The landscape of metabolic brain alterations in Alzheimer's disease

Abstract

INTRODUCTION: Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in brain has been missing. METHODS: We metabolically profiled 500 samples from the dorsolateral prefrontal cortex.Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures. RESULTS: We observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than b-amyloid pathology.DISCUSSION: This work provides a comprehensive reference map of metabolic brain changes in AD which lays the foundation for future mechanistic follow-up studies..

AutoFocus: A hierarchical framework to explore multi-omic disease associations spanning multiple scales of biomolecular interaction

“…All statistical models were corrected for age at death, sex, BMI, post-mortem interval, years of education, and APOE genotype. To maintain consistency with previous studies published on the ROS/MAP dataset 41 , the FDR p-value correction method was used instead of Bonferroni, leading to a dense distribution of significant hits across the tree ( Figure 4a ). Both phenotypes had robust metabolic associations, as metabolites made up 20% and 26% of significant hits in NFT and CD, respectively, even though metabolites only made up 8.14% of the underlying dataset.…”

“…For 500 of the brain tissue samples of the ROS/MAP cohort, brain metabolomic profiling was performed through non-targeted ultrahigh-performance liquid chromatography and gas chromatography separation, coupled with mass spectrometry on the Metabolon Inc. platform (667 metabolites) 41 . Brain proteomic profiles were collected on 265 ROS/MAP samples using tandem mass tag (TMT)-MS and downloaded from the AMP-AD Knowledge Portal (https://adknowledgeportal.synapse.org, 7,526 proteins), details of data collection and processing have been previously described 68 .…”

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

“…The ROSMAP cohort used in this study included 469 human subjects with matched clinical, brain metabolomics, and brain bulk transcriptome data (Table S1): 324 females aged 88 ± 4 and 145 males aged 87 ± 4, respectively. AD phenotypes were defined by cogdx based on original study 33 . The Braak staging and CERAD score were also used to define AD progression.…”

“…The Religious Order Study and Rush Memory and Aging Project (ROSMAP) cohort were utilized for both metabolomics 33 (Synapse ID: syn26401311) and transcriptomics (Synapse ID: syn21241740). Samples were isolated from the dorsolateral prefrontal cortex (DLPFC) of 473 human subjects, along with clinical metadata ( (cogdx), which defined control (cogdx = 1), MCI (cogdx = 2 and 3), AD (cogdx = 4 and 5), and other dementia (cogdx = 6); 33 (2) Braak staging, which is a semiquantitative measure of neurofibrillary tangles, with individuals assigned to one of three Braak subgroups from light to severe, I-II, III-IV, and V-VI; and (3) Consortium to Establish a Registry for AD (CERAD) score, 35 which is a semiquantitative measure of neuritic plaques, with all individuals assigned to two subgroups:…”

Brain cross-omics integration in Alzheimer’s disease

“…A custom protocol developed for the brain samples can be found on Synapse at syn10235609. The dorsolateral prefrontal cortex (DLPFC) metabolomic data from the ROSMAP studies quantified on the Metabolon Precision Metabolomics platform and preprocessed by the ADMC as described in [153] were downloaded from Synapse in July 2021 (syn25878459). The platform measured a total of 1,055 metabolites in the ROSMAP dataset.…”