The new neurobiology of dementia

Abstract

The repeated failures of clinical trials of disease-modifying treatments for Alzheimer's disease (AD) have highlighted the urgent need to better understand molecular mechanisms underlying AD pathogenesis in order to identify targets for effective treatments. Accumulating evidence suggests that metabolic abnormalities are important risk factors for AD and may play a key role in disease progression. We have combined deep molecular phenotyping of brain and blood tissue samples with analyses of longitudinal epidemiological data from well characterized cohorts of older individuals to identify distinct metabolic abnormalities associated with severity of AD pathology and the eventual expression of clinical symptoms. Using targeted and quantitative metabolomics analyses, we have identified perturbations in several metabolic pathways that underlie AD pathogenesis. These pathways include abnormalities in brain glucose utilization, phospholipid and fatty acid metabolism, cholesterol/oxysterol biosynthesis as well as polyamine metabolism and transmethylation reactions. Together, our studies suggest that AD is a pervasive metabolic disorder with dysregulation in multiple interacting biochemical pathways that may trigger accumulation of pathology in vulnerable brain regions leading to neurodegeneration and cognitive impairment. Strikingly, many of these biochemical reactions are targeted by commonly used medications for non-AD indications, raising the possibility that some of these drugs may protect against development of AD. We have combined insights from deep molecular phenotyping of brain and blood tissue samples with analyses of real-world prescription datasets to test the hypothesis that drugs targeting abnormal metabolism may alter the risk of incident AD. These studies suggest that metabolic perturbations are key players underlying the neurobiology of dementia and may offer novel targets for effective treatments