Wörheide, Maria A.

AbstractBackgroundOur Alzheimer Disease Metabolomics Consortium (ADMC), part of the Accelerating Medicines Partnership for AD (AMP‐AD) and in partnership with AD Neuroimaging Initiative (ADNI), applied state‐of‐the‐art metabolomics and lipidomics technologies combined with genomic and imaging data to map metabolic failures across the trajectory of the disease. Our studies confirmed that peripheral metabolic changes influenced by the exposome inform about cognitive changes, brain imaging changes, and ATN markers for disease confirming that peripheral and central changes are connected, in part through the metabolome.MethodsTo map the biochemical changes in AD, we used various targeted and untargeted metabolic platforms to profile ∼800 postmortem brain tissue, and ∼ 5000 blood samples.ResultsRecently, we built a comprehensive reference map of extensive AD‐related metabolic changes in brain, spanning multiple AD‐related traits, including neuropathological b‐amyloid and tau tangle burden, as well as late‐life cognitive performance. Using this resource, we extracted novel metabolic including bioenergetic pathways, cholesterol metabolism, neuroinflammation, broad impairment of osmoregulation, an imbalance between excitatory/inhibitory neurotransmitter ratios and identification of tau load as a potential driver of metabolic dysfunction in the AD brain, with minimal contributions from b‐amyloid load. As AD and progressive supranuclear palsy (PSP) share the pathological feature of tauopathy and metabolic alterations, we compared their metabolomic profiles to identify shared biological pathways that could be targeted for therapeutic interventions. Our findings indicate that both diseases display oxidative stress, mitochondrial dysfunction, and tau‐induced polyamine stress response.ConclusionOverall, through our studies, (1) We identified biochemical processes altered in AD, with findings supported across both metabolomic and proteomic data, indicating multimodal deregulation. (2) Our research pinpointed widespread AD‐related biochemical changes across various brain regions with differing levels of neuropathology. While there are many overlapping changes across the brain regions, each region also has its distinct metabolic alterations. (3) We identified biochemical processes disrupted by AD, with parallel findings in other neurodegenerative diseases, hinting at broader implications in neurodegenerative research. Currently, we are working on mapping widespread connections of the brain metabolome with various determinants of AD namely genome, gut microbiome, exposome, and linking with peripheral metabolic alterations in AD.

AbstractBackgroundMetabolic dysregulation is one of the hallmarks of Alzheimer’s disease (AD). Alterations in metabolism have been associated with AD‐related comorbidities, cognitive decline, and AD brain pathology. Brain regions are differentially affected with AD neuropathology and exhibit metabolic heterogeneity. Therefore, to build a more comprehensive picture of metabolic impact of AD, region‐specific AD‐associated metabolic changes need to be determined.MethodWe profiled 344 brain samples from the Mayo Clinic brain bank using Metabolon’s untargeted metabolomics platform, covering 182 samples from the cerebellum (CER) and 162 samples from the temporal cortex (TCX). Generalized linear models were used to assess the association of metabolic profiles with AD. Models included confounder correction for age at death, sex, and number of APOE‐ε4 alleles. To extend this study to four more brain regions, we included results from previously published brain metabolomics studies based on samples from three independent cohorts, including dorsolateral prefrontal cortex (DLPFC) from ROS/MAP, parietal lobe (PTL) from Washington University School of Medicine (WUSM), inferior temporal gyrus (ITG) and middle frontal gyrus (MFG) from Baltimore Longitudinal Study of Aging (BLSA).ResultIn the Mayo cohort, a total of 190 out of the 658 metabolites were significantly associated with AD. Out of the 190, 127 metabolites associated only in the CER region, 37 metabolites associated only in the TCX region, and 26 metabolites were associated in both brain regions. There were no metabolites commonly regulated in all the 6 brain regions under investigation. DLPFC and CER had the highest overlap of 70 metabolites, followed by DLPFC and PTL with 64 metabolites, and CER and PTL with 47 metabolites. For functional interpretation of our findings, each metabolite was further categorized with a sub‐pathway annotation provided by Metabolon. 3 of the 88 pathways including methionine cycle, phospholipid metabolism, and glutathione metabolism, were commonly regulated in the six brain regions under investigation.ConclusionWe present a first global perspective on AD‐associated metabolic alterations across six brain regions. This study will pave the way to fill the gap in our understanding of region‐specific metabolic deregulations associated with AD pathophysiology.

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 the 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 amyloid beta pathology. Discussion This work provides a comprehensive reference map of metabolic brain changes in AD that lays the foundation for future mechanistic follow‐up studies.