Alzheimer’s Disease Biomarkers Have Distinct Associations with Specific Hippocampal Subfield Volumes

Article type: Research Article

Authors: Müller-Ehrenberg, Lisa^{a; *} | Riphagen, Joost M.^a | Verhey, Frans R.J.^a | Sack, Alexander T.^b | Jacobs, Heidi I.L.^{a; b; c; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands | [b] Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands | [c] Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

Correspondence: [] Correspondence to: Heidi Jacobs, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Uns40 Box 34, PO BOX 616, 6200 MD Maastricht, The Netherlands. E-mail: [email protected] and Lisa Müller-Ehrenberg, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Uns40 Box 34, PO BOX 616, 6200 MD Maastricht, The Netherlands. Tel.: +31 43 388 1025; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer ’s disease Neuroimaging Initiative (ADNI) database (http://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: Measures of amyloid-β (Aβ) and phosphorylated tau (p-tau) concentrations in cerebrospinal fluid are extensively used for diagnostic and research purposes in Alzheimer’s disease (AD) as correlates of cortical thinning and cognitive outcomes. The present study investigated the relationship of Aβ and p-tau with hippocampal subfield volumes Cornu Ammonis (CA) 1–4, dentate gyrus (DG), and subiculum. Subfields were segmented from T1-weighted images from the ADNI-population using FreeSurfer v6. Linear and polynomial regression models revealed distinct associations of Aβ and p-tau with subfield volumes. Aβ had a quadratic relationship with all hippocampal subfield volumes and the inflection point was higher than the validated cut-off for Aβ. For p-tau the relationships were linear, except for CA3, in which it was quadratic. For the CA1 and CA3, these quadratic relationships with Aβ were only observed when p-tau was low. Amyloid and p-tau contributed equally to the explained variance in CA4 and DG volume. Subicular volume was best explained by Aβ alone. These biomarker relationships with hippocampal subfield volumes seem to mirror the hippocampal-specific topography of Aβ and tau reported in neuropathological staging models. In addition, using continuous values of Aβ reveals positive patterns with imaging markers for individuals around the positivity threshold that would be masked when using dichotomized biomarker groups, which can be important for early detection and accurate inclusion of potential participants at risk for AD in clinical trials.

Keywords: Aging, Alzheimer’s disease, amyloid, hippocampus, polynomial, subfields, tau

DOI: 10.3233/JAD-180676

Journal: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 811-823, 2018