Cell composition, transcriptomic, and functional pathway changes in the hippocampus in Alzheimer's disease and overlap with lead (Pb) exposure signatures.

Lead (Pb) is associated with Alzheimer's disease (AD); however, the relationships between Pb and AD hippocampal transcription remains unclear. We evaluated overlap between Pb-response signatures and cell-type-independent AD transcriptomic signatures. Three toxicology studies (two neuronal cell lines, one mouse hippocampus) provided Pb-response genes. Five human postmortem hippocampal AD case-control transcriptional datasets (n=90 AD, n=106 normal cognition) were cell type deconvoluted and tested with beta regression. Differential gene expression, adjusted for age, sex, and estimated cell-types, were meta-analyzed. Overlapping Pb and AD genes and biological pathways were identified (p adj <0.05). Consistent Pb response was observed at 25 genes ( INPP5F , KIF20B , KIFC1 ) and 47 pathways (ensheathment of neurons, glial cell differentiation, regulation of nervous system processes). Relative to controls, AD samples had fewer neurons (-2.46%), greater microglia (0.42%), astrocytes (0.31%), oligodendrocytes (0.46%), and endothelial cells (0.95%), and 1,455 differentially expressed genes, which were enriched for cellular energy production and metabolism pathways. Six genes ( EHD3 , LAP3 , NRXN3 , PPP1R16B , RPL29 , THRA) and four pathways (synaptic vesicle maturation, vesicle docking) overlapped between Pb and AD. We identified overlapping Pb and AD transcriptomic signatures and pathways, providing molecular context for epidemiologic associations.