Alzheimer disease therapy: can the amyloid cascade be halted?

In the not too distant future, clinical management of Alzheimer disease (AD) is likely to resemble the present management of atherosclerotic disease. Sometime before an individual reaches age 50, an internist will initiate a screening program to determine that person’s risk for developing AD. This assessment will include a comprehensive genetic screen for AD-risk loci, determination of plasma amyloid β peptide (Aβ) levels, family history of AD, and, perhaps, potential environmental risks. Depending on the risk prediction, a follow-up visit with an Alzheimer specialist may be scheduled. During this visit, an amyloid-binding agent will be injected and used to evaluate the extent of amyloid deposition in the brain. Based on the amount of deposition present and the initial risk assessment, the specialist will then develop a personalized therapeutic regimen. This regimen might consist of an Aβ vaccination, an amyloid-lowering drug, an anti-inflammatory agent, a neuronal growth factor, an antioxidant, or a combination of these approaches. The efficacy of therapy will be monitored by measurement of plasma Aβ levels, imaging of amyloid in the brain, and volumetric scanning of the brain. Primary screening, along with monitoring of the presymptomatic indicators of disease, and appropriate intervention will significantly reduce one’s risk for developing AD. Although proposal of such a scenario might seem highly speculative, recent and expected advances in (a) understanding the pathogenesis of AD, (b) identifying the genetic factors that confer risk for AD, (c) validating potential biomarkers for AD, and (d) developing therapeutic agents that target both Aβ and downstream pathological changes greatly increase the likelihood that AD will be managed successfully in the future. AD is the leading cause of dementia in the elderly Estimates of prevalence vary, but 1‐5% of the population over age 65, and 20‐40% of the population over age 85, may be affected by AD (1). Given the increasing number of elderly individuals in industrialized societies, AD represents a burgeoning epidemic that exacts a tremendous toll on the individuals it affects, along with their families and caregivers. Moreover, AD has a tremendous negative economic impact amounting to over $100 billion a year. Treatment of AD in the US reportedly costs more per patient than management of other major age-associated diseases (2, 3). Beginning with short-term memory loss, and continuing with more widespread cognitive and emotional dysfunction, typical late-onset AD (LOAD) occurs after age 65 and follows an insidious 5- to 15-year course. Although AD usually presents without motor or sensory alterations, rare variants (such as spastic paraparesis) with atypical clinical presentations are occasionally recognized (4, 5). Even today, definitive diagnosis of AD is only possible through postmortem analysis of the brain (1). This histopathological analysis of the brain demonstrates the classic triad of AD pathology: (a) senile plaques containing Aβ, (b) neurofibrillary tangles (NFTs) containing tau, and (c) widespread neuronal loss in the hippocampus and select cortical and subcortical areas.