light chain (NfL; Quanterix Simoa). A transdiagnostic validation cohort included 35 adults with sporadic late-onset Alzheimer’s disease (M_age=69.4; 60% female) and 56 controls (M_age=68.8, 50% female) who completed the same CSF and clinical outcome measures cross-sectionally. Levels of CCL11, CCL2, B2M, BGLAP, and CSF2 were linearly combined into a composite score in which each protein was equally weighted and higher values reflected “pro-youthful” levels. We evaluated the relationship between baseline CSF rejuvenation composite levels on global cognitive, functional, and NfL outcomes via linear mixed-effects models for longitudinal models (discovery cohort) or regression for cross-sectional models (validation cohort), adjusting for age, sex, and education.

Baseline CSF rejuvenation composite levels showed an interaction with mutation carrier status (yes/no) on global cognitive, functional, and plasma NfL progression over time (ps<0.05). Mutation carriers with higher baseline CSF rejuvenation proteins evidenced significantly slower clinical decline, a relationship that was not present in clinically normal noncarrier adults. Within mutation carriers, higher baseline rejuvenation protein levels (upper vs. lower tertial) associated with an estimated 184% slower cognitive, 53% slower functional, and 48% slower NfL progression over 5-years. In the transdiagnostic validation cohort, there was also an interaction between CSF rejuvenation composite levels and AD diagnosis on clinical outcomes. Higher CSF rejuvenation composite was associated with better functional and cognitive performances, and lower NfL among individuals with AD, a relationship that was not observed in clinically normal adults.

Proteins that show mechanistic evidence for brain rejuvenation in animal models of aging show protective relationships against clinical changes in adults with ADRDs and warrant further validation as targets of interest.