NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Plasma Amyloid- as a Predictor of Dementia and Cognitive Decline A Systematic Review and Meta-analysis Alain Koyama, SM; Olivia I. Okereke, MD, SM; Ting Yang, MD; Deborah Blacker, MD, ScD; Dennis J. Selkoe, MD; Francine Grodstein, ScD Background: Preclinical prediction of Alzheimer dis- ease (AD) is important and critical to effective interven- tion. Plasma levels of amyloid- (A) peptides have been a principal focus of the growing literature on blood- based biomarkers, but studies to date have varied in de- sign, assay methods, and sample size, making it difficult to readily interpret the overall data. Objective: To conduct a systematic review and meta- analysis of relevant prospective studies to determine whether plasma amyloid- levels may predict develop- ment of dementia, AD, and cognitive decline. Design: We searched prospective studies published be- tween 1995 and 2011 indexed in the MEDLINE, EMBASE, and PsycINFO databases. Selected studies included those measuring at least 1 relevant plasma amyloid- species (A 40 ,A 42 , or A 42 :A 40 ratio) and reporting an effect estimate for dementia, AD, or cognitive change. Main Outcome Measures: Using a standardized ex- traction form, appropriate study parameters on subject information, exposure, and outcome were extracted. Ran- dom effects models were used to generate summary risk ratios and 95% confidence intervals comparing the bot- tom vs top quantiles for each plasma measure. Results: Thirteen studies with a total of 10 303 sub- jects met inclusion criteria for meta-analysis. Lower A 42 : A 40 ratios were significantly associated with develop- ment of AD (summary risk ratio, 1.60; 95% CI, 1.04- 2.46; P = .03) and dementia (risk ratio, 1.67; 95% CI, 1.02- 2.75; P = .04). Significant heterogeneity was found for both summary estimates, which could not be explained by par- ticipants’ age, sex distribution, the study’s follow-up time, or year of publication. Plasma levels of A 40 and A 42 alone were not significantly associated with either outcome. Conclusions: Overall, the literature indicates that plasma A 42 :A 40 ratios predict development of AD and demen- tia. However, significant heterogeneity in the meta- analysis underlines the need for substantial further in- vestigation of plasma amyloid- levels as a preclinical biomarker. Arch Neurol. 2012;69(7):824-831. Published online March 26, 2012. doi:10.1001/archneurol.2011.1841 A N ENORMOUS PUBLIC health burden is caused by senile dementia, with Alz- heimer disease (AD) alone being the seventh-leading cause of death in the United States and costing an estimated $172 billion annu- ally. 1 Current therapies to treat AD are minimally effective and do not alter the dis- ease process. It is widely believed that novel therapeutic agents expected to be de- veloped in the coming years will be opti- mally administered preclinically before pa- tients develop full dementia. Thus, preclinical prediction of dementia through biomarkers is an important field, critical to effective intervention and disease modi- fication. 2 Although the Alzheimer Asso- ciation and the National Institute on Ag- ing recently established research guidelines for identifying preclinical dementia using neuroimaging and cerebrospinal fluid pro- teins, 3 a blood-based biomarker would be less invasive and more cost-effective than cerebrospinal fluid or imaging-based meth- ods. Moreover, a blood-based biomarker Author Affil Department University o Francisco (M Department Harvard Sch (Drs Okerek Grodstein), C Laboratory, D Medicine (D Grodstein) a Neurologic D Department Yang and Sel Women’s Ho Medical Scho Department Massachuset (Dr Blacker) Massachuset Author Affiliations are listed at the end of this article. ARCH NEUROL / VOL 69 (NO. 7), JULY 2012 WWW.ARCHNEUROL.COM 824 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 05/23/2020