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There is an urgent need to identify modifiable environmental risk factors that reduce the incidence of Alzheimer's disease (AD). The B‐like vitamin choline plays key roles in body‐ and brain‐related functions. Choline produced endogenously by the phosphatidylethanolamine N‐methyltransferase protein in the liver is not sufficient for adequate physiological functions, necessitating daily dietary intake. ~90% of Americans do not reach the recommended daily intake of dietary choline. Thus, it's imperative to determine whether dietary choline deficiency increases disease outcomes. Here, we placed 3xTg‐AD, a model of AD, and non‐transgenic (NonTg) control mice on either a standard laboratory diet with sufficient choline (ChN; 2.0 g/kg choline bitartrate) or a choline‐deficient diet (Ch‐; 0.0 g/kg choline bitartrate) from 3 to 12 (early to late adulthood) months of age. A Ch‐ diet reduced blood plasma choline levels, increased weight, and impaired both motor function and glucose metabolism in NonTg mice, with 3xTg‐AD mice showing greater deficits. Tissue analyses showed cardiac and liver pathology, elevated soluble and insoluble Amyloid‐β and Thioflavin S structures, and tau hyperphosphorylation at various pathological epitopes in the hippocampus and cortex of 3xTg‐AD Ch‐ mice. To gain mechanistic insight, we performed unbiased proteomics of hippocampal and blood plasma samples. Dietary choline deficiency altered hippocampal networks associated with microtubule function and postsynaptic membrane regulation. In plasma, dietary choline deficiency altered protein networks associated with insulin metabolism, mitochondrial function, inflammation, and fructose metabolic processing. Our data highlight that dietary choline intake is necessary to prevent systems‐wide organ pathology and reduce hallmark AD pathologies.

RASopathies are a family of related syndromes caused by mutations in regulators of the RAS/Extracellular Regulated Kinase 1/2 (ERK1/2) signaling cascade that often result in neurological deficits. RASopathy mutations in upstream regulatory components, such as NF1 , PTPN11/SHP2 , and RAS have been well-characterized, but mutation-specific differences in the pathogenesis of nervous system abnormalities remain poorly understood, especially those involving mutations downstream of RAS . Here, we assessed cellular and behavioral phenotypes in mice expressing a Raf1 L613V gain-of-function mutation associated with the RASopathy, Noonan Syndrome. We report that Raf1 L613V/wt mutants do not exhibit a significantly altered number of excitatory or inhibitory neurons in the cortex. However, we observed a significant increase in the number of specific glial subtypes in the forebrain. The density of GFAP + astrocytes was significantly increased in the adult Raf1 L613V/wt cortex and hippocampus relative to controls. OLIG2 + oligodendrocyte progenitor cells were also increased in number in mutant cortices, but we detected no significant change in myelination. Behavioral analyses revealed no significant changes in voluntary locomotor activity, anxiety-like behavior, or sociability. Surprisingly, Raf1 L613V/wt mice performed better than controls in select aspects of the water radial-arm maze, Morris water maze, and cued fear conditioning tasks. Overall, these data show that increased astrocyte and oligodendrocyte progenitor cell (OPC) density in the cortex coincides with enhanced cognition in Raf1 L613V/wt mutants and further highlight the distinct effects of RASopathy mutations on nervous system development and function.