Alzheimer’s disease (AD) is a neurodegenerative disease of the brain, characterized by a slowly progressive dementia. This insidious disease is growing in importance because it affects millions of older patients. Clinical symptoms of AD include cognitive decline, irreversible memory loss, disorientation and language impairment. Major neuropathology observations of postmortem AD brain include the presence of senile plaques containing β-amyloid (Aβ) aggregates and neurofibrillary tangles containing highly phosphorylated tau proteins (Figure 1A).1,2 Several genomic factors have been linked to AD. Familial AD (or early onset AD) has been reported to have mutations in genes encoding β-amyloid precursor protein (APP), presenilin 1, presenilin 2 and Apolipoprotein E (APOE).3 The exact mechanisms of these mutations, which lead to the development of AD, are not fully understood; however, formation of plaques comprised of Aβ peptide in the brain is a pivotal event in the pathology of Alzheimer’s disease. Significant evidence suggests that accumulation and aggregation of Aβ peptides may play a major causative role in AD pathogenesis.2,4 The excessive burden of Aβ, produced by various mechanisms, may represent the starting point of neurodegenerative events, and may initiate a cascade of events (β-amyloid cascade, Figure 1B) that includes gliosis, inflammatory changes, neuritic/synaptic change, tangles and transmitter loss.2 Currently, there is no definitive method to diagnose AD, except by postmortem evaluation and staining of the brain tissue, which demonstrates the existence of Aβ plaques.
Recent reports have suggested that β-amyloid aggregates in the brain play a key role in a cascade of events leading to AD.2,5 Thus, the development of diagnostic imaging agents targeting Aβ aggregates is very important in the diagnosis and treatment of AD. Novel PET imaging agents specifically targeting the Aβ plaques may lead to early detection of AD pathology, differential diagnosis of patients with dementia, and for monitoring patients who are undergoing drug treatment designed to reverse the Aβ buildup in the brain.
Indeed, diagnosis and treatment of AD have been hampered by the absence of reliable non-invasive markers for the underlying pathology. Diagnosis based on consensus criteria is approximately 81% sensitive and 70% specific by comparison to the gold standard of pathology at autopsy.6 In addition to errors of misdiagnosis in patients with AD, there is significant under diagnosis; approximately 10% of community dwelling elderly still have undiagnosed dementia, and community physicians may fail to diagnose up to 33% of mild dementia cases.7 Thus, there is a need for a biomarker that can be applied in the community setting and can help physicians separate those patients who do not have AD from those who have pathological signs and should be evaluated further. Additionally, there are a large number of patients who, upon comprehensive diagnostic testing, are found to have cognitive impairment but are not demented and thus, do not meet diagnostic criteria for AD (e.g., patients with mild cognitive impairment, MCI). Some, but not all of these patients will go on to develop AD within 3-5 years. A reliable biomarker might aid prognostic evaluation by documenting the presence or absence of AD related pathology.
Based on the definitions of AD endorsed by the American Academy of Neurology, American Psychiatric Association (DSM-IV) and others, patients without abnormal amyloid plaque levels do not meet currently accepted neuropathological criteria for AD. This definition of AD, which includes amyloid plaques as a required feature, is supported by more than 100 years of autopsy data. Therefore, based on this widely-endorsed definition of AD, the use of a test for ruling-out the presence of amyloid plaque pathology in subjects with clinical signs and symptoms of cognitive impairment will, effectively, rule-out the diagnosis of AD, and lead to more careful evaluation and appropriate treatment for alternative causes of cognitive deficits. Moreover, the use of a test for ruling-in the presence of abnormal levels of Aβ plaques in the brain of subjects with signs and symptoms of cognitive impairment will lead to the selection of patients who warrant more detailed work-up for the possible diagnosis of AD or MCI.
The differential diagnosis for AD includes a large number of other diseases. At early stages of disease (e.g. MCI), frequent confounds include cognitive impairment as a result of underlying depression, effects of CNS active medications, inadequately treated or end stage medical conditions affecting other organ systems, and even normal age-related changes. At later stages of disease, more common confounds include vascular dementia, frontal temporal lobar dementia (FTLD) complex, dementia with Lewy bodies (DLB) as well as rarer neurodegenerative diseases such as Creutzfeld Jacob Disease (CJD). Importantly, AD subjects will always have Aβ plaques, whereas amyloid is seen not at all, or only sporadically in most of these other diseases. In each case, appropriate prognosis and treatment requires accurate diagnostic assessment.