Brain <scp>DNA</scp> Methylation Atlas of <i> App ^NL‐G‐F </i> Alzheimer's Disease Model Mice Across Age and Region Reveals Choline‐Induced Resilience

Alzheimer's disease (AD) is the most common type of dementia. Current treatments for AD are inadequate, and there is a need to design preventive strategies that would improve the resistance or resilience to AD pathology. Because aberrant brain DNA methylation (DNAm) is associated with hallmarks of AD, we tested the hypothesis that a nutritional approach using choline, an essential nutrient and methyl donor, would modulate DNAm to ameliorate AD pathologies. Previous studies showed that perinatal choline supplementation (PCS) reduced AD-like neuropathology and inflammation while improving cognitive performance in AD mouse models. Here we investigated hippocampal and cerebral cortical DNAm patterns by reduced representation bisulfite sequencing from 3 to 12 months in wild-type (WT) and App^NL-G-F AD model mice fed a 1.1 g/kg control or 5.5 g/kg PCS diet from conception to weaning. App^NL-G-F mice showed extensive CpG DNAm changes, which were associated with the age-dependent progression of amyloidosis. PCS induced genotype-specific DNAm patterns and reversed DNAm changes in multiple genes in App^NL-G-F mice. By associating DNAm with matched transcriptomics, we found that DNAm in App^NL-G-F mice correlated with the expression of microglial genes, while DNAm-associated genes modulated by PCS were related to synaptic function. Moreover, we found that methylation levels of several CpGs were associated with levels of beta amyloidosis, relating epigenetic changes to neuropathology. Overall, our data suggest that DNAm in the brain serves as an epigenetic mechanism for abnormal gene expression in App^NL-G-F mice and indicate that PCS may promote resilience to synaptic dysfunction through modulating DNAm.