The genome is the totality of information that directs the making and the maintenance of you and every other living organism. Scattered among the familiar genes that code for the proteins of life are other genes. This is a book about the genes we call microRNA. It is 30 years since their discovery. They are gene regulators, every bit as vital as their more famous gene cousins. MicroRNAs fine-tune how much protein is made in our cells, each one coordinating the activity of hundreds of genes and bringing precision to the ‘noise’ of gene expression. Without them, life is virtually impossible. This introduction provides a personal account of what fascinated the author about these genes enough to make him redirect his research to microRNAs. The journey from studying pharmacology in the UK, to the USA where his interest in the brain disease epilepsy began, and later to Dublin, to work at the Royal College of Surgeons in Ireland. It lays out the contents and style of the book, which is part history of science, describing what we know and the experiments that underpin our understanding, and part memoir of the author’s own research, and the applications of microRNAs in medicine.

When companies working in the pharmaceutical sector choose to develop new products, they have a certain set of choices. They can decide not to develop anything new, they can choose to make incremental improvements to existing products or choose to create something entirely new. In the short term, firms are also under pressure by shareholders to provide value, which may discourage longer-term investments. This may lead to an affinity for incremental discoveries and pursuits that are more likely to succeed in the short-term, such as me-too drugs. Chapter 11 explores how financial considerations influence the rate and direction of drug development, using antibiotics as a primary case example. Additionally, the chapter explores why there is missing novelty in drug development and how we might stimulate more breakthroughs in the future.

The topic of clinical trials is introduced using the example of the MRC trial in streptomycin in TB. The role of randomization, the subject of design of experiments and ethical problems in conducting trials in patients are covered.

Drug development teams once focused on study design and company priorities, must now expand their efforts to include the professional, patient, and policy advocacy landscape. These groups are essential to setting research and policy priorities and are influential voices in securing funding at the federal, state, and private investment levels, as well as input to optimize the probability of success of clinical development programs. Professional associations and patient advocacy groups also enable collaboration across industry to address challenges that require resources beyond any one entity. This is particularly relevant to complex conditions such as Alzheimer’s disease.

The COVID-19 pandemic caused enormous disruption of clinical, research, and academic services around the world. This chapter focuses on the impact of COVID-19 on clinical trials and reflects upon the various measures taken to continue research work while minimizing risk to participants. Through careful observations, we conclude that it is imperative to continue Alzheimer’s disease (AD) drug development programs. With proper infection prevention protocols and precautions in place, it is possible to preserve the safety of both study participants, and investigators/research staff while moving forward with essential drug development processes for the benefit of study participants, and patients in general. Such protocols, once perfected, need to become a part of all institutional review boards and study protocols in order to avoid any loss or delay of essential work in the future.

Drug development is a long and arduous process that requires many researchers at different types of institutions. These include researchers in university settings, researchers in government settings, researchers in non-profit organizations and researchers in the pharmaceutical industry. The pharmaceutical industry itself is heterogeneous, ranging from tiny biotech companies to large multi-national organizations. This chapte emphasizes drug development efforts by the pharmaceutical industry but will also make note of the many collaborations between pharma and researchers at other types of institutions.

Animal model systems play a fundamental role in the development and evaluation of novel treatments for Alzheimer’s disease (AD). The examination of safety and tolerability in animal models is a necessary first step prior to any human clinical trials. Equally important, preclinical testing of novel therapeutics in disease relevant models is required for the determination if a potential therapeutic should advance. There are a number of important considerations in the preclinical workflow that range from selection of the most appropriate animal model related to drug mechanism of action, as well as what AD-relevant measures are to be evaluated to determine if a candidate therapy should advance. In this chapter we highlight the process of preclinical animal model testing for novel therapeutics in AD, as well as detail several of the models utilized and the measures relevant to AD. We also include the emerging approaches to provide better AD animal models (MODEL-AD) as well as emerging approaches to refine the process of identifying new treatments (TREAT-AD).

Drug discovery and development is a long and arduous process and is particularly challenging for Alzheimer’s disease given the incomplete understanding of molecular mechanisms, variability in clinical presentation, relatively slow disease progression, and heterogeneous patient population. The lack of predictive preclinical models combined with the long and expensive clinical trials raise additional barriers to therapeutic development. Tens of thousands of academic publications identify potential biomarkers, molecular mechanisms, preclinical models, and interventions, yet very few have led to industry-sponsored drug development programs. In this chapter, we will describe one academic program’s approach to bridging the “valley of death.” The Stanford University SPARK Program helps academics advance their projects through the applied science stage of development, reducing the risk to potential industry partners. SPARK uses simple and easily replicated principles to ensure that more academic discoveries find their way to impact patients and to benefit society. Approximately 60% of SPARK projects advance to industry partnerships or directly into university-sponsored clinical trials.

