Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

Abstract

Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late‐life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344‐AD rats that overexpress mutant human amyloid precursor protein and presenilin‐1 and wild‐type (WT) controls to determine whether inducing obesity with a high‐fat/high‐sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up‐regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC‐dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long‐term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD‐induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD‐induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.image

Obesity Facilitates Sex-Specific Improvement In Cognition And Neuronal Function In A Rat Model Of Alzheimer’s Disease

“…Here we report acceleration of Aβ plaque deposition and neuronal loss by obesity which agrees with previous studies using non-varied diets of high-fat or HCHF in rodent models of AD (Knight et al, 2014; Lin et al, 2016; Nam et al, 2017, 2018a; Sah et al, 2017; Walker et al, 2017; Medrano-Jiménez et al, 2019; Rollins et al, 2019; Bracko et al, 2020; Robison et al, 2020; Mazzei et al, 2021; Anderson et al, 2023). Importantly, we made novel observations of obesity concurrently driving neuroprotective processes in presence of accelerated AD pathology, including increased myelin and reduced activation of non-plaque-associated microglia.…”

Obesity Improves Neuronal Metabolism and Functional Hyperemia in a Rat Model of Early Ad Pathology

“…Despite the lack of genotype effect, obese TgAD rats had a trend of lower hippocampal glucose uptake compared to obese nTg rats. The larger attenuation of glucose uptake in TgAD rats parallels the observed compromise in spatial working memory in obese TgAD rats but not in nTg rats by Anderson (Anderson et al 2023). It is also worth noting that the body mass of male TgF344-AD rats at 6.5 months of age positively correlates with soluble Aβ 42 concentration (Anderson et al 2023), suggesting an increased risk of AD.…”

“…The attenuated glucose uptake was likely detrimental for maintaining brain function in both nTg and TgAD rats. The attenuation in glucose uptake might be due to ine cient uptake and utilization of glucose caused by dysregulation of mitochondrial and neurotransmission pathways, downregulation in ETC complexes I, III, IV, and V and attenuated expression of Slc16a3/MCT4 (monocarboxylate transporter 4) leading to compromised ATP synthesis, accelerated ROS generation, and altered glycolytic ux as observed by Anderson in 6.5-month-old TgF344-AD rats fed with Western diet (Anderson et al 2023). The lack of genotype effect is expected in light of minimal amyloid at 6 months of age in this model.…”

“…Western diet or high caloric/fat diet that induces obesity also leads to increased risk of AD as shown in middle-aged adults (Hoscheidt et al 2022) and in several animal models of AD presymptomatically (e.g. 6.5-month-old TgF344-AD rats (Anderson et al 2023) and 4-month-old APP/PS1 mice (Bracko et al 2020)). Obesity, which is also associated with cerebrovascular dysfunction and disease (Brzecka and Ejma 2015; Letra and Sena 2017), is a modi able risk factor that may exacerbate cognitive decline associated with Aβ deposition (Clark et al 2019; Balasubramanian et al 2021).…”

Sex-Specific Association of Body Mass Index with Hippocampal Subfield Volume and Cognitive Function in Non-Demented Chinese Older Adults

“…In recent years, an increasing number of studies have linked obesity to cognitive decline, particularly in relation to Alzheimer's disease (AD) [2][3][4][5][6][7]. Notably, a recent study identified midlife obesity as one of the primary modifiable factors strongly correlated with Brain Sci.…”