Precision pharmacology for Alzheimer's disease
Massimo Fiandaca independent.academia.edu
The complex multifactorial nature of polygenic Alzheimer&#39;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
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.

Systems biology approaches may be useful for studying the mechanisms underlying alcohol&#39;s harmful effects on the brain. Such approaches already are used in the study of Alzheimer&#39;s disease (AD), a progressive neurodegenerative disorder that, with the overall increase in life expectancy, will affect an increasing proportion of the population and become an increasingly serious public health concern. Systems biology approaches such as complementary DNA (cDNA) microarray analyses have helped identify several genes whose expression is altered in patients exhibiting the earliest stages of AD. Several of these genes are involved in the release of messenger molecules from the ends of nerve cells (i.e., in synaptic vesicle functioning), and their particular role in AD must be investigated further using conventional molecular biological approaches. Similarly, protein array analyses have identified candidate proteins that may play a role in the development of AD. Finally, proteomic app...

Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer’s disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long ti...

Alzheimer&#39;s disease (AD) is a complex and multifactorial disease. In order to understand the genetic influence in the progression of AD, and to identify novel pharmaceutical agents and their associated targets, the present study discusses computational modeling and biomarker evaluation approaches. Based on mechanistic signaling pathway approaches, various computational models, including biochemical and morphological models, are discussed to explore the strategies that may be used to target AD treatment. Different biomarkers are interpreted on the basis of morphological and functional features of amyloid β plaques and unstable microtubule‑associated tau protein, which is involved in neurodegeneration. Furthermore, imaging and cerebrospinal fluids are also considered to be key methods in the identification of novel markers for AD. In conclusion, the present study reviews various biochemical and morphological computational models and biomarkers to interpret novel targets and agonis...