Association of low plasma Aβ42/Aβ40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease

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Abstract

Background: To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD-related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease. Objective: To determine whether plasma levels of amyloid β protein (Aβ40 and Aβ42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD. Design: Using well-established sandwich enzyme-linked immunosorbent assays, plasma Aβ40 and Aβ42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD. Setting: Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry. Patients: We followed up 563 cognitively normal white volunteers (median age, 78 years; 62% female) who had at least 1 follow-up visit after measurement of baseline plasma Aβ levels. Main Outcome Measures: The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart. Results: During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Aβ42/Aβ40 ratios in the lower quartiles showed significantly greater risk of MCI orAD(P=.04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Aβ42/Aβ40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95% confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Aβ42/Aβ40 ratios had greater cognitive decline (P=.02). Conclusion: The plasma Aβ42/Aβ40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.

Original languageEnglish (US)
Pages (from-to)354-362
Number of pages9
JournalArchives of Neurology
Volume64
Issue number3
DOIs
StatePublished - Mar 2007

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Alzheimer Disease
Apolipoproteins E
Dementia
Biomarkers
Genotype
Amyloidogenic Proteins
Cognitive Dysfunction
Alzheimer's Disease
Mild Cognitive Impairment
Plasma
Registries
Volunteers
Heart Diseases
Primary Health Care
Healthy Volunteers
Enzyme-Linked Immunosorbent Assay
Cholesterol
Regression Analysis
Outcome Assessment (Health Care)
Confidence Intervals

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

@article{e4150db980d843a1947fb7d462008e7b,
title = "Association of low plasma Aβ42/Aβ40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease",
abstract = "Background: To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD-related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease. Objective: To determine whether plasma levels of amyloid β protein (Aβ40 and Aβ42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD. Design: Using well-established sandwich enzyme-linked immunosorbent assays, plasma Aβ40 and Aβ42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD. Setting: Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry. Patients: We followed up 563 cognitively normal white volunteers (median age, 78 years; 62{\%} female) who had at least 1 follow-up visit after measurement of baseline plasma Aβ levels. Main Outcome Measures: The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart. Results: During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Aβ42/Aβ40 ratios in the lower quartiles showed significantly greater risk of MCI orAD(P=.04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Aβ42/Aβ40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95{\%} confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Aβ42/Aβ40 ratios had greater cognitive decline (P=.02). Conclusion: The plasma Aβ42/Aβ40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.",
author = "{Graff Radford}, {Neill R} and Juliana Crook and Lucas, {John A} and Boeve, {Bradley F} and Knopman, {David S} and Ivnik, {Robert J.} and Smith, {Glenn E.} and Younkin, {Linda H.} and Petersen, {Ronald Carl} and Younkin, {Steven G}",
year = "2007",
month = "3",
doi = "10.1001/archneur.64.3.354",
language = "English (US)",
volume = "64",
pages = "354--362",
journal = "Archives of Neurology",
issn = "0003-9942",
publisher = "American Medical Association",
number = "3",

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TY - JOUR

T1 - Association of low plasma Aβ42/Aβ40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease

AU - Graff Radford, Neill R

AU - Crook, Juliana

AU - Lucas, John A

AU - Boeve, Bradley F

AU - Knopman, David S

AU - Ivnik, Robert J.

AU - Smith, Glenn E.

AU - Younkin, Linda H.

AU - Petersen, Ronald Carl

AU - Younkin, Steven G

PY - 2007/3

Y1 - 2007/3

N2 - Background: To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD-related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease. Objective: To determine whether plasma levels of amyloid β protein (Aβ40 and Aβ42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD. Design: Using well-established sandwich enzyme-linked immunosorbent assays, plasma Aβ40 and Aβ42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD. Setting: Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry. Patients: We followed up 563 cognitively normal white volunteers (median age, 78 years; 62% female) who had at least 1 follow-up visit after measurement of baseline plasma Aβ levels. Main Outcome Measures: The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart. Results: During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Aβ42/Aβ40 ratios in the lower quartiles showed significantly greater risk of MCI orAD(P=.04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Aβ42/Aβ40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95% confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Aβ42/Aβ40 ratios had greater cognitive decline (P=.02). Conclusion: The plasma Aβ42/Aβ40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.

AB - Background: To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD-related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease. Objective: To determine whether plasma levels of amyloid β protein (Aβ40 and Aβ42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD. Design: Using well-established sandwich enzyme-linked immunosorbent assays, plasma Aβ40 and Aβ42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD. Setting: Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry. Patients: We followed up 563 cognitively normal white volunteers (median age, 78 years; 62% female) who had at least 1 follow-up visit after measurement of baseline plasma Aβ levels. Main Outcome Measures: The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart. Results: During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Aβ42/Aβ40 ratios in the lower quartiles showed significantly greater risk of MCI orAD(P=.04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Aβ42/Aβ40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95% confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Aβ42/Aβ40 ratios had greater cognitive decline (P=.02). Conclusion: The plasma Aβ42/Aβ40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.

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