We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life.
- Authors
Walker, Keenan A.; Chen, Jingsha; Shi, Liu; Yang, Yunju; Fornage, Myriam; Zhou, Linda; Schlosser, Pascal; Surapaneni, Aditya; Grams, Morgan E.; Duggan, Michael R.; Peng, Zhongsheng; Gomez, Gabriela T.; Tin, Adrienne; Hoogeveen, Ron C.; Sullivan, Kevin J.; Ganz, Peter; Lindbohm, Joni V.; Kivimaki, Mika; Nevado-Holgado, Alejo J.; Buckley, Noel
- Abstract
A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife. Editor's summary: Pathological changes involved in Alzheimer's disease (AD) occur decades before the onset of cognitive deficits but are not well understood. Here, Walker and colleagues used proteomics and genomics on a cohort of middle-aged adults followed longitudinally and identified pathway-specific plasma proteins that increased dementia risk up to 25 years later. The pathway signature of these proteins was characterized by dysregulated immune signaling and proteostasis in the earliest preclinical stages and abnormal coagulation and complement signaling around 10 years before dementia onset. The study indicates that distinct biological mechanisms may be relevant in earlier and later preclinical stages of AD. –Daniela Neuhofer
- Subjects
DISEASE risk factors; MIDDLE-aged persons; POSTMORTEM changes; PROTEOMICS; BLOOD proteins; ALZHEIMER'S disease
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 705, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adf5681