Brain reserve contributes to distinguishing preclinical Alzheimer’s stages 1 and 2
Authors: Yildirim Zerrin , Delen Firuze , Berron David , Baumeister Hannah , Ziegler Gabriel , Schütze Hartmut , Glanz Wenzel , Dobisch Laura , Peters Oliver , Freiesleben Silka Dawn , Schneider Luisa-Sophie , Priller Josef , Spruth Eike Jakob , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Schott Björn-Hendrik , Meiberth Dix , Buerger Katharina , Janowitz Daniel , Perneczky Robert , Rauchmann Boris-Stephan , Teipel Stefan , Kilimann Ingo , Laske Christoph , Munk Matthias H. , Spottke Annika , Roy Nina , Heneka Michael , Brosseron Frederic , Wagner Michael , Roeske Sandra , Ramirez Alfredo , Ewers Michael , Dechent Peter , Hetzer Stefan , Scheffler Klaus , Kleineidam Luca , Wolfsgruber Steffen , Yakupov Renat , Schmid Matthias , Berger Moritz , Gurvit Hakan , Jessen Frank , Duzel Emrah 
Published: March 2023

Abstract
Background
In preclinical Alzheimer’s disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions.

Methods
We tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol.

Results
In asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs.

Conclusions
These data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline.