Disrupting Alzheimer's Disease Research

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that devastates the brain—affecting cognitive function, memory, visual spatial perception, abstract thinking, and eventually loss of bodily functions. Based on the latest Rand report on dementia and AD, the current costs in lives lost, families shattered, careers disrupted, and financial futures ruined is much too high. And with the projected increases in the number of individuals affected by AD and related dementias in coming years, the global costs become unendurable and insupportable. Many pharmaceutical companies have dismantled their AD treatment discovery programs because of failed experimental therapeutics in costly Phase III clinical trials. Recently, a paradigm shift to focus earlier in the disease process to include preclinical populations with mild cognitive impairment (MCI) due to AD has emerged. It is anticipated that at earlier stages, before functional impairments and severe neuronal damage has occurred, potential treatments might be more effective. But unless we take deliberate steps to disrupt the status quo, there is growing concern that AD research in this country will remain seriously underfunded. A situation this complex requires novel approaches in at least three ways: (1) to accelerate research breakthroughs by fostering new thinking about neuroscience and AD by those currently not working in the area, (2) to incentivize computational researchers to mine public databases such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and (3) to focus on an aspect of the science that has the greatest potential to trigger a groundswell in advocacy, too long absent in the AD community. As a benchmark, the history of heart disease research has demonstrated the importance and relevance of elucidating biologic sex differences for better-tailored detection, treatment, and prevention interventions. The research focus benefited both women and men and transformed the body politics. It is time for a concerted focus to do the same for AD. What might AD research look like if science and advocacy coalesced to crowdsource such a challenge to a global network of millions of problem solvers and experts worldwide? This innovation model supports the development of new ideas and paradigms, innovative tools from global investigators in multiple disciplines within medical science, but also in engineering, computer science, and mathematics. Why not apply it to elucidate the causes and consequences of male/ female (sex) differences in the destructive physical changes and atrophy in the brain, how those changes translate into progression of physical symptoms, and the influence of genetics and hormones on the development of AD in both men and women? The 2013 Geoffrey Beene Global NeuroDiscovery Challenge on male/female differences in the presymptomatic, early symptomatic, and late dementia stages of AD, with $100,000 in prize awards, attempts to leverage large sets of clinical data and novel analytical approaches. The challenge is seeking to encourage multidisciplinary teams to analyze public datasets from the National Institute on Aging and other research centers for differences between men and women in cognition, biomarkers, and progressive neurodegenerative decline due to AD. Figure 1 is a representative announcement for the challenge. Women are disproportionally affected by AD; two-thirds of AD patients in the United States are women. This disparity may be due in part to women’s longer life spans, but recent research in MCI is beginning to point toward differences between men and women in the pathology and progression of this disease. Anatomical, molecular, functional, hormonal, and cognitive differences in the brain between males and females have been reported in many species including humans. What biological sex differences in the brain mean for impairments in memory and progressive neurodegenerative diseases such as AD is not known. However, studies are accumulating that show a distinct male/female difference in the onset, course, and presentation of AD. For example, one study reported that women had more neurofibrillary tangles. Increased AD pathology was associated with a nearly 3-fold increase of clinical AD in men, compared with a more than 20-fold increase in women. These and other data suggest that the same degree of cognitive impairment is associated with greater structural damage in men compared with women. In the ADNI, patients were grouped into three clinical categories—probable AD, amnestic mild cognitive impairment (aMCI), and healthy controls. Men and women in the AD and aMCI groups showed different patterns of decline through time. In another ADNI study of brain atrophy rates, statistical mapping revealed significant age and sex differences, with rates of brain atrophy being about 1.0%–1.5% faster in women than in men. The Mayo Clinic Study of