A diverse spectrum of biological processes has been associated with the pathophysiology of dementia, which affects over 55 million people worldwide. Although our understanding of the molecular mechanisms involved in the early stages of dementia is still limited, efforts have been made in recent years to use proteomics platforms and biobanks to predict an individual's risk of developing the disease.
The results published in the journal Nature Aging this year mark a significant advance in the search for blood tests that can detect Alzheimer's and other forms of dementia at a very early, pre-symptomatic stage. The scientists examined blood samples from over 50,000 healthy adults from the UK Biobank, 1,417 of whom developed dementia within 14 years. They found that high blood levels of four proteins – GFAP, NEFL, GDF15 and LTBP2 – were significantly associated with a later diagnosis of dementia.
In some patients, plasma levels of these proteins were outside the normal range more than ten years before the onset of symptoms. GFAP, a protein that provides structural support for astrocytes, has already been proposed as a diagnostic marker for Alzheimer's disease (as has GDF15). The current study now shows that individuals with high blood levels of GFAP are more than twice as likely to develop dementia and almost three times as likely to develop Alzheimer's disease compared to individuals with normal levels.
The authors used machine learning to develop prediction algorithms that combine the values of the four biomarkers with demographic factors such as age, gender, education level and family history. They trained the model with data from two-thirds of the study participants and tested its performance using data from the remaining 17,549 individuals. The model predicted the occurrence of three subtypes of dementia (including Alzheimer's disease) with approximately 90% accuracy more than ten years before the official diagnosis.
In another study from 2023, Walker and colleagues identified 32 plasma proteins associated with dementia, which play a role in protein homeostasis, immunological and synaptic functions, as well as extracellular matrix organisation. The association of 15 of these proteins with clinically relevant findings was replicated in two independent cohorts. Twelve of the proteins associated with dementia were linked in this study to known biomarkers of neurodegenerative or neuroinflammatory diseases in cerebrospinal fluid. Eight candidate proteins showed abnormal expression in the brain tissue of Alzheimer's patients, although some of the proteins most strongly associated with dementia risk (e.g. the above-mentioned GDF15) could not be detected in the samples.
Network analyses were able to provide a protein signature for dementia risk, which is characterised by dysregulation of specific immune and autophagy pathways in adults in mid-life, some 20 years before the onset of dementia, and by abnormal coagulation and complement signalling pathways, some 10 years before the onset of dementia. Genetic analyses have validated nine candidate proteins as markers for mid-life Alzheimer's disease and indicated a causal role for alpha 1-antichymotrypsin, a protease inhibitor, in Alzheimer's pathogenesis.
However, there is still disagreement as to whether the available data should already be used to develop blood tests for the general public that identify individuals at high risk of developing dementia. In the opinion of many researchers, the new biomarkers should rather be further validated before they can be used as clinical screening tools.
References:
Walker KA, Chen J, Shi L, Yang Y, …, Boerwinkle E, Ballantyne CM, Coresh J (2023) Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Science Translational Medicine 15: eafd5681
Guo Y, You J, Zhang Y, ..., Feng J-F, Cheng W, Yu J-T (2024) Plasma proteomic profiles predict future dementia in healthy adults. Nature Aging 4:247
Nature News: https://doi.org/10.1038/d41586-024-00418-9
Image credit: iStock/Brickclay
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