More than a century has flown by since Alois Alzheimer first described the deadly disease that would come to bear his name, but the last drug was approved 14 years ago. Given this sorry state of affairs, one might consider AD research a wasteland, yet nothing could be further from the truth. In the past 20 years, science has made astounding progress in understanding the molecular and cellular mechanisms of the disease. However, despite efforts to design the perfect drug to attack AD at its heart, trial after trial has failed. How did we get here, and how do we move forward? On more than 600 pages, 59 authors in the field address these questions in a new book called Developing Therapeutics for Alzheimer’s Disease: Progress and Challenges. Michael Wolfe of Brigham and Women’s Hospital in Boston edited the project, published by Academic Press.
“There have been a lot of high-profile failures,” Wolfe told Alzforum. “It is important that people understand that progress has been made, and that lessons must be learned from each failure.” Wolfe foresees the 23-chapter book as a comprehensive overview for new investigators in the field. Beyond providing a hefty review of the past, present, and future challenges of AD research and clinical endeavors, Wolfe said he hopes the book will challenge new researchers to think about what is missing from its pages.
Wolfe conceived of the book two years ago. He gathered leading AD researchers to pen chapters, in many cases about their own discoveries. In the foreword, Wolfe’s long-time colleague David Teplow, University of California, Los Angeles, highlights Wolfe’s research that led to the discovery of γ-secretase, the enzyme that churns out the infamous Aβ peptides. “Mike has assembled a ‘dream team’ of the world’s most respected AD clinicians and basic science researchers to create what currently is the most comprehensive analysis of research into the causes and treatment of AD,” Teplow wrote.
Sandwiched between the preface and end—in which Wolfe summarizes the book’s highlights and discusses drugs in the development pipeline—lie 22 chapters that cover the various lines of attack researchers have mounted against AD in decades past.
First, Dennis Selkoe of Brigham and Women’s Hospital tells the story of how researchers came to understand the key biological drivers of AD, starting with its symptoms, then moving to the plaque and tangle pathology researchers first observed, then to the early genetic discoveries in APP and presenilin genes that gave rise to the amyloid cascade hypothesis. Chapter 2 dives further into the genetic underpinnings of AD, moving to risk factors pulled out of genome-wide association studies.
After this warm-up, the book switches into intervention mode. The next seven chapters focus on therapeutic strategies aimed at conquering AD’s star villain, Aβ. Efforts to shut down its production by blocking the proteases that make it occupy three chapters on inhibitors of β-secretase, γ-secretase, and the more targeted modulators of γ-secretase (GSMs), respectively. Beyond production, the focus moves to strategies to make Aβ shape up or ship out. Chapter 6 covers Aβ assembly blockers, while 7 tackles Aβ immunotherapy. This includes both active (Aβ vaccines) and passive (anti-Aβ antibody) approaches. Chapter 8 details a strategy of Aβ damage control by way of blocking Aβ oligomer receptors, such as cellular prion protein (PrPc) poised on the surface of would-be neuronal victims. Rounding out the Aβ portion of the book is a chapter on pathways of Aβ clearance, including its transport across the blood-brain barrier.
Following a chapter on AD’s biggest genetic risk factor, ApoE, which describes efforts to target the apolipoprotein despite limited knowledge of its basic biology, the book marches into tau territory. The next five chapters address strategies aimed at stabilizing the microtubules with which tau associates, blocking tau phosphorylation, ramping up its degradation, targeting it with antibodies, and breaking apart its aggregates.
Despite his assertion that Aβ and tau are central to the AD pathogenic process, Wolfe included other therapeutic approaches in the book. The need for non-Aβ/tau strategies is underscored by the fact that researchers are still questioning whether they will be able to target these instigators before the damage is done, Wolfe told Alzforum. The next three chapters cover protective strategies such as neurotrophic factors, which may shield neurons from assault inflicted by Aβ/tau, symptomatic treatments such as the well-known cholinesterase inhibitors as well as molecules that boost signals from other transmitter systems, and agents that prevent oxidative stress and mitochondrial malfunctions.
The book then departs from the what and heads toward the how and when. It discusses the myriad challenges of conducting clinical trials, including regulatory issues, exposing true disease-modifying effects, accurately using biomarkers, and the ethical and logistical hurdles inherent to secondary prevention trials. Central as they are to both participant selection and tracking drug response, the use of imaging and CSF biomarkers are the focus of the following two chapters.
The book’s penultimate focus addresses what is perhaps the most successful AD “treatment” so far—a healthy lifestyle. Michelle Carlson of Johns Hopkins University in Baltimore describes the epidemiological studies and intervention trials conducted in this arena, including physical exercise, cognitive engagement, aka “brain training,” and social enrichment.
Capping the book, Wolfe incites the reader to join the battle against AD by framing unanswered questions in the field and calling for increased and more efficient funding for research and trials. He ends on an optimistic note: “The bottom line is that there is reason for hope and for confidence that our efforts will continue to lead to advances that bring us closer to the day when AD is a preventable and treatable disease.” For more information on Alzheimer’s therapeutics, see the Alzforum therapeutics database.—Jessica Shugart
No Available Further Reading