Preface Free

Alzheimer's disease (AD) is a multifactorial neurological disorder and the most common form of dementia, severely affecting the well-being of millions of patients and caregivers worldwide. There are no reliable diagnosis or fully approved disease modifying therapies for AD. The palliative treatments targeting symptoms are temporary, and do not directly target the mechanisms underlying the disease pathophysiology. The exact mechanisms of pathogenesis are not fully understood owing to its multifactorial nature. The multifaceted toxicity comprised of complex multiple disease routes and targets has been a major hurdle in the development of viable diagnosis and treatment. The literature evidence reveals that the disease pathogenesis is mostly non-genetic, while clear genetic risk factors do exist and further insights will be forthcoming. The generation, misfolding, accumulation and aggregation of proteins, namely extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) of tau in the brain have been considered to be hallmarks of disease pathology, while others are being investigated. A number of drug candidates targeting protein aggregation pathways or other targets have distressingly failed at various stages of clinical trials. Notwithstanding the failures, decades of academic and clinical research efforts have provided a reasonable understanding of the disease pathology. By and large, recent findings have disclosed a great deal of information on the disease mechanisms of AD pathology with implications for the development of reliable diagnostics and therapeutics.

This book intends to cover recent findings in the field of AD to benefit non-specialist readers, newcomers, and advanced researchers from the viewpoint of multifactorial disease mechanisms, to help in identifying viable diagnostic biomarkers and drug targets. Aptly, the book is divided into three major sections, viz., pathophysiology, diagnostic and therapeutic modalities. The pathophysiology section comprising chapters 1–11 provides insights into various aspects of disease mechanisms underlying the cause of multifaceted toxicity in AD. The biochemical signaling between the gastrointestinal tract and the CNS, namely the gut–brain-axis, is revolutionizing the way we deliberate causes for diseases and newer treatment options. In this context, the gut microbiome link to AD and gut microbiome-targeted treatment options are discussed in Chapter 12. The diagnostic modalities with emphasis on multiplexed and multimodal analysis, and circulating biomarkers for the development of reliable and precision diagnosis are described in chapters 13–15. Under the therapeutic modalities section, chapters 16 and 17 present overviews of various design approaches to effectively modulate Aβ and tau toxicities with critical discussion on future directions. Advanced theoretical and computational tools and methods to aid the development of diagnostic and therapeutic modalities are described in Chapter 18. The targeted protein degradation as a new therapeutic avenue is described in Chapter 19. The status of cell-based therapies with future directions are discussed in Chapter 20. Model systems play a crucial role in the study of disease mechanisms, and for the development and evaluation of diagnostic and therapeutic modalities. Various animal, cellular and 3D culture model systems and their relevance in AD research are described in Chapter 21. The study of ethnic and racial differences is critical in understanding the disease pathology and management, and this important topic is discussed in Chapter 22.

In general, each chapter provides a tutorial description of an important and contemporary topic in the field of AD using striking figures, attractive illustrations, thought-provoking concepts and perspectives for future developments. The aim of such organization is to provide an effective overview of the topic for non-specialists including graduate and undergraduate students, and specialists to effectively navigate the literature. The contents of the book are expected to apprise readers and advanced researchers with multifactorial disease mechanisms based on the scientific and technological advancements accomplished over the years.

The recent findings on the disease mechanisms offer the necessary impetus to the development of early and effective diagnosis and therapy. It is evident from the innumerable failures at clinical stages that the traditional way of targeting individual biomarkers, targets or pathways has limitations in terms of viability and success. Innovative ideas must consider multiple biomarkers or targets in designing diagnostic and therapeutic tools to tackle AD (Chapter 1). The accurate detection and imaging of multiple core (Aβ and tau species, microRNA among others in the brain or in the body fluids such as CSF, blood and saliva) and indirect biomarkers require multimodal techniques (PET, MRI, MS, optical, etc.) to analyse their ratios and levels to develop reliable diagnostic platforms (Chapter 15). Similarly, novel multipronged strategies to target multiple disease pathways are necessary to develop effective therapeutic agents to modulate the multifaceted toxicity of AD. In addition, methods of overcoming the blood–brain barrier (BBB), and development of effective cellular, animal and 3D-cell culture models to study AD need special attention.

In a nutshell, various contemporary and advanced topics are presented in a lucid and interconnected manner to provide valuable information on the understanding of disease pathophysiology, current perspective and future directions on diagnostic and therapeutic modalities with potential implications to find realistic solutions for AD in the near future.

T. Govindaraju

Jawaharlal Nehru Centre for Advanced Scientific Research

India