Alzheimer’s disease (AD) may be the most vexing problem facing societies as the world populations age. Many other chronic diseases associated with aging are showing a slowing of progression as effective therapies are developed (www.alzstudygroup.org
). However, there are no therapies available for AD that alter the underlying disease process, and as such, the prevalence continues to increase.[1
] Estimates from the Alzheimer’s Association suggest that, in the U.S. alone, there are approximately 5.3 million persons with AD, and the figures on a worldwide basis for dementia are estimated to be 20–30 M.
While there currently are no disease-modifying therapies for AD, over 100 compounds are in various phases of development by many pharmaceutical companies. A challenge in the development of new therapies for AD stems from the uncertainty of the underlying diagnosis. Alzheimer’s disease can be identified quite accurately in its mid-stages by most clinicians, but in the earlier phases of the disease process, a precise diagnosis can be elusive. The American Academy of Neurology in an evidence-based medicine review of the literature on dementia and AD concluded that clinicians are quite accurate in the later stages of the disease when the clinical diagnosis is compared to autopsy confirmation.[3
] However, when the clinical signs are mild and there is a more variable expression of the clinical features and less certainty in the diagnosis.
In the past decade, the condition is known as mild cognitive impairment (MCI) has come to represent a syndrome with only early features of what might evolve into clinical AD.[4
] Mild cognitive impairment refers to the clinical condition in which subjects are usually only mildly impaired in memory with relative preservation of other cognitive domains and functional activities, and they do not meet criteria for dementia. This entity has stimulated a great deal of research on the prodromal stages of what will become fully developed clinical AD.[5
] However, as clinicians make the diagnosis with increasingly subtle features of the syndrome, they gain sensitivity at picking up early cases but sacrifice specificity with respect to the precise outcome of the early prodromal condition. This has become evident with the recent reports of randomized clinical trials designed to develop treatments for MCI.[6
] The annual progression rate from MCI to Alzheimer’s disease varied greatly in these trials from 5–6% per year to 16% per year. Some of this variability was due to the design of the studies, but other features, such as lack of specificity concerning the clinical criteria, played a role.
As research on MCI has accumulated, it has become apparent that the specificity of the clinical outcome can be enhanced using neuroimaging and biomarkers.[8
] As a result of this growing literature, a large study in the United States, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was developed to address some of these issues.[10
] In parallel, comparable efforts in Japan (J-ADNI), Europe (E-ADNI) and a counterpart study in Australia have been developed, and there is increasing expectation that these studies will complement each other. These results will allow for the prediction of outcomes of persons with MCI and, ideally, eventually, even asymptomatic persons who are at risk for developing AD and other dementias.
In recent years, there has been an evolving theoretical framework that the AD process likely begins years, if not decades, prior to the development of clinical symptoms, even at the MCI stage.[12
] While the precise temporal relationship among the various pathologic entities involved in AD is not certain, many investigators believe that the deposition of the Aβ peptide may be the initiating event (). Currently, Aβ deposition can be inferred in the cerebrospinal fluid (CSF) and/or through amyloid imaging techniques.[13
] Following the deposition of Aβ, there may be a rise in the expression of certain species of tau proteins, particularly total tau and the hyperphosphorylated form (p-tau) and an index of a decrease in synaptic integrity as indexed by FDG PET.[14
] Subsequently, evidence of neuronal damage may become manifest through the development of atrophy of certain structures such as the hippocampus and enterorhinal cortex as imaged on MRI. Following this cascade of events or at some point during their development, cognitive changes appear. If this scenario is partly accurate, then imaging and chemical biomarkers may become the mainstay in predicting which individuals are likely to develop the clinical syndrome we now call AD. So, what is the evidence for this putative constellation of events?
Theoretical time course of amyloid deposition relative to subsequent neurodegeneration and cognitive decline.