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Protective genes and pathways in Alzheimer's disease: moving towards precision interventions.

ABSTRACT: Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that is characterized by neurodegeneration, cognitive impairment, and an eventual inability to perform daily tasks. The etiology of Alzheimer's is complex, with numerous environmental and genetic factors contributing to the disease. Late-onset AD is highly heritable (60 to 80%), and over 40 risk loci for AD have been identified via large genome-wide association studies, most of which are common variants with small effect sizes. Although these discoveries have provided novel insight on biological contributors to AD, disease-modifying treatments remain elusive. Recently, the concepts of resistance to pathology and resilience against the downstream consequences of pathology have been of particular interest in the Alzheimer's field as studies continue to identify individuals who evade the pathology of the disease even into late life and individuals who have all of the neuropathological features of AD but evade downstream neurodegeneration and cognitive impairment. It has been hypothesized that a shift in focus from Alzheimer's risk to resilience presents an opportunity to uncover novel biological mechanisms of AD and to identify promising therapeutic targets for the disease. This review will highlight a selection of genes and variants that have been reported to confer protection from AD within the literature and will also discuss evidence for the biological underpinnings behind their protective effect with a focus on genes involved in lipid metabolism, cellular trafficking, endosomal and lysosomal function, synaptic function, and inflammation. Finally, we offer some recommendations in areas where the field can rapidly advance towards precision interventions that leverage the ideas of protection and resilience for the development of novel therapeutic strategies.

SUBMITTER: Seto M

PROVIDER: S-EPMC8086309 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective disease-modifying pathway-based targeted therapies. PP is based on an exploratory and integrative strategy to complex diseases such as brain proteinopathies including AD, aimed at identifying simultaneous aberrant molecular pathways and predicting their temporal impact on the systems levels. The depiction of pathway-based molecular signatures of complex diseases contributes to the accurate and mechanistic stratification of distinct subcohorts of individuals at the earliest compensatory stage when treatment intervention may reverse, stop, or delay the disease. In addition, individualized drug selection may optimize treatment safety by decreasing risk and amplitude of side effects and adverse reactions. From a methodological point of view, comprehensive "omics"-based biomarkers will guide the exploration of spatio-temporal systems-wide morpho-functional shifts along the continuum of AD pathophysiology, from adaptation to irreversible failure. The Alzheimer Precision Medicine Initiative (APMI) and the APMI cohort program (APMI-CP) have commenced to facilitate a paradigm shift towards effective drug discovery and development in AD.

Project description:Along with the two hallmark pathologies—intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques—transcriptional studies suggest that Alzheimer's disease (AD) results from dysfunction of many cellular pathways including synaptic transmission, cytoskeletal dynamics, and apoptosis. While these studies consistently point to the same pathways involved in AD, there is no consensus on which genes in each pathway are disease-relevant, much less on whether these genes play causative roles or are downstream effects of disease progression. To address these issues, we have performed a large-scale transcriptional analysis in brain of individuals with advanced AD and non-demented controls, focusing specifically on CA1 and the relatively less affected CA3. For comparisons between regions and across disease status, we find consistency in both pathway enrichment as well as specific differentially expressed genes across several studies. Furthermore, genes that show decreased expression with AD progression also tend to show enrichment in CA3 (and vice versa), suggesting that transcription levels in a region may reflect that region's vulnerability to disease. In particular, we find several strong candidate vulnerability (ABCA1, MT1H, PDK4, RHOBTB3) and protection (FAM13A1, LINGO2, UNC13C) genes based on expression patterns. We have also applied weighted gene coexpression network analysis (WGCNA) to explore the pathophysiology of AD from a systems perspective, finding modules for major cell types, which each show distinct disease-relevant expression patterns. In particular, a microglial module shows increased expression in the brain of non-demented controls harboring early NFT pathology, suggesting that microglial activation is an early event in AD progression. Total RNA obtained from 60um sections of frozen human hippocampus was collected using scalpel dissection. Control and AD brains were matched for all non-disease characteristics as closely as possible. CA1 and CA3 dissections for a given individual were taken from the same section. Several region- and disease-related comparisons were performed.

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Protective genes and pathways in Alzheimer's disease: moving towards precision interventions.

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