Abstract
Alzheimer disease (AD) is the sixth leading cause of death in the United States. Incidence rates increase exponentially from age 65 years on. Onset of AD before age 60 (EOAD) and at 65 years and older (LOAD) share similar postmortem findings, but vary in their clinical presentations. Therapeutic disappointments, the complex genetics of LOAD, and new findings related to regional progression of pathology have led to new hypotheses that emphasize either the vulnerability of the aging brain with respect to stress, or a neuron-to-neuron transmission process similar to what is observed in prion disorders. Mounting evidence suggests that the initial physiologic changes (preclinical phase) that place the brain on the pathway to LOAD occur at least 20 years before dementia symptoms appear. This initial preclinical phase is followed by a phase whereby cognitive impairment, but no functional impairment, is present (mild cognitive impairment), which is then followed by the third phase of dementia. Diagnosis of AD has primarily been one of exclusion of all other causes of reversible and irreversible dementia. Overlapping clinical presentations of diseases causing neurodegeneration, however, create challenges for accurate diagnosis. Use of clinical magnetic resonance and PET imaging modalities increase the specificity of diagnosis. Several new promising experimental approaches are discussed in other articles elsewhere in this issue.