In:
Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
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 biological pathways mechanistically relevant in the earliest phase of disease and a lack of protein biomarkers available to capture the biological systems involved. Method To discover early biomarkers and further understand on a molecular level the systemic factors that may promote neurodegeneration, we used a large‐scale proteomic platform to relate 4,877 plasma proteins measured in middle‐aged adults to dementia risk over a 25‐year period ( n =10,981; 1,874 incident dementia cases) in the Atherosclerosis Risk in Communities (ARIC) study ( Figure 1 ). Dementia‐associated proteins were related to 20‐year cognitive decline in the Whitehall II study, and to AD risk and CSF biomarkers European Medical Information Framework‐AD study. Result Proteome‐wide association study in ARIC discovered 32 midlife dementia‐associated plasma proteins, the majority of which were involved in either immune function, proteostasis/autophagy, or extracellular matrix organization ( Figure 2 ). We replicated the relationship between candidate proteins and neurocognitive outcomes in multiple independent cohorts and demonstrated a relationship between dementia‐associated plasma proteins and cerebrospinal fluid markers of Aß42, p‐tau181, neurodegeneration, and neuroinflammation ( Figure 3 ). Using network analysis, we identified 19 co‐expressed protein modules, 4 of which were strongly associated with either short‐term and long‐term dementia risk ( Figure 4 ). Pathway analyses conducted for the dementia‐associated protein modules suggested dysregulation of specific immune pathways (e.g., JAK‐STAT signaling, Toll‐like receptor activation) and disrupted proteostasis/autophagy and extracellular matrix organization during midlife ∼20 years before dementia onset, and abnormal coagulation/complement signaling ∼10 years before dementia onset ( Figure 5 ). We used two‐sample Mendelian randomization to identify which midlife plasma proteins and protein networks may play a mechanistic role in Alzheimer’s disease, and demonstrated that many of the dementia‐associated proteins may play a causal role in systemic inflammatory and autoimmune diseases associated with heightened AD/dementia risk. Conclusion This work sheds light on the complexity of the systemic immune response in the decades preceding dementia onset and highlights multiple potential biomarkers and therapeutic targets for early AD.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2201940-6
