Amyloid, Tau, TDP-43, APOE4, neurofilament levels: the list of proteins, genes and biomarkers involved in Alzheimer’s Disease has slowly grown, but we still do not understand much of the basic biology behind this disease. In a groundbreaking proteogenomic study, Walker et al. identified 32 candidate proteins strongly associated with dementia, 12 of which overlap with known signatures of Alzheimer’s Disease. The varied biological processes controlled by these proteins suggest systemic changes both within and outside of the brain that occur decades before any detectable disease appears.
It’s one of the biggest black boxes in medicine: what causes Alzheimer’s Disease? Many of the features of Alzheimer’s have been identified, including its characteristic amyloid protein plaques and tau neurofibrillary tangles found in the brain. However, the underlying causes of these protein abnormalities remain unknown. Several lines of evidence suggest that systemic factors outside of the central nervous system, such as circulating proteins, also influence the disease process.
What is clear is that Alzheimer’s is a complex disease, meaning it is not governed by a single gene or biological process. Medication aimed at eliminating amyloid plaques alone, typically in later-stage disease, has shown only a modest clinical benefit. Searches for biomarkers and genes to predict Alzheimer’s onset, or protection from it, have yielded interesting research directions, but nothing yet with broad clinical benefit.
By broadening the search for Alzheimer’s-associated biological signals to the whole body rather than just the central nervous system, researchers can uncover relationships between systemic changes and the development of Alzheimer’s Disease. Hopefully, a broader search can answer some of the fundamental questions still underlying this disease.
Proteogenomics Study Reveals New Signatures of Alzheimer’s Development
A new study has done just that; in a remarkable paper published recently in Science Translational Medicine, Walker et al. used a large-scale proteomics platform to look for signatures of dementia and Alzheimer’s risk in the plasma of middle-aged adults. The authors’ data came from 10,981 patients whose blood had been drawn for the unrelated Atherosclerosis Risk in Communities study (ARIC) over the course of a 25-year period.
From 4877 initial plasma proteins, the authors identified 32 proteins and four protein coexpression “modules” in middle-aged plasma that are strongly associated with dementia risk in the subsequent decades. The dementia-associated proteins fell primarily into four overlapping categories: proteostasis, immunity, synaptic function, and extracellular matrix (ECM) organization. This demonstrates a full complement of disrupted biological processes in middle age that contribute to later development of dementia that are systemic, and not limited to the brain.
By grouping proteins by their coexpression, the authors also identified four protein “modules” or networks. These modules were linked by their expression signatures but also seem to correlate to certain timeframes before disease onset. This suggests that at different time points, particularly over 15 years prior to onset or within 15 years of onset, distinct disease-related processes are taking place. Taking that into consideration will be important for future studies of early stages of the disease.
Finally, the authors also overlapped their findings on dementia risk-related proteins with Alzheimer’s risk. They found that 12 of the proteins were associated with CSF biomarkers of Alzheimer’s Disease, neurodegeneration, or neuroinflammation, and that 8 of the candidate proteins were abnormally expressed in postmortem Alzheimer’s brain tissue. Interestingly, the proteins associated with dementia the strongest did not show up in Alzheimer’s brains, suggesting that processes outside of the brain likely still influence disease physiology.
Future Research into Complex Alzheimer’s Disease Mechanisms
Interestingly, it seems like the most profound findings from this study are not likely to be for predicting Alzheimer’s Disease onset, but in actually elucidating the mechanisms underlying Alzheimer’s Disease initiation and progression, a thrilling prospect for the prevention and treatment of this disease. The authors did demonstrate that combining their identified risk factors with traditional risk factors for dementia in a machine learning model for disease prediction moderately improved its accuracy.
Excitingly, the authors also showed that many of the proteins identified in their study have been identified using independent methods in other cohorts as potential Alzheimer’s-related proteins of interest. Walker et al.’s identification of a “timeline” of when these biological processes may go wrong in middle age provides another tool for investigating the mechanisms in these pathways and how they ultimately cause dementia. Eight of the identified proteins are targeted by known drugs, opening up avenues for drug repurposing studies. Taken together, this study is an exciting breakthrough in the basic science underpinning the cause and progression of Alzheimer’s Disease.
Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help
Groundbreaking studies like these are made possible by technological advances making biological data generation, storage and analysis faster and more accessible than ever before. From pipeline development and software engineering to deploying existing bioinformatics tools, Bridge Informatics can help you on every step of your research journey.
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Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].