Imaging and cerebrospinal fluid biomarkers in early preclinical alzheimer disease

Andrei G. Vlassenko, Lena McCue, Mateusz S. Jasielec, Yi Su, Brian A. Gordon, Chengjie Xiong, David M. Holtzman, Tammie L. S. Benzinger, John C. Morris, Anne M. Fagan

Deposition of Aβ-containing plaques as evidenced by amyloid imaging and CSF Aβ42 is an early indicator of preclinical Alzheimer disease (AD). To better understand their relationship during the earliest preclinical stages, we investigated baseline CSF markers in cognitively normal individuals at different stages of amyloid deposition defined by longitudinal amyloid imaging with Pittsburgh Compound B (PIB): 1) PIB-negative at baseline and follow-up (PIB-, normal); 2) PIB- at baseline but PIB-positive at follow-up (PIB converters, early preclinical AD); and 3) PIB-positive at baseline and follow-up (PIB+, preclinical AD). Cognitively normal individuals (n=164) who had undergone baseline PIB scan and CSF collection within one year of each other and at least one additional PIB follow-up were included. Amyloid status was defined dichotomously using an a priori mean cortical cut-off. PIB converters (n=20) at baseline exhibited significantly lower CSF Aβ42 compared to those who remained PIB- (n=123), but higher compared to PIB+ group (n=21). A robust negative correlation (r=-0.879, p=0.0001) between CSF Aβ42 and absolute (but sub-threshold) PIB binding was observed during this early preclinical stage. The negative correlation was not as strong once individuals were PIB+ (r=-0.456, p=0.038), and there was no correlation in the stable PIB- group (p=0.905) or in the group (n=10) with early symptomatic AD (p=0.537). CSF Ab42 levels are tightly coupled with cortical amyloid load in the earliest stages of preclinical AD, and began to decrease dramatically prior to the point when an abnormal threshold of cortical accumulation is detected with amyloid imaging. This article is protected by copyright. All rights reserved.