In:
Alzheimer's & Dementia, Wiley, Vol. 16, No. S5 ( 2020-12)
Abstract:
While plasma levels of several etiologically relevant molecules have been associated with Alzheimer’s disease and dementia more broadly, information about the full range of changes in the plasma proteome that precede dementia is lacking. Accordingly, this study used modified aptamer technology (SOMAscan) to examine the relationship between the plasma levels of 4,877 proteins and risk for incident dementia in a large community‐based sample. Methods Plasma levels of 4,877 proteins were measured in non‐demented participants who attended visit 5 of the Atherosclerosis Risk in Communities (ARIC) study (2011‐2013; Figure 1A). We examined the association of log2 protein levels with incident dementia risk over 5 years using Cox proportional hazard models adjusted for demographic and cardiovascular risk factors. Dementia‐associated proteins were then measured from plasma samples collected 18 years earlier (visit 3; 1993‐1995) and related to dementia risk between visits 3 and 5 (Figure 1B). Candidate proteins were related to measures of brain structure (by MRI) and amyloid burden (by PET). Ingenuity Pathway Analyses and Mendelian randomization were used to inform biological pathways and causal relationships. Results Among 4,144 participants seen at visit 5 (age: 75 (SD 5)), there were 444 incident dementia cases over the next 5 years. In a proteome‐wide analysis, 50 proteins were significantly associated with incident dementia at a Bonferroni‐corrected threshold ( P 〈 1.03e‐05; Figure 2A). When these dementia‐associated proteins were measured in plasma collected almost 20 years earlier (n=11,069; 1,131 dementia cases), 21 of the 50 proteins continued to show a significant association with incident dementia ( P 〈 0.001; Figure 2B). We found causal associations with Alzheimer’s disease for two of the top five dementia‐associated proteins using Mendelian randomization, and we demonstrated a relationship between protein levels and neuroimaging measures of atrophy, white matter disease, and cerebral amyloid. A systems‐level analysis of dementia‐associated proteins implicated biological mechanisms involved in metabolic and inflammatory signaling, coagulation and prothrombin activation, and innate immune function, among others (Figure 3). Conclusions These findings provide insight into the plasma proteomic patterns that precede the onset of dementia in old age and middle age and highlight novel molecules and mechanistic pathways for further study.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2201940-6
