Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging

Dimitrios Kapogiannis, Maja Mustapic, Michelle D. Shardell, Sean T. Berkowitz, Thomas C. Diehl, Ryan D. Spangler, Joyce Tran, Michael P. Lazaropoulos, Sahil Chawla, Seema Gulyani, Erez Eitan, Yang An, Chiung Wei Huang, Esther Oh, Constantine G Lyketsos, Susan M. Resnick, Edward J. Goetzl, Luigi Ferrucci

Research output: Contribution to journalArticle

Abstract

Importance: Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1). Objective: To validate nEV biomarkers as AD predictors. Design, Setting, Participants: This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- A nd sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. Main Outcomes and Measures: Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. Results: Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: Mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: Mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. Conclusions and Relevance: We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

Original languageEnglish (US)
JournalJAMA Neurology
DOIs
StatePublished - Jan 1 2019

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Baltimore
Longitudinal Studies
Alzheimer Disease
Biomarkers
Insulin Receptor Substrate Proteins
Area Under Curve
Sensitivity and Specificity
Extracellular Vesicles
Research
Hematologic Tests

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Kapogiannis, D., Mustapic, M., Shardell, M. D., Berkowitz, S. T., Diehl, T. C., Spangler, R. D., ... Ferrucci, L. (2019). Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2019.2462

Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging. / Kapogiannis, Dimitrios; Mustapic, Maja; Shardell, Michelle D.; Berkowitz, Sean T.; Diehl, Thomas C.; Spangler, Ryan D.; Tran, Joyce; Lazaropoulos, Michael P.; Chawla, Sahil; Gulyani, Seema; Eitan, Erez; An, Yang; Huang, Chiung Wei; Oh, Esther; Lyketsos, Constantine G; Resnick, Susan M.; Goetzl, Edward J.; Ferrucci, Luigi.

In: JAMA Neurology, 01.01.2019.

Research output: Contribution to journalArticle

Kapogiannis, D, Mustapic, M, Shardell, MD, Berkowitz, ST, Diehl, TC, Spangler, RD, Tran, J, Lazaropoulos, MP, Chawla, S, Gulyani, S, Eitan, E, An, Y, Huang, CW, Oh, E, Lyketsos, CG, Resnick, SM, Goetzl, EJ & Ferrucci, L 2019, 'Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging', JAMA Neurology. https://doi.org/10.1001/jamaneurol.2019.2462
Kapogiannis, Dimitrios ; Mustapic, Maja ; Shardell, Michelle D. ; Berkowitz, Sean T. ; Diehl, Thomas C. ; Spangler, Ryan D. ; Tran, Joyce ; Lazaropoulos, Michael P. ; Chawla, Sahil ; Gulyani, Seema ; Eitan, Erez ; An, Yang ; Huang, Chiung Wei ; Oh, Esther ; Lyketsos, Constantine G ; Resnick, Susan M. ; Goetzl, Edward J. ; Ferrucci, Luigi. / Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging. In: JAMA Neurology. 2019.
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abstract = "Importance: Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1). Objective: To validate nEV biomarkers as AD predictors. Design, Setting, Participants: This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- A nd sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. Main Outcomes and Measures: Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. Results: Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13{\%}]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45{\%}]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6{\%} area under curve (AUC), 81.8{\%} sensitivity, and 85.8{\%} specificity for predicting AD. The model was validated in the test BLSA set (80{\%} AUC, 55.6{\%} sensitivity, 88.7{\%} specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: Mean [SD] age, 74.03 [8.73] years; 18 women [51.43{\%}] and 29 controls: Mean [SD] age, 72.14 [7.86] years; 23 women [79.31{\%}]), nEV biomarkers achieved discrimination with 98.9{\%} AUC, 100{\%} sensitivity, and 94.7{\%} specificity in the training set and 76.7{\%} AUC, 91.7{\%} sensitivity, and 60{\%} specificity in the test set. Conclusions and Relevance: We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.",
author = "Dimitrios Kapogiannis and Maja Mustapic and Shardell, {Michelle D.} and Berkowitz, {Sean T.} and Diehl, {Thomas C.} and Spangler, {Ryan D.} and Joyce Tran and Lazaropoulos, {Michael P.} and Sahil Chawla and Seema Gulyani and Erez Eitan and Yang An and Huang, {Chiung Wei} and Esther Oh and Lyketsos, {Constantine G} and Resnick, {Susan M.} and Goetzl, {Edward J.} and Luigi Ferrucci",
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T1 - Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging

AU - Kapogiannis, Dimitrios

AU - Mustapic, Maja

AU - Shardell, Michelle D.

AU - Berkowitz, Sean T.

AU - Diehl, Thomas C.

AU - Spangler, Ryan D.

AU - Tran, Joyce

AU - Lazaropoulos, Michael P.

AU - Chawla, Sahil

AU - Gulyani, Seema

AU - Eitan, Erez

AU - An, Yang

AU - Huang, Chiung Wei

AU - Oh, Esther

AU - Lyketsos, Constantine G

AU - Resnick, Susan M.

AU - Goetzl, Edward J.

AU - Ferrucci, Luigi

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Importance: Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1). Objective: To validate nEV biomarkers as AD predictors. Design, Setting, Participants: This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- A nd sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. Main Outcomes and Measures: Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. Results: Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: Mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: Mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. Conclusions and Relevance: We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

AB - Importance: Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1). Objective: To validate nEV biomarkers as AD predictors. Design, Setting, Participants: This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- A nd sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. Main Outcomes and Measures: Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. Results: Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: Mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: Mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. Conclusions and Relevance: We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

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