Setbacks and promises for drugs against Alzheimer's disease

Abstract

EMBO Reports (2018) e46714 A diagnosis of Alzheimer's disease (AD) is a devastating experience, both for patients and their families. The most common type of dementia, AD, slowly builds up in the brain, creeping in the parts that control memory, thought, and language, and ultimately destroys the patient's ability to interact with the human and physical environment. About 50 million people in the world suffer from dementia, and the number is set to triplicate by 2050 (Fig 1). As the risk of AD rapidly increases beyond the age of 65, and as the human population is aging, much of the forecasted increase of people with dementia will take place in low‐ and middle‐income countries, according to the World Health Organization (Fig 1). Given the increasing prevalence and the severity of AD, enormous financial and human resources—both public and private—have been devoted to finding a cure; in addition, a successful drug would reap immense revenues. So far, however, scientists still do not fully understand the causes of the disease, and treatment is mainly focused at slowing or delaying symptoms to help patients maintain their mental functions. Figure 1. Dementia, a public health priority WHO infographic about the symptoms of dementia, the cause, the number of people affected and its cost.Source: World Health Organization. Reproduced with permission. The hallmark of AD is the accumulation of extracellular plaques from amyloid‐β (Aβ) protein—which is derived from a membrane protein called amyloid precursor protein (APP)—and of intracellular neurofibrillary tangles of tau protein in brain cells (Fig 2). These aggregates gradually lead to neuron loss, synaptic dysfunction, and progressive cognitive degeneration (Fig 3). This so‐called amyloid cascade hypothesis has been the reference point for most research and drug development. Most attempts to slow the progression of the disease or to revert its effects target the amyloid‐β and tau proteins to prevent …