Brain reserve contributes to distinguishing preclinical Alzheimer's stages 1 and 2

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.

Keywords: Alzheimer’s disease (AD); Amyloid pathologic change; Aß42/40; Brain reserve; Cerebrospinal fluid (CSF); Hippocampus; Magnetic resonance imaging (MRI); Medial temporal lobe; Memory; Subjective cognitive decline (SCD).

Fig. 1

Hypothetical volumes of memory regions in amyloid-negative (A−) asymptomatic healthy controls, A− subjective cognitive decline (SCDs), stages 1 and 2. According to a continuum model, volumes should be gradually smaller from A− asymptomatic to 2. According to a brain reserve model, stage 1 should have higher volumes than A− asymptomatic (“higher than expected”), while stage 2 should show the expected decrease. The A− SCD group serves as a control that any volume differences between stages 1 and 2 are not solely attributable to the presence of memory complaints

Fig. 2

Bilateral volumes of the CA1 subfield (in mm³) in asymptomatic individuals and those with SCD. Aß42/40 positive asymptomatic individuals (stage 1) have larger CA1 subfields (p = 0.014) than asymptomatic and Aß42/40 neg. For SCDs, those that are amyloid-positive (stage 2) have smaller CA1 volumes than those that are amyloid-negative. Stage 1 individuals have larger CA1 volumes than stage 2 individuals (p < 0.001). Box and whisker plots show median (thick horizontal lines), minimum and maximum values (lower and upper end of whiskers), and outliers (circle, star). Whiskers below each box show the first quartile range and those above the fourth quartile range of data