PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease

Abstract

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical "one-size-fits-all" approach in drug discovery towards biomarker guided "molecularly" tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

Keywords: Alzheimer’s disease; biomarkers; precision medicine; precision medicine initiative; systems biology.

Figure 1

The systems biology (SB) paradigm for complex multifactorial diseases: from SB-based approaches to precision medicine. Pipeline. Multifactorial diseases involve genomics, interactomes, and environmental contributions for which SB-based approaches are needed. Comprehensive screenings of individuals, groups, and subgroups need to start with advanced genome sequencing methods in order to unveil specific variants and genomic signatures for basic risk assessment at genomic level (i.e. intrinsic susceptibility to disease) (point 1). From here, further comprehensive systems-level analyses, with SB multi-omics networks methods, both experimental and computational, are needed (point 2) (–16). These advanced methods, with incorporation of new standardized techniques and guidelines, are expected to reveal specific molecular signatures and biomarker patterns in time and space, underlying mechanisms and actual disease risk and disease stage, towards mechanistically-based, rational-tailored interventions, preventive and/or therapeutic (i.e. “true precision medicine” paradigm) (–15)

Figure 2

Intervention paradigm for future secondary prevention of neurodegenerative diseases and dementia disorders at the preclinical level according to specific biomarker abnormalities, with the goal of allowing treatment decisions on the use of specific disease-modifying drugs. Concurrent tailored risk factor modification can optimize outcomes (as measured by cognitive and functional preclinical measures). Such approach can lead to a reduced incidence of neurodegenerative diseases and dementia disorders or a delayed progression from the preclinical stage to the full-blown clinical syndrome