INS NYC 2024 Program

Paper	Paper Session 12 Program Schedule 02/16/2024 01:45 pm - 03:15 pm Room: West Side Ballroom - Salon 2 Paper Session 12: Mild Cognitive Impairment Final Abstract #4 Plasma proteomic predictors of domain-specific longitudinal cognitive decline Hailey Kresge, Vanderbilt University Medical Center, Nashville, United States Kahraman Tanriverdi, Vanderbilt University Medical Center, Nashville, United States Antonina Risitano, Vanderbilt University Medical Center, Nashville, United States Corey Bolton, Vanderbilt University Medical Center, Nashville, United States Kimberly Pechman, Vanderbilt University Medical Center, Nashville, United States Katherine Gifford, Vanderbilt University Medical Center, Nashville, United States Jane Freedman, Vanderbilt University Medical Center, Nashville, United States Timothy Hohman, Vanderbilt University Medical Center, Nashville, United States Angela Jefferson, Vanderbilt University Medical Center, Nashville, United States Category: MCI (Mild Cognitive Impairment) Keyword 1: dementia - Alzheimer's disease Keyword 2: cognitive course Keyword 3: aging (normal) Objective: Recent technological advances have enabled large-scale proteomic profiling of plasma, which has been widely applied to the study of Alzheimer’s disease (AD). However, studies that have comprehensively examined domain-specific longitudinal cognitive decline as an outcome from plasma protein levels assessed prior to the onset of clinical dementia are limited. This project aimed to identify plasma proteins predictive of cognitive decline across a robust neuropsychological protocol over a 7-year follow-up period. Participants and Methods: Vanderbilt Memory and Aging Project participants (n=332, 73±7 years, 41% female) free of clinical dementia at study entry underwent fasting blood draw and comprehensive serial neuropsychological assessment over a 7-year period (mean follow-up=5.8 years). Baseline plasma abundance values were measured using the Olink® Explore 3072 platform. Plasma protein levels are reported as Normalized Protein eXpression (NPX) values, an arbitrary unit for protein abundance used by Olink platforms on a Log2 scale. Only protein data with (a) <20% of participants having a value that is missing or below the limit of detection and (b) an inter-plate coefficient of variation <20% were included in analyses, yielding 2008 proteins that served as predictors in analytical models. Linear mixed-effects regressions related protein levels to longitudinal neuropsychological outcomes, adjusting for age, sex, race/ethnicity, education, baseline cognitive status, apolipoprotein E ε4 status, and follow-up time. False discovery rate correction was applied to the a priori significance threshold. Results: Regression analyses yielded 504 proteins that predicted longitudinal decline in at least one neuropsychological domain [episodic memory (52 proteins), language (212 proteins), information processing speed (360 proteins), executive function (86 proteins), visuospatial skills (123 proteins)]. Four proteins predicted decline across all domains, including well-established plasma proteins altered in AD, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP), and exciting novel plasma signals, junctional adhesion molecule 3 (JAM3) and spondin-1. Conclusions: We conducted large-scale discovery-based proteomics analyses and identified plasma proteins at study entry among a cohort of older adults free of clinical dementia that predict subsequent cognitive decline over a 7-year follow-up period. Four proteins predicted decline across all domains, including NFL, GFAP, JAM3, and spondin-1. Both NFL and GFAP are known to be elevated in the plasma of patients with AD, with NFL serving as a marker of non-specific neurodegeneration and GFAP serving as a marker of astrogliosis. JAM3 is a vascular endothelial tight junction protein, with emerging evidence supporting a role of JAM3 in maintaining cerebrovascular integrity. Spondin-1 is an extracellular matrix protein that has been shown to reduce amyloid beta and cognitive impairment in AD mouse models and has been recently highlighted in a genome-wide association study for the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog). Overall, results reveal promising potential plasma biomarkers for cognitive decline, but replication is still needed.

Paper

02/16/2024
01:45 pm - 03:15 pm
Room: West Side Ballroom - Salon 2

Paper Session 12: Mild Cognitive Impairment

Final Abstract #4

Plasma proteomic predictors of domain-specific longitudinal cognitive decline

Hailey Kresge, Vanderbilt University Medical Center, Nashville, United States
Kahraman Tanriverdi, Vanderbilt University Medical Center, Nashville, United States
Antonina Risitano, Vanderbilt University Medical Center, Nashville, United States
Corey Bolton, Vanderbilt University Medical Center, Nashville, United States
Kimberly Pechman, Vanderbilt University Medical Center, Nashville, United States
Katherine Gifford, Vanderbilt University Medical Center, Nashville, United States
Jane Freedman, Vanderbilt University Medical Center, Nashville, United States
Timothy Hohman, Vanderbilt University Medical Center, Nashville, United States
Angela Jefferson, Vanderbilt University Medical Center, Nashville, United States

Category: MCI (Mild Cognitive Impairment)

Keyword 1: dementia - Alzheimer's disease
Keyword 2: cognitive course
Keyword 3: aging (normal)

Objective:

Recent technological advances have enabled large-scale proteomic profiling of plasma, which has been widely applied to the study of Alzheimer’s disease (AD). However, studies that have comprehensively examined domain-specific longitudinal cognitive decline as an outcome from plasma protein levels assessed prior to the onset of clinical dementia are limited. This project aimed to identify plasma proteins predictive of cognitive decline across a robust neuropsychological protocol over a 7-year follow-up period.

Participants and Methods:

Vanderbilt Memory and Aging Project participants (n=332, 73±7 years, 41% female) free of clinical dementia at study entry underwent fasting blood draw and comprehensive serial neuropsychological assessment over a 7-year period (mean follow-up=5.8 years). Baseline plasma abundance values were measured using the Olink® Explore 3072 platform. Plasma protein levels are reported as Normalized Protein eXpression (NPX) values, an arbitrary unit for protein abundance used by Olink platforms on a Log2 scale. Only protein data with (a) <20% of participants having a value that is missing or below the limit of detection and (b) an inter-plate coefficient of variation <20% were included in analyses, yielding 2008 proteins that served as predictors in analytical models. Linear mixed-effects regressions related protein levels to longitudinal neuropsychological outcomes, adjusting for age, sex, race/ethnicity, education, baseline cognitive status, apolipoprotein E ε4 status, and follow-up time. False discovery rate correction was applied to the a priori significance threshold.

Results:

Regression analyses yielded 504 proteins that predicted longitudinal decline in at least one neuropsychological domain [episodic memory (52 proteins), language (212 proteins), information processing speed (360 proteins), executive function (86 proteins), visuospatial skills (123 proteins)]. Four proteins predicted decline across all domains, including well-established plasma proteins altered in AD, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP), and exciting novel plasma signals, junctional adhesion molecule 3 (JAM3) and spondin-1.

Conclusions:

We conducted large-scale discovery-based proteomics analyses and identified plasma proteins at study entry among a cohort of older adults free of clinical dementia that predict subsequent cognitive decline over a 7-year follow-up period. Four proteins predicted decline across all domains, including NFL, GFAP, JAM3, and spondin-1. Both NFL and GFAP are known to be elevated in the plasma of patients with AD, with NFL serving as a marker of non-specific neurodegeneration and GFAP serving as a marker of astrogliosis. JAM3 is a vascular endothelial tight junction protein, with emerging evidence supporting a role of JAM3 in maintaining cerebrovascular integrity. Spondin-1 is an extracellular matrix protein that has been shown to reduce amyloid beta and cognitive impairment in AD mouse models and has been recently highlighted in a genome-wide association study for the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog). Overall, results reveal promising potential plasma biomarkers for cognitive decline, but replication is still needed.