Neuropathological correlates of vulnerability and resilience in the cerebellum in Alzheimer's disease

Novel evidence of cerebellar atrophy in the granule cell layer of the lateral cerebellar cortex (or 'cognitive cerebellum'), and loss of a specific cerebellar synapse type in this region, the cerebellar glomerulus. Both correlated with dementia status and Braak stages IV through VI, in a cohort with complete neuropathological characterization. Although there have been recent brain imaging studies suggesting a role for cerebellum in Alzheimer's disease, we believe our study constitutes some of the most concrete neuropathological evidence to date of anatomic and synaptic substrates that are disrupted in AD. These changes in this cerebellar region may even play a role in the etiology of cognitive symptoms. Novel evidence that individuals with lower postmortem cerebellar weights showed more cognitive decline, independent of classical neuropathology markers such as Braak stage, Thal phase, or Corsortium to Establish a Registry for Alzheimer's Disease (CERAD) score, suggesting a role for this brain region in dementia, using advanced statistical analysis of a large unbiased population cohort (n = 605), the Adult Changes in Thought (ACT) study. Conversely, a measure of how intact the cerebellum was correlated with less dementia, independent of classical neuropathology markers and cerebral cortical weight, again, in the ACT cohort of 605 brain donors. We believe that this novel finding has relevance and implications for the identification of resilience factors, which may protect against the development of dementia.