The landscape of metabolic brain alterations in Alzheimer’s disease

Abstract

We present a comprehensive reference map of metabolic brain changes in Alzheimer’s disease (AD). In a multi-center study within the Accelerating Medicines Partnership in AD, we metabolically profiled 500 samples from the dorsolateral prefrontal cortex (DLPFC) and 83 samples from the temporal cortex (TCX). In the DLPFC, 298 metabolites were correlated with AD-related traits, including late-life cognitive performance and neuropathological β-amyloid and tau tangle burden. Out of these 298 metabolites, 35 replicated in TCX and a previous study. A conditional analysis suggests that metabolic associations with tangle burden were largely independent of β-amyloid load in the brain. Our results provide evidence of brain alterations in bioenergetic pathways, cholesterol metabolism, neuroinflammation, osmoregulation, and other pathways. In a detailed investigation of the glutamate/GABA neurotransmitter pathway, we demonstrate how integration of complementary omics data can provide a comprehensive view of dysregulated biochemical processes. All associations are available as an interactive network at https://omicscience.org/apps/brainmwas/.

Predictive metabolic networks reveal sex‐ and APOE genotype‐specific metabolic signatures and drivers for precision medicine in Alzheimer's disease

“…Higher levels of serum alpha‐AAA are associated with decreased cognitive function 5 . Consistent with previous observations, we detected positive associations of AD cognitive function with multiple amino acids, including tryptophan, citrulline, sarcosine, aspartic acid, and taurine 5,11,14,18–20 …”

“…5 Consistent with previous observations, we detected positive associations of AD cognitive function with multiple amino acids, including tryptophan, citrulline, sarcosine, aspartic acid, and taurine. 5,11,14,[18][19][20] Our study has several limitations. First, the AbsoluteIDQ-p180 system is a targeted metabolomic platform with limited set of metabolites, including amino acids (21), biogenic amines (21), hexose (1), acylcarnitines (40), lysophosphatidylcholines (14), phosphatidylcholines (76), and sphingolipids (15).…”

“…Metabolomics is the newest omics that measures thousands of metabolites reflecting alterations in genetic, transcriptomic, proteomic profiles, and influences from the environment 5,6 . A large number of studies using metabolomics and lipidomics platforms has provided new biochemical insights about disease mechanisms and early changes in disease, and provided support that peripheral metabolic changes inform about central changes and ATN (cerebrospinal fluid [CSF] Aβ 1‐42 [A]; CSF p‐tau [T]; fluorodeoxyglucose positron emission tomography [FDG‐PET; N]) markers of disease 7–20 …”

Brain and serum lipidomic profiles implicate Lands cycle acyl chain remodeling association with APOEε4 and mild cognitive impairment

“…Additionally, lipidomic data confirm lipid dyshomeostasis associated with AD in autopsy brain (Batra et al, 2022), cerebrospinal fluid (CSF) (Dakterzada et al, 2023;Do et al, 2023), human plasma (Li et al, 2023), and animal models (Chan et al, 2012;Mcintire et al, 2012) pointing to the potential for specific pathway(s) in lipid metabolism to underlie multiple AD disease mechanisms. Specifically, the loss of polyunsaturated fatty acid (PUFA) includingdocosahexaenoic acid (DHA), across multiple lipid classes is regularly observed in these studies.…”

Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease

“…A custom protocol developed for the brain samples can be found on Synapse at syn10235609. The DLPFC metabolomic data from the ROS-MAP studies quantified on the Metabolon Precision Metabolomics platform and preprocessed by the ADMC as described in [164] were downloaded from Synapse in July 2021 (syn25878459). The platform measured a total of 1,055 metabolites in the ROSMAP dataset.…”