Genome-wide association studies on Alzheimer’s disease (AD) have shown that its biological process is very complex and not limited to the accumulation of β Amyloid protein (Aβ）and tau protein. Systemic factors and biological processes outside the central nervous system may also affect the risk of dementia and AD.
Proteins, as systemic circulating factors, may be driving factors for complex central nervous system diseases, and researchers have been searching for biomarkers in plasma that can represent pathological progression. However, currently, large-scale proteomic analysis of dementia is mainly focused on the elderly, and cross-sectional design is difficult to explain protein-related changes during long-term preclinical disease processes.
In this study, Keenan A. Walker and his team from the Behavioral Neuroscience Laboratory of the National Institute on Aging conducted proteomic research on population data spanning 25 years and discovered 32 plasma proteins associated with dementia, which are related to biological functions such as protein homeostasis, immunity, synaptic function, and extracellular matrix. The researchers also identified protein network characteristics associated with dementia risk in different stages of disease progression.
The research data came from the Atherosclerosis Risk Population Study (ARIC), which included 10981 participants with a baseline age of 60 years and 54% women. After 25 years of follow-up, 1874 participants were diagnosed with dementia before the end of follow-up.
At baseline, 4877 plasma protein levels were recorded, of which 452 were significantly associated with the risk of dementia 25 years later. After adjusting for relevant factors, 26 proteins remained significantly associated with dementia risk. Among them, GDF15 is involved in metabolism and immune regulation, with the strongest correlation with dementia risk. Other proteins play roles in neuronal/synaptic function, innate and adaptive immune signaling, ubiquitination and autophagy, extracellular matrix tissue/protein breakdown, and coagulation, respectively.
A total of 32 proteins associated with dementia risk were identified for participants aged 40-50 (n=5285) who were limited to protein collection. These proteins are associated with brain Aβ positive, elevated levels of p-tau in cerebrospinal fluid, neurodegenerative diseases, and neuroinflammation are associated. It was also found that the expression of multiple proteins in the brain of AD patients was significantly higher than that of the control group.
In order to clarify the relationship between protein types and dementia risk at different stages, researchers defined the occurrence of dementia within 15 years after protein measurement as a recent risk of dementia (which may already have neuropathological changes), and the occurrence of dementia after 15 years as a long-term risk of dementia. The protein types with the highest correlation between the two periods were different, but GDF15 maintained a robust association with dementia risk throughout the follow-up period.
Researchers divided these proteins into 19 non-overlapping protein modules based on their characteristics. The protein modules significantly associated with the recent risk of dementia are rich in complement and coagulation proteins, which are enriched in liver tissue. The protein modules significantly associated with the risk of long-term dementia are rich in the JAK-STAT signaling pathway, cytokine signaling pathway, helper T cell 1 (TH1), and TH2 cell differentiation proteins, and are shown to be enriched in multiple tissues such as the appendix, lymph nodes, and salivary glands. The results showed changes in immune characteristics during the progression of dementia, and different biological mechanisms may be related to the early and late preclinical stages of AD.
Next, the researchers selected 13 proteins to create a predictive model for all-cause dementia, with an area under curve (AUC) of 0.66. Correspondingly, demographic factors, APOE4, and the AUC of the prediction model composed of cardiovascular risk factors are 0.77. Adding candidate proteins to the demographic/cardiovascular risk factor model improved prediction accuracy with an AUC of 0.78.
Overall, the study identified 32 plasma proteins in middle-aged individuals, which are closely related to the risk of dementia in subsequent decades. These proteins mainly involve four biological processes: protein homeostasis, immunity, synaptic function, and extracellular matrix tissue. And with age and disease progression, the peripheral biological pathways associated with subsequent dementia risk have also changed.
Walker KA, Chen J, Shi L, Yang Y, et al. Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Sci Transl Med. 2023 Jul 19;15(705):eadf5681. doi: 10.1126/scitranslmed.adf5681. Epub 2023 Jul 19. PMID: 37467317.