Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer's disease

Abstract

Although neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect, as some people exhibit normal cognition despite high levels of Alzheimer's disease (AD) pathology. We compared the cellular, synaptic, and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: (1) pathological AD with normal cognition ("AD-Resilient"), (2) pathological AD with AD-typical dementia ("AD-Dementia"), and (3) pathologically normal with normal cognition ("Normal Comparison"). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared with the AD-Dementia group, and increased densities of glial fibrillary acidic protein astrocytes compared with both the AD-Dementia and Normal Comparison groups. Further, in a discovery-type antibody microarray protein analysis, we identified a number of candidate protein abnormalities that were associated with a particular diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.

Figure 1

Comparison of densities of (A) amyloid-β plaques, (B) PHFTau neurofibrillary tangles, (C) NeuN neurons, (D) GFAP astrocytes, (E) synaptopodin spines and (F) synaptophsin expression among AD-Resilient (AD-R), AD-Demenita (AD-D) and Normal Comparison (NC) groups. Graphs portray means with standard error bars. Statistical probability of individual between group differences are indicatd with p-values from posthoc comparsions. Photomicrographs depict immunostained appearances of representative cases from each group. Photomicrographs A–E were from layer III while the lower magnification photomicrograph F encompasses layers I – IV.

Figure 2

Antibody Microarray Analyses. A) Plot of principal components analysis applied to the antibody microarray full data set generated using the first (PC1) and second (PC2) components. Normal Comparison (N) cases clustered distinctly from AD-Dementia (A) and AD-Resilient (R) groups. Both AD-Resilient and AD-Dementia groups were more mixed and showed a more dispersed pattern on the plot. B) Heat map generated using 57 proteins differentially expressed in any of the three groups compared to the others (selected by one-way ANOVA, p-value ≤ 0.01). Hierarchical clustering was applied to the proteins to help visualize the differences. Euclidean distance and complete linkage were used when computing hierarchical clustering of proteins. Five missing values on the heat map are colored in dark gray. Color scale indicates ordinally induced log2 expression levels of proteins.