Rend. Fis. Acc. Lincei (2015) 26:251–262 DOI 10.1007/s12210-015-0453-y Alzheimer’s disease: addressing a twenty-first century plague Christopher M. Dobson1 Received: 11 July 2015 / Accepted: 13 July 2015 / Published online: 19 August 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Alzheimer’s disease represents one of the plagues of Egypt, recorded in the Book of Exodus, are greatest challenges to the social fabric and health care thought to have occurred between ca. 1500 and 1200 BCE, systems of the world since the great plagues of the Middle although there has been much speculation about the origins Ages. At the present time, there are some 40 million suf- of these events, including whether or not they are mythical, ferers from this disease worldwide, but it is predicted that or if they could have represented the consequences of a this number will rise to nearly 150 million by 2050. The period of climate change. In more recent history, devas- predominant reason for this rapidly increasing prevalence tating ‘plagues’ are better documented, such as the ‘Plague is the increase in longevity that has resulted from the of Athens’ in 430–426 BCE, which followed severe over- tremendous advances in public health and hygiene and in crowding in the city, accompanied by insanitary condi- medical and surgical interventions over the last century. tions, as people took refuge from the approaching Spartan This article discusses recent progress in our understanding army during the Peloponnesian War. It is thought that a of the molecular origins of Alzheimer’s disease and third of the population of Athens could have died from emerging ideas for new and rational therapeutic strategies disease at this time, speculated to be anything from typhoid by which to combat its onset and progression. to measles. Another well-documented plague from antiquity was the Keywords Protein misfolding Á Amyloid formation Á ‘Plague of Justinian’, which occurred in 541–544 AD in Neurodegenerative diseases Á Protein homeostasis Á Constantinople and throughout the Byzantine Empire. Aggregation mechanisms There is increasing evidence that this pandemic was the first recorded outbreak of bubonic plague, the disease that more than any other is often simply described as ‘the 1 Introduction plague’. Frequent outbreaks occurred in mediaeval Europe, the infection having spread from Asia along the increas- Plagues, or the rapid emergence of outbreaks of fatal dis- ingly heavily used trade routes. The most famous of these eases, have been a prominent feature of the human con- episodes was the ‘Great Mortality’ or the ‘Black Death’ dition throughout history (Dobson 2015). The ‘biblical’ that afflicted Europe in 1347–1353 AD, and is estimated to have killed one third of the population of the continent and to have caused unprecedented social and economic The 2014 International Feltrinelli Prize for Medicine was awarded by upheaval. There were other periodic outbreaks of bubonic the Accademia Nazionale dei Lincei to Prof. Christopher M. Dobson. This paper is an account of the lecture that the awardee delivered plague, including the ‘Great Plague’ of London in 1665, during the presentation ceremony on the 14 of November 2014. although none was as devastating as that of the mid-four- teenth century. Other diseases, however, ravaged the world, & Christopher M. Dobson including measles and smallpox, which spread like wildfire [email protected] amongst the populations of ‘new worlds’ such as the 1 Department of Chemistry, University of Cambridge, Americas and Australasia with the arrival of European Lensfield Road, Cambridge CB2 1EW, UK colonists, as the indigenous people had no immunity to 123 252 Rend. Fis. Acc. Lincei (2015) 26:251–262 these diseases that were previously unknown in those conditions, notably cancer and cardiovascular disease, regions (Dobson 2015; Haines and Steckel 2014). which are now the greatest causes of death in much of the With the massive overcrowding that occurred in cities as world outside sub-Saharan Africa. In the last few decades, a result of the increasing industrialisation in the nineteenth however, there has been a dramatic increase in another century, outbreaks of infectious diseases such as cholera group of disorders, collectively called dementias, of which and typhoid became common until the importance of the most common is Alzheimer’s disease (AD) (Knowles public health and hygiene became recognised. Then, in the et al. 2014). Dementia has recently been called a ‘twenty- aftermath of the First World War, perhaps the most lethal first century plague’, and indeed its rapidly increasing pandemic of all time occurred, the ‘Spanish flu’ of incidence and currently incurable nature is giving rise to 1918–1919, which is thought to have caused the deaths of the type of fears that in the past were associated