Associations of Plasma GDF15, CRP, and IL-6 With Cognitive Trajectories in Patients With Frontotemporal Lobar Degeneration

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Background and ObjectivesPlasma growth differentiation factor 15 (GDF15), a TGFbeta family cytokine, has been robustly identified from proteomics discovery work as linked to adverse brain aging; immune dysregulation may be a core component of frontotemporal lobar degeneration (FTLD), yet biomarkers tracking immune contributions to FTLD are lacking. We examined associations between peripheral GDF15 with neurobehavioral trajectories in FTLD and contrasted findings to known inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6). MethodsBaseline plasma GDF15, IL-6, and CRP were measured through SomaScan in participants enrolled in the ALLFTD consortium. Genetic screening–identified FTLD pathogenic variants in the microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) genes. Baseline and longitudinal plasma neurofilament light chain (NfL) concentrations were measured with Simoa. Separate linear-mixed effects (LME) models examined cognitive and NfL trajectories as a function of baseline GDF15 level, time (years since baseline), and their interaction. Parallel LME models examined how CRP and IL-6 related to neurobehavioral trajectories. Separate LME models were fit in each of the FTLD-causing genes to determine prognostic relevance by genetic group. All LME models controlled for baseline age, sex, and education. ResultsOur cohort consisted of 269 individuals (median age = 59; 51% female; sporadic = 74, MAPT = 37, GRN = 32, C9orf72 = 49, clinical normal controls without a pathogenic variant = 77). Across sporadic and autosomal dominant FTLD, higher baseline GDF15 associated with steeper global cognitive decline (β = −0.13, p = 0.002), particularly associated with executive functioning trajectories (β = −0.11, p = 0.0006), as well as steeper rises in NfL levels (β = 0.08, p = 0.001) over time. By contrast, CRP and IL-6 did not demonstrate statistically significant relationships with global cognitive (CRP: β = −0.01, p = 0.9; IL-6: β = −0.01, p = 0.9) or NfL trajectories (CRP: β = 0.04, p = 0.1; IL-6: β = 0.04, p = 0.7). DiscussionHigher baseline GDF15 associated with accelerated rates of cognitive decline and plasma NfL elevations. GDF15 may be more sensitive to FTLD-related progression than standard inflammatory biomarkers. Integrating GDF15 into a biomarker panel may help predict progression of cognitive decline in FTLD.

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