Although Alzheimer’s disease (AD) was first described clinically and pathologically more than 100 years ago, it has only been over the last 30 years that clinicians and scientists have been able to unravel many of the scientific underpinnings of AD as well as several of the other causes of dementia. Because AD causes or contributes to dementia in about 30 million people worldwide and because of better overall medical care, we are facing a looming crisis. It is predicted that unless an effective therapy is developed, the prevalence of AD will triple over the next 30 to 40 years. An underlying principle that has emerged is that most neurodegenerative diseases, including AD, Parkinson disease, frontotemporal dementias, and prion diseases, appear to be disorders of protein aggregation in which normally soluble proteins become insoluble and accumulate in the brain, leading to neurotoxicity. Important clinical, genetic, and diagnostic advances, as well as a better understanding of pathophysiology, have led the field to the point where we are now poised to make important contributions to modify the course of different dementing diseases. There is even the possibility of delaying or preventing dementia.
Chapters 59 to 69 deal with various aspects of AD, which cause or contribute to approximately 70% to 75% of cases of dementia. In Chapter 59, Hassenstab, Burns, and Morris provide an update on the clinical and neuropsychological features of AD. They emphasize the importance of obtaining a history from a knowledgeable informant in determining whether an individual has developed cognitive impairment and if so, provide clinical and psychological methods to accurately quantify current cognitive and functional status. Utilizing purely clinical techniques, diagnosis of dementia caused by AD can be made quite accurately though imaging (see Chapter 62 by Brewer, Sepulcre, and Johnson) and fluid biomarker techniques (see Chapter 63 by Fagan) are proving to be very useful adjuncts. Structural and functional neuroimaging techniques are demonstrating the time course of changes in brain structure and function in relation to the clinical onset and progression of disease. Both measures appear to begin to become abnormal a few years before the onset of detectable cognitive change. Amyloid imaging as well as CSF measures of Aβ42 appear to detect the onset of amyloid deposition in the brain as long as 10 to 15 years before cognitive decline and an increase in CSF tau, which occurs a few years before cognitive decline, marks the onset of neurodegeneration. These imaging and fluid biomarker techniques strongly add to both diagnostic and prognostic accuracy and will likely be very valuable in assisting in the enrollment of participants in both treatment and secondary prevention trials that are just beginning. In Chapter 60, Tanzi describes how the discovery of different genes that cause dominantly inherited AD has revolutionized our understanding of AD by pointing us to which pathways are key in disease causation. These studies clearly point to the role of Aβ in instigating disease in that mutations in PS1, PS2, and APP almost all cause an increase in production in either all Aβ species or more commonly an increase in production of Aβ42. Further, APOE, the most important genetic risk factor for AD, also influences Aβ metabolism, not by increasing synthesis but by influencing its aggregation and clearance. Additional new genetic risk factors have been uncovered and how they impact disease is still being sorted out. In Chapter 61, Morgan describes how researchers have taken advantage of the knowledge of the genes that cause or contribute to AD by creating many different genetic mouse models in which various pathological and behavioral phenotypes that mimic aspects of AD can be seen. This has been a colorful and productive area of research and is beginning to reap benefits, as disease modifying therapies are now being tested in humans based on promising data coming from these different models.
Although currently no therapies have been proved to delay the onset or slow the cognitive decline in AD, in Chapter 64 Sano and Neugroschl describe the current pharmacological therapies that have been shown to improve the symptoms of AD, including cholinesterase inhibitors and memantine, as well as results from a host of other studies. In Chapter 65, Grill and Cummings describe the very exciting work that is emerging on potential disease-modifying therapies for AD. Many different small molecules and biological therapies such as antibodies that target Aβ have shown promising preclinical data in animals. These treatments are in both early as well as later trials in AD. Additional targets such as tau and inflammation are also beginning to be tested now and in the near future.
A variety of other diseases contribute to or lead to dementia in addition to AD. The most common neurodegenerative diseases in individuals greater than age 65 outside of AD are dementia with Lewy bodies and dementia in Parkinson disease, described by Karantzoulis and Galvin in Chapter 66. These disorders feature the accumulation of synuclein in the brain. Many cases also feature Aβ accumulation. Another very common contributor to dementia either alone or more frequently in combination with AD is vascular dementia, described in Chapter 68 by Chui. Although not a frequent cause of dementia in the elderly, frontotemporal dementia (FTD) is a common cause of dementia in individuals less than 60 years of age. In Chapter 67, Naasan and Miller beautifully describe the varied clinical and neuroimaging features of FTD, which present with either behavioral or language abnormalities. Importantly, the genetics and pathology of FTD clearly show it to be more than one disease, in which different genes and proteins can contribute. Improvements in diagnostic and biomarkers methods in this area should allow for promising treatment development as pathophysiological mechanisms emerge. Finally, although not a common cause of dementia, Chapter 70 by Watts and Geschwind describes diseases caused by prions. These diseases can cause rapidly progressive dementia in both humans and animals. Some of the major insights into a variety of neurodegenerative diseases have emerged from studies of prion disease, which can be both genetic and infectious.
It is clear that a major public health crisis is in the process of emerging because of the fact that lifespan is increasing and with that, dementing disorders, especially AD, are becoming more and more common. We have seen a clinical and scientific revolution in this area over the last 30 years in that the genetic and pathophysiological basis for these disorders is now much better understood. This is leading to the emergence of better diagnostic methods as well as promising disease-modifying therapies. It seems likely that over the next decades there will be a real chance that effective therapies for AD and other neurodegenerative diseases will become a reality. That day cannot come too soon.