with the 50 million people (more than the toll that resulted from the plagues of infectious diseases of the type discussed above. War itself). There is now increasing evidence that this ‘plague’ was the result of a strain of influenza similar to that of ‘bird flu’, outbreaks of which have generated much 3 The increasing number of cases of Alzheimer’s concern in recent years (Dobson 2015). disease Alzheimer first described the disease that bears his name in 2 Changes in human behaviour and the spread a lecture in 1906, after studying the case of a 51-year old of disease woman, Auguste Deter who was admitted to the Frankfurt Asylum suffering from severe dementia. At the time, her The modern investigation of such pandemics reveals close case was a curiosity, and indeed it is evident that she was links with rapid changes in human activities and lifestyles. suffering from a rare early onset form of AD. Indeed it was All of the classic plagues are of infectious diseases, both only some 40 years ago that AD began to be recognised as bacterial and viral, whose spread was dramatically an increasingly common condition among the elderly, but enhanced by increasing population densities, a process since then the number of cases has increased dramatically beginning with the change from a hunter-gatherer lifestyle within our ageing populations (Alzheimer’s Association more than 10,000 years ago, and by the increasing number 2015). The number of cases in the USA, for example, now of people travelling ever more rapidly over larger distances exceeds 5 million, and it is estimated that there are some 40 carrying the infectious agents; both of these factors million sufferers worldwide. This number is anticipated to increase the risk of transmission, particularly to popula- rise to about 135 million by 2050, of whom more than 70 % tions that have not previously been exposed to such dis- will be in low or middle income nations; AD is, therefore, eases. The changes in human behaviour that resulted in no longer a phenomenon confined to the wealthy nations of outbreaks of disease were, however, accompanied by an the world (Fig. 1). This increase in the number of cases is increasing realisation of their causes and of effective means entirely attributable to the increasing number of people over of prevention and treatment. Improvements in sanitation the age of 65, where the incidence of symptoms is between and hygiene, and the development of vaccines and of 1 and 2 % of the population, rising to between one-third and antibiotics, have been dramatic, such that in much of the one-half of those living to the age of 85. world the chances of dying from the classic infectious The financial burdens of this condition are enormous diseases that plagued humanity until modern times have because of the need for continuous care of patients, often been hugely reduced. The risk of pandemics has not been for years. In the USA, for example, the costs of AD are completely abolished, however, as resistant strains of many estimated to approach $200 billion this year and are pre- diseases that were thought to be have been largely sup- dicted to exceed $1 trillion by 2050 (Fig. 2); indeed in the pressed, such as tuberculosis, have emerged, and ‘new’ next 35 years, the cost of care and associated issues for AD types of disease have appeared, such as HIV/AIDS and sufferers in the USA alone is anticipated to be approxi- Ebola (Dobson 2015; Peacock 2014). Even in such cases, mately $20 trillion. Moreover, the extremely debilitating however, modern science has so far managed to limit and uniquely distressing nature of dementia has huge significantly the severity of these more recent ‘plagues’. implications for the stability of society and tremendous The decline in the number of cases of infectious disease challenges for the health care systems of the world. It is for has led to greatly increased lifespans in most parts of the this reason that dementia has recently become recognised modern world; life expectancy in the most highly devel- as an emerging international catastrophe, resulting in the oped countries is now about 80 years compared to first G8 Dementia Summit in London in 2013 where the approximately 50 years a century ago. The result, however, need to increase spending on research into the nature of the has been a large increase in cases of non-infectious disease, and into new approaches to the development of 123 Rend. Fis. Acc. Lincei (2015) 26:251–262 253 Fig. 1 Global life expectancy for both sexes in 2012. Source World Health Organization Map Production: Health Statistics and Information Systems (HIS), World Health Organization (2014) Fig. 2 Predicted costs of Alzheimer’s disease in the USA. 1070 Taken from ‘Changing the Trajectory of Alzheimer’s Disease: A National 906 Imperative’. Alzheimer’s Association, May 2010.