Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease.
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 beta protein (Abeta40 and Abeta42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD.


METHODS
Using well-established sandwich enzyme-linked immunosorbent assays, plasma Abeta40 and Abeta42 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.


METHODS
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 Abeta levels.


METHODS
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 Abeta42/Abeta40 ratios in the lower quartiles showed significantly greater risk of MCI or AD (P = .04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Abeta42/Abeta40 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 Abeta42/Abeta40 ratios had greater cognitive decline (P = .02).


CONCLUSIONS
The plasma Abeta42/Abeta40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.
Graff-Radford
Neill R
NR
Department of Neuroscience, Mayo College of Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA. graffradford.neill@mayo.edu
Crook
Julia E
JE
Lucas
John
J
Boeve
Bradley F
BF
Knopman
David S
DS
Ivnik
Robert J
RJ
Smith
Glenn E
GE
Younkin
Linda H
LH
Petersen
Ronald C
RC
Younkin
Steven G
SG
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood*; D016229:Amyloid beta-Peptides / Q000097:blood*; D003072:Cognition Disorders / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015577:Geriatric Assessment; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*; D016016:Proportional Hazards Models; D012111:Residence Characteristics; D012189:Retrospective Studies; D012306:Risk
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)