Alzheimer's disease (AD) afflicts an estimated 24 million people in the world, with an expected increase to over 80 million people by the year 2040 . AD causes an insidious and progressive loss of cognitive function and independence, taking a heavy personal and financial toll on the patient and the family. Because of the severity and increasing prevalence of the disease in the population, it is urgent that better treatments be developed.
The only identified deterministic factors for the development of AD are the presence of mutations in one of three genes - amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) - or duplication of APP. Approximately 50% of people from these kindreds are mutation carriers destined to develop dementia of the Alzheimer's type, generally at an early age (~30 to 50 years). In the present review, we define autosomal-dominant Alzheimer's disease (ADAD) as dominantly inherited AD with pathological confirmation. Other terms, such as familial AD and early-onset AD, may encompass ADAD, but may also include AD from nondominant causes such as the apolipoprotein E4 allele or sporadic Alzheimer's disease (SAD). Although ADAD represents fewer than 1% of all AD cases, it is a critically important area of study because the pathological features of the disease are similar to the more common sporadic form, because causative mutations have known biochemical consequences that are believed to underlie the much more prevalent sporadic form of the disease, and because it is possible to identify and study presymptomatic individuals decades before they are destined to develop clinical disease. The opportunity to determine the sequence of biomarker changes in presymptomatic gene carriers who are destined to develop AD is likely to reveal critical information about the pathobiological cascade that culminates in symptomatic disease.
The realization that AD is a major and growing public health problem with aging populations has added urgency to the search for improved therapeutics. Many proposed treatments for AD currently target slowing or halting of the underlying disease (that is, putative disease-modifying interventions), but they are not likely to reverse the extensive neuronal death already present at the onset of symptoms. For individuals and families at risk for ADAD, such interventions have the potential to delay or even prevent dementia in asymptomatic individuals, in addition to slowing progression in those with symptoms. These at-risk individuals offer a potential proof of concept for presymptomatic disease modification, with implications for AD more generally.
ADAD families have provided important insights into the pathogenesis of AD in the past several decades. Discovery of human genetic mutations has facilitated the development of the transgenic animal models used in AD research today. Knowledge of the molecular mechanisms of the identified mutations has catalyzed identification of the causative pathogenic events in AD in humans. Indeed, this avenue of research has provided the most compelling case for a unifying theory of AD.
In addition to contributing to advances in the basic scientific understanding of AD, ADAD families represent an ideal population for preventative and treatment trials for several reasons. First, there is near certainty (~100%) regarding development of the disease with a known mutation that enables prevention studies and increases the power of treating minimally or presymptomatic patients. Second, the approximate age at which symptoms are likely to develop can be predicted in individuals who are completely asymptomatic, allowing therapeutic trials years or decades before clinical onset. Finally, ADAD research participants are highly motivated, relatively young, and have minimal co-morbidities. By engaging those at risk for ADAD, uniquely informative scientific information about disease progression, biomarkers and changes due to therapeutic treatments are expected to lead to advancements in drug development.
Disease-modifying therapeutics have been largely developed with animal models based on human disease-causing mutations. ADAD caused by known mutations most closely resembles those models, and therefore is more likely to respond to disease-modifying treatments. Results from treatment trials in ADAD will bridge cellular and mouse therapeutic research with SAD therapeutic research. Because the clinical and pathological phenotypes of ADAD are similar to the more common late-onset AD, drugs that prove successful in the prevention or delay of dementia for ADAD are likely to provide guidance for future prevention and disease modification in late-onset AD. Successful implementation of prevention and symptomatic studies will therefore inform about the causes of AD and will provide guidance for future therapeutic development.
In the present review, we present historical and current information about ADAD, including: discovery of the genetic mutations; clinical, pathological, imaging and biomarker findings; the explosion of understanding about AD based on basic science studies of genetic mutations and development of AD animal models from the mutations; and an international multicenter effort to understand the cascade of events leading to AD toward future trials to treat - and even prevent - the onset of dementia in those with mutations.