Chen, Coty

Abstract Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer’s disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer’s disease and Parkinson’s disease (Stanford Alzheimer’s Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer’s disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 ‘hub’ protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

AbstractBackgroundGrowth Differentiation Factor 15 (GDF15) is a TGF‐beta superfamily protein upregulated during immune‐mediated stress responses. Peripheral GDF15 is linked to adverse aging across organ systems including the brain. Immune dysregulation is implicated in frontotemporal dementia (FTD) pathogenesis. We examined how plasma GDF15 levels associated with longitudinal cognitive and neurofilament light chain (NfL) trajectories in adults with FTD and controls. Furthermore, we tested the utility of GDF15 as a prognostic biomarker against common inflammatory proteins (CRP and IL6).Method231 adults with FTD (24.35% sporadic FTD syndromes; 19.19% MAPT; 19.56% GRN; 22.14% C9orf72 pathogenic carriers) and 40 normal controls from the ALLFTD Consortium completed longitudinal neuropsychological testing and a blood draw with plasma analyzed on SomaScan V4.0 (baseline only: GDF15, CRP, and IL6) and Simoa (longitudinal: NfL). CRP and IL6 were selected as control markers to test the specificity of GDF15. Linear mixed effects models separately examined longitudinal cognition (global, executive functioning, memory, and language z‐scores) and plasma NfL levels as a function of baseline plasma GDF15, time, and their interaction, controlling for baseline age, sex, and education. Parallel models were conducted for CRP and IL6.ResultIn the whole cohort, higher baseline plasma GDF15 levels associated with steeper global cognitive decline (b = ‐3.91, p = 0.0092) and NfL accumulation (b = 3.88, p = 0.00088) over time. When examining cognitive domains, we found GDF15 only associated with worse executive functioning trajectories (b = ‐3.19, p = 0.0021). In contrast, baseline levels of CRP and IL6 did not display statistically significant relationships with cognitive or NfL trajectories. Prognostic effects of GDF15 remained statistically significant when restricting analyses to those with FTD pathogenic variants (b = ‐2.98, p = 0.0054 [global cognition], b = 2.69, p = 0.0098 [NfL]).ConclusionAdults with FTD and higher baseline peripheral GDF15 levels exhibit accelerated cognitive decline and neurodegeneration. Our results support GDF15 as a potential prognosticator of adverse clinical outcomes in FTD and highlight the relevance of GDF15‐specific pathways in FTD progression. Plasma GDF15 may provide utility over commonly examined inflammatory proteins and further work to explore its clinical value is indicated.

AbstractBackgroundSex differences in neurodegenerative diseases can impact accurate diagnosis and management. Emerging data suggest there may be sex differences in frontotemporal dementia (FTD) prevalence and clinical manifestation. However, prior studies lacked longitudinal assessment and were limited in capturing sex differences in earliest stages of disease (e.g., preclinical). We evaluated how sex impacts longitudinal clinical outcomes in individuals carrying autosomal dominant variants for FTD.Method337 participants carrying pathogenic variants in MAPT, GRN, or C9orf72 completed longitudinal evaluations (2.4 average visits, range = 1‐6), including neuropsychological and functional assessments, and plasma analyzed for neurofilament light chain (NfL). FTLD Clinical Dementia Rating Scale (FTLD‐CDR) classified disease stage at study entry (FTLD‐CDR = 0: asymptomatic; FTLD‐CDR = 0.5: MCI; FTLD‐CDR> 0.5: Dementia). Linear mixed‐effects models evaluated the effect of sex on longitudinal clinical trajectories, including the effect of disease stage at study entry.ResultMale and female carriers were similarly distributed with respect to baseline demographics and most clinical outcomes. However, women exhibited higher baseline NfL than men. Not accounting for disease stage, men and women did not show statistical differences on cognitive, functional, or NfL trajectories. However, when accounting for disease stage, there was a significant interaction between baseline disease stage, sex, and time on cognitive, NfL, and functional trajectories. While sex differences were not statistically significant among asymptomatic carriers, women with MCI/dementia evidenced more rapid cognitive, NfL and functional decline over time compared to men. To evaluate the role of pathology burden, we tested the interaction between baseline NfL, sex, and time on clinical outcomes stratified by disease stage. In asymptomatic participants, women showed an attenuated adverse relationship between baseline NfL and clinical trajectories compared to men. No statistically significant sex differences were evident in the relationship between baseline NfL and clinical outcomes in participants with MCI/dementia.ConclusionIn familial FTD, women evidenced steeper clinical declines than men after symptom onset. Accounting for pathology, baseline NfL was a stronger predictor of clinical decline in asymptomatic men compared to women. NfL may be a less sensitive prognostic tool for clinical progression in women with FTD, particularly early in disease. This may reflect early “cognitive resilience” to neurodegeneration in women.