Environmental risk factors and the developmental basis for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The hallmark pathological features of AD (amyloid plaques and associated proteins) are present in normal aging individuals, suggesting that AD may result from the acceleration of normal age-related processes in the brain. The sporadic nature of most AD cases strongly argues for an environmental link that may drive AD pathogenesis; however, it is