Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. AD is characterized clinically by cognitive, behavioral, and learning and memory impairments and neuropathologically by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), neuroinflammation, and synaptic and neuronal loss. Although AD was first described over a century ago, there is no cure and the limited treatment options do little to slow the progression of the devastating disease. Because of these reasons, there has been a significant interest in preventative strategies for AD. Previous studies have shown that perinatal choline supplementation can improve learning and memory, dampen neuroinflammation, diminish cholinergic deficits, reduce brain amyloidosis, and increase neurogenesis in AD model mice. In these studies, we investigated the roles of perinatal choline supplementation on anxiety and exploratory behavior, spatial and fearful learning and memory, brain Aβ42 deposition, and gene expression in the AppNL-G-F AD mouse model. We found that there were slight anxiety-related behavior changes in AppNL-G-F mice compared to wildtype mice. AppNL-G-F mice had impaired spatial learning that could be prevented by perinatal choline supplementation at early ages (3- and 6-months-old) but not a later age (12-months-old). Fearful learning and memory deficits were found in AppNL-G-F mice at 9- and 12-months of age and could be abolished by perinatal choline supplementation. Perinatal choline supplementation significantly reduced Aβ42 deposition across the brain in AppNL-G-F mice. The AppNL-G-F transcriptome was characterized by changes in genes related to inflammatory, neuronal and synaptic, energy, and metabolic pathways and led to a distinct transcriptional signature from wildtype mice. Perinatal choline supplementation was able to significantly reduce the transcriptional deficits found in AppNL-G-F mice and led to the identification of choline responsive AD-pathology-associated genes (CRADPAGs). Lastly, some of the CRADPAGs identified using AppNL-G-F AD model mice correlated significantly with AD diagnosis, clinical dementia rating, and AD pathologies in a human data set. Together, the results from these studies and the previously published data suggest that adequate choline intake during development may serve as a strategy to prevent or reduce AD dementia and pathologies. / 2025-01-24T00:00:00Z