F5–04–03: Molecular neuropathology in Alzheimer's disease without dementia: Focus on synapses

Neuritic plaques and neurofibrillary tangles pathologically define Alzheimer's disease and are roughly correlated with cognitive impairment and severity of dementia. However, it has long been recognized that some people maintain normal cognition despite high levels of AD pathology. Using a novel cognition x pathology stratification approach in the Rush Religious Orders Study cohort, we categorized participants into three groups for comparative investigation: 1) pathological AD who had normal cognition (“AD-Resilient”), 2) pathological AD with AD-typical dementia (“AD-Dementia)” and 3) pathologically normal with normal cognition (“Normal Comparison”). In initial studies of the mid-frontal cortex we compared synaptic, cellular and biochemical features between groups. Synaptic proteome patterns in 233 measured proteins and the candidate proteins that best distinguish groups and correlate with cognitive and AD pathological features will also be discussed. We found that the AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared to the AD-Dementia group. Comparing densities of neurons and glia, we found increased densities of GFAP astrocytes in the AD-Resilient group compared to both the AD-Dementia and Normal Comparison group. In a discovery antibody microarray analysis of >500 proteins we found that proteomic clustering was more coherent in the Normal Comparison group than either AD group, but several candidate proteins were identified that differentiated the two AD groups. This series of studies provides molecular insight into how synapses may remain resilient even in the face of considerable AD related histopathology.