• Evaluation of a long-term study (14.1 years) involving 52,645 participants without dementia-related diseases at baseline, and identification of putative disease-predicting proteins in blood plasma.
• Elevated levels of plasma proteins NEFL, GFAP, GDF15 and LTBP2 are significantly associated with an increased risk of developing dementia, including Alzheimer’s disease and vascular dementia.
• Combining these plasma protein levels with Demographic data and cognitive tests substantially improves the predictive accuracy for future dementia-related diseases.

Recent advances in proteomic research have spotlighted the potential of blood plasma proteins in predicting the onset of dementia-related diseases, including all-cause dementia (ACD), Alzheimer’s disease (AD) and vascular dementia (VaD). Understanding these biomarkers not only aids in early diagnosis but also in mapping the progression of these neurodegenerative diseases. A recent study by Guo et al. (2024) has identified specific proteins associated with dementia, the extent of their impact on disease risk, their predictive accuracy, and their relationship with disease progression.

Identification of dementia-associated proteins

The study initially focused on identifying specific plasma proteins associated with the risk of developing dementia. In total, it found 184, 16, and 139 proteins to be generally associated with ACD, AD, and VaD, respectively. Refined model criteria highlighted proteins such as NEFL, GFAP, GDF15, and LTBP2 to be significantly associated with those diseases.

Magnitude of protein contribution to disease prediction

Further analysis provided a ranking of these proteins based on their importance in association with dementia. NEFL and GFAP, in particular, stood out for their strong disease-correlation, indicating that their levels in the blood plasma could serve as significant markers for predicting dementia risk.

Predictive accuracy of plasma proteins over time

Further, the study investigated the predictive prowess of these plasma proteins, revealing that, especially when combined with demographic and cognitive test data, they could significantly enhance the accuracy of predicting future dementia. This combination approach allowed for more precise forecasting (“area under the curve” up to 0.9) over spans of 5-10 years or more.

Relationship between plasma proteins and progression risk

A deeper examination of the relationship between elevated levels of these proteins and the risk of clinical progression revealed that individuals with higher baseline levels of NEFL, GFAP, GDF15, and LTBP2 faced an increased risk of developing dementia. High GFAP levels for example, nearly tripled the likelihood of developing AD.

Backtracking of trajectories

Lastly, the research ventured into backtracking the trajectories of these plasma proteins, aiming to pinpoint when deviations from normal levels began. This analysis revealed that changes in levels of proteins such as NEFL, GFAP, GDF15, and LTBP2 can be traced back to at least 10 years before the clinical diagnosis of dementia.

This progression from identifying dementia-associated proteins to understanding their predictive accuracy and backtracking their trajectories may offer a comprehensive approach for early dementia intervention. By adding more proteins as biomarkers, this work provides options to detect and follow dementia beyond amyloid and tau.

This article refers to:

Guo Y, You J, Zhang Y, Liu W-S, Huang Y-Y, Zhang Y-R, Zhang W, Dong Q, Feng J-F, Cheng W, Yu J-T (2024) Plasma proteomic profiles predict future dementia in healthy adults. Nat Aging 4:247–260. DOI: 10.1038/s43587-023-00565-0