Synaptic pruning genes networks in Alzheimer's disease: correlations with neuropathology and cognitive decline

Synaptic pruning (SP) is a critical process in brain development and maintenance, essential for refining neural circuits by eliminating weak or redundant synapses. Dysregulation of SP has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Studying the regulation of SP genes across the lifespan and their variation by sex and age is crucial to understanding the interplay between aging, sex, and AD pathogenesis. This study comprehensively analyzes the expression of SP-related genes, including complement system components (C1QA, C1QB, C1QC, C1S, C1R, C3), microglial regulators (ITGB2, ITGAM), and astrocytic factors (MERTK, MEGF10), as well as synaptic protective signals (CD47, SIRPA) in 2294 non-demented healthy controls (NDHC) and 1555 AD patients, stratified by sex, age, and brain area. Our findings reveal significant upregulation of most SP-related genes in AD brains, except for CD47 and SIRPA. Sex-specific patterns emerged, with males exhibiting stronger associations between complement genes and AD pathology, compared to females. Notably, in NDHC, females displayed higher baseline expression of SP-related genes (except CD47), but these sex differences diminished in AD, indicating disease-driven convergence. Age-related dynamics further highlighted distinct profiles, with males showing progressive upregulation of SP genes in NDHC, whereas females exhibited early senescence-like suppression followed by late-life compensatory changes. In AD, males demonstrated early complement dysregulation, while females displayed a pronounced inflammatory shift in advanced age. Region-specific analyses revealed heterogeneity, with the diencephalon showing the highest gene expression in NDHC males, while AD flattened regional differences in males but amplified variability in females. Correlation analyses linked complement and microglial genes to amyloid and tau pathology, with sex-specific associations. Principal component analysis (PCA) and Gene Ontology (GO) highlighted disrupted coordination between microglia, astrocytes, and neurons in AD. Protein expression analysis using the Human Protein Atlas revealed sex-specific differences in the localization of complement and microglial proteins in the prefrontal cortex. These findings underscore the complex interplay of sex, age, and regional factors in SP regulation, implicating complement overactivation, microglial dysfunction, and astrocytic phagocytosis in AD pathogenesis.