Affiliations: [a] The Litwin-Zucker Research Center, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA | [b] FIDMAG Hermanas Hospitalarias Research Foundation & CIBERSAM, Sant Boi de Llobregat, Spain | [c] Hofstra North Shore LIJ School of Medicine, Hempstead, NY, USA
Correspondence:
[*]
Correspondence to: Terry E. Goldberg, PhD, 350 Community Drive, Manhasset, NY 11030, USA. Tel.: +1 516 562 0410; Fax: +1 516 562 0401; E-mail: tgoldber@northwell.edu.
Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (htpp://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
Abstract: Background:The earliest stage of preclinical Alzheimer’s disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. Objective:To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. Methods:We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). Results:In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = –0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p < 0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau. Conclusions:The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.
Keywords: Aβ42, brain atrophy, cerebrospinal fluid, cognition, p-tau, preclinical AD
