Inflammation and the pathological progression of Alzheimer’s disease are associated with low circulating choline levels

Abstract

Deficiency of dietary choline, an essential nutrient, is observed worldwide, with ~ 90% of Americans being deficient. Previous work highlights a relationship between decreased choline intake and an increased risk for cognitive decline and Alzheimer’s disease (AD). The associations between blood circulating choline and the pathological progression in both mild cognitive impairment (MCI) and AD remain unknown. Here, we examined these associations in a cohort of patients with MCI with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderate to frequent neuritic plaques, Braak stage = IV) or severe AD (frequent neuritic plaques, Braak stage = VI), compared to age-matched controls. Metabolomic analysis was performed on serum from the AD cohort. We then assessed the effects of dietary choline deficiency (Ch−) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice, two rodent models of AD. The levels of circulating choline were reduced while pro-inflammatory cytokine TNFα was elevated in serum of both MCI sparse and high pathology cases. Reduced choline and elevated TNFα correlated with higher neuritic plaque density and Braak stage. In AD patients, we found reductions in choline, its derivative acetylcholine (ACh), and elevated TNFα. Choline and ACh levels were negatively correlated with neuritic plaque load, Braak stage, and TNFα, but positively correlated with MMSE, and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were significantly associated with circuiting choline levels. In 3xTg-AD mice, the Ch− diet increased amyloid-β levels and tau phosphorylation in cortical tissue, and TNFα in both blood and cortical tissue, paralleling the severe human-AD profile. Conversely, the Ch+ diet increased choline and ACh while reducing amyloid-β and TNFα levels in brains of APP/PS1 mice. Collectively, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of adequate dietary choline intake to offset disease.

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

“…However, MCS has now demonstrated structural/functional benefits in several AD-relevant models, namely Tg2576 (this report), APP/PS1 (Alldred et al 2021; Dave et al 2023), Ts65Dn (Velazquez et al 2013; Powers et al 2016; Strupp et al 2016; Powers et al 2017; Alldred et al 2021; Alldred et al 2023) and 3xTg mice (Dave et al 2023). Moreover, increasing evidence suggests that humans with AD have low serum choline and are improved by dietary choline (Dave et al 2023; Judd et al 2023a; b).…”

“…In Alzheimer’s disease (AD), changes to the diet have been recommended (Bourre 2006; Power et al 2019; Mao et al 2021; Lobo et al 2022), including MCS (Strupp et al 2016; Velazquez et al 2020; Dave et al 2023; Judd et al 2023a; b). One reason for the recommendation is that serum levels of choline are low in individuals with AD (Dave et al 2023; Judd et al 2023b).…”

“…One reason for the recommendation is that serum levels of choline are low in individuals with AD (Dave et al 2023; Judd et al 2023b). In addition, using mouse models of AD, increased choline improved many characteristics of the disease, ranging from inflammation to glucose metabolism and the hallmark amyloid and tau pathology (Dave et al 2023; Judd et al 2023a; b). In the Ts65Dn mouse model of Down syndrome (DS) and AD, MCS led to improved memory and attention in Ts65Dn offspring (Strupp et al 2016; Powers et al 2017; Powers et al 2021).…”

Perinatal choline supplementation prevents learning and memory deficits and reduces brain amyloid Aβ42 deposition in AppNL-G-F Alzheimer’s disease model mice

“…Choline supplementation also reduces brain amyloid deposition in APP.PS1 AD model mice [ 10 , 16 , 17 ]. In contrast, maternal choline deficiency has negative effects on brain development, cognitive performance, and adult neurogenesis [ 18 , 19 ] and low levels of dietary choline intake are associated with AD-neuropathological progression and increased risk for dementia and AD [ 20 , 21 ]. Together, these data support the notion that adequate choline consumption may be a potential avenue for AD prevention or risk mitigation.…”

Association between choline supplementation and Alzheimer’s disease risk: a systematic review protocol

“…More compelling results linking Alzheimer’s disease and low choline intake, on the one hand, and the neuroprotective effect of supplementing choline in AD have been reported in animal models ( Velazquez et al, 2019 , 2020 ; Wang et al, 2019 ). Furthermore, recent studies reported an association between AD progression and low circulating choline levels in humans ( Judd et al, 2023 ). In mice, dietary choline deficiency affected the function of the hippocampal network related to microtubules, regulation of the postsynaptic membrane, and the networks of proteins associated with mitochondrial function and inflammation ( Dave et al, 2023 ).…”