There is currently just one disease-modifying therapy for Alzheimer’s disease (AD). Increasingly, AD R&D is being performed by academic groups and early-stage biotech companies. Many of these programs stall in the “valley of death”, due to insufficient funding, expertise, and tools required to develop and commercialize drugs. To bridge this gap, the venture philanthropy model has emerged as a complimentary driver of translational research amongst public and private funders. Venture philanthropy combines deep disease-focused expertise and networks, with funding in high-risk/high-reward drug programs. Funding is structured to enable returns on investment, which are reinvested into further drug development projects. Venture philanthropies have contributed to advancing more preclinical AD candidates into clinical trials and helping academic and early-stage biotech programs reach critical scientific and business milestones. With recent examples of successful returns on investment, more capital is available to feed the AD therapeutic pipeline, expand clinical trials, and develop biomarkers to support these programs.

Therapeutic development is complex, best compared to capital expenditures for national infrastructural investments. Therapeutic development involves many partners. Alzheimer’s disease therapeutic development has been especially challenging. The disease course is long and slow, the biology complex and elusive, and trials are cumbersome and costly. Nonetheless, scientific understanding and approaches have reached a tipping point that warrant greater attention and investment. In this complex landscape, philanthropy is unlikely to address all challenges, but instead can play critical roles filling in where other funding sources are less suited. In this chapter, we outline four areas for philanthropic investment: therapeutic development prior to clinical testing, ensuring that diverse perspectives remain intellectual contributors to the field, providing personal perspectives to drive priorities toward patient needs, and fostering cultural change in science to promote greater collaboration. These investments are an important part of a larger ecosystem but can play an outsized role in accelerating scientific progress.

Early-stage drug development efforts for Alzheimer’s disease (AD) therapeutics often occur within academia and start-up companies and are often supported by National Institutes of Health (NIH) funding. The National Institute on Aging’s (NIA’s) seed funding through the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs provide innovators with non-dilutive funding that supports key early-stage drug developments. Since 2015, the NIA small business funding programs have become a valuable source of seed funding available that enabled start-up companies to reach critical value inflection points. This chapter includes examples of five companies that received NIA small business funding at the preclinical stage of development and advanced their innovations to clinical trials: AgeneBio, Alector, Avid Radiopharmaceuticals, Cognition Therapeutics and Tetra Therapeutics. The NIH and NIA have launched several strategic initiatives and funding opportunities to enable small businesses to reach key value inflection points.

Statistical issues are prominent in Alzheimer’s disease (AD) clinical trials due to the enormous challenges in this disease. The complexity of the disease and intervention pathways challenge drug discovery efforts, but measurement and analysis complexities and subjective outcomes also interfere with successful drug development. Variability across disease stage, disease sub-types, comorbidities and concomitant treatments (between-subject), and non-equivalent forms, good and bad days, and rater inconsistencies (within-subject) increase the chance of failure. AD-specific statistical expertise is critical for success, in contrast to most disease areas that require less disease-specific statistical knowledge. Use of global statistical tests and composites, correcting for covariates, and model selection increase the chance of a clearly positive outcome for active treatments and a clearly negative outcome for inactive or harmful treatments.

Alzheimer’s disease (AD) drug development is a complex process that proceeds from identification of a biological target; to testing of candidate therapies in in vitro assays; assessment of efficacy in animal models and assessment of safety in several animal species; clinical testing in humans in Phase1, Phase 2, and Phase 3 clinical trials; regulatory review by agencies in all countries in which the drug might be marketed; and eventual commercialization. This process requires more than a decade to accomplish. The process involves substantial infrastructure resources; multiple stakeholders; and funding from a variety sources along the developmental pathway. This is the complex ecosystem that supports AD drug development.

The National Institutes of Health (NIH) is the largest funder of Alzheimer’s disease and related demententias (AD/ADRD) research in the world. The National Institute on Aging (NIA), part of the NIH, leads the federal effort on AD/ADRD research. Since 2005 the NIA has been developing a robust translational research program for the treatment and prevention of AD dementia. In 2011, the National Alzheimer’s Project Act became law and ordered the creation of a National Plan to Address Alzheimer’s Disease. The National Plan was first released in 2012 and the first goal of the plan is to find effective ways to treat or prevent dementia by 2025. Since the first the release of the first National Plan in 2012, NIA’s funding for AD/ADRD research has steadily increased, allowing continued expansion and diversification of the drug development portfolio and the development of translational infrastructure programs to accelerate the discovery of effective therapies.

Until recently, only five medicines have been approved for treatment of patients with Alzheimer’s disease (AD). Unfortunately, these agents offer just mild and temporary symptomatic improvement, without slowing progression of the disease itself. The Harrington Discovery Institute of University Hospitals Health System in Cleveland addresses this problem through a unique model that advances a diversified portfolio of new medicines for both treatment and prevention of AD. The institute identifies academic scientists in the USA, UK, and Canada who have made exceptionally innovative basic science discoveries related to AD and provides them with both financial support and critical programmatic direction. This latter contribution entails guidance and oversight from eminent drug developers whose collective expertise would normally only be available within a large pharmaceutical company. This enables academic scientists to bridge the “valley of death” between their scientific discoveries and development of medicines. As a result, HDI is bringing new medicines with novel mechanisms of action into the clinic for Alzheimer’s disease.