Late-onset Alzheimer’s disease (LoAD) accounts for >90% of AD cases, and the preclinical phase of LoAD is crucial for diagnosis and intervention.
The pathological changes (like amyloid deposition and tau accumulation) that accompany LoAD show a characteristic pattern of emergence and spread across the brain. Some brain regions are affected to a much greater degree than are others.
The underlying neurochemistry of these spatial patterns, and their biological basis is not understood and may hold the keys to diagnosis, and in the case of brain areas that are relatively protected even at late stages of the disease, to protective intervention.
Current questions and approaches
In this work, we measure the levels of thousands of proteins (the proteome) and metabolites (the metabolome) at hundreds of sites across the cortex and cerebellum, sampling the whole surface at about 5mm resolution.
The resulting data live in a very high dimensional space (thousands of dimensions). To get traction on the underlying patterns, we collaborate with Duke Biostatistician Dr. Pixu Shi to develop sophisticated statistical tools based on spatial principal component analysis and partial least squares discriminant analysis.
We also use bioinformatics methods to integrate the metabolome and proteome for pathway and network analysis. Our collaborator Dr. Michael Lutz provides powerful tools adapted from gene set enrichment analysis to work with our data, and to compare our data with data from human patients with AD
Some of the specific questions we are interested in are:
- What are the biochemical differences between brain regions like the entorhinal cortex that are highly vulnerable to AD pathology and regions like the cerebellum that seem to be relatively protected?
- How do a high sugar diet and low levels of exercise impact this chemistry?
- Why do macaques develop biomarkers of AD and show mild cognitive impairment but then do not progress to the most devastating stages of AD pathology? Is there something different about their whole brain biochemistry, when compared with humans, that is protective?