Growth Differentiation Factor 15 Is Associated With Alzheimer’s Disease Risk

Abstract

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases

“…Previous MR studies on Alzheimer's disease 10,12,[25][26][27][28][29][30][31][32][33] suggest potential causal associations with BIN1, CCL27, C3, CD33, CD4 T cells, GDF-15 and SVEP1, whereas MR studies on Parkinson's disease suggest a potential causal association with GPNMB, IL-6 and MIP1b. Compared with these studies, we used a stricter P value cutoff with multiple testing correction and were able to replicate associations between BIN1, CD33 and Alzheimer's disease and those between GPNMB and Parkinson's disease.…”

“…To our knowledge, this is the most comprehensive MR and triangulation study to date on immune system-and BBB-related biomarkers as risk factors of dementia-causing diseases. Our MR focused on 1,827 biomarkers whereas earlier MR analyses included fewer than 200 biomarkers specific to these systems 10,12,[25][26][27][28][29][30][31][32][33] . We obtained the strongest causal evidence for autoimmunity-and inflammation-related AZGP1 (ref.…”

The expression pattern of GDF15 in human brain changes during aging and in Alzheimer’s disease

“…Several studies in humans have found an association between high circulating levels of GDF15 and the risk of dementia, cerebrovascular disease, cognitive impairment, and brain atrophy, which are clinical features of many neurodegenerative diseases ( Fuchs et al, 2013 ; Chai et al, 2016 ; Jiang et al, 2016 ; Nasrabady et al, 2018 ). In particular, some studies suggested that high circulating levels of GDF15 are associated with the risk of developing AD, as well as other neurodegenerative diseases, and considered this protein as a promising diagnostic biomarker and therapeutic target of several neurodegenerative diseases ( Chai et al, 2016 ; Wu et al, 2021 ; Xue et al, 2022 ). On the other hand, other studies have found no difference in the circulating level of GDF15 in AD patients compared to age-matched healthy controls ( Conte et al, 2021 ), or showed that exogenous recombinant GDF15 can promote Aβ clearance activity of microglial cultured cells ( Kim et al, 2018 ).…”

Response of Circulating Inflammatory Markers to Intermittent Hypoxia-Hyperoxia Training in Healthy Elderly People and Patients with Mild Cognitive Impairment

“…Although some suggested that GDF15 is not associated with AD, others demonstrated specific roles for GDF15 in the development of AD [ 20 ]. Elevated GDF15 was associated with a higher risk of AD and lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance [ 21 , 22 ]. Moreover, exogenous recombinant GDF-15 diminished antibody levels in microglial cell culture, and being injected in the brain parenchyma of 5XFAD mice also led to a decrease in Aβ plaques [ 23 ].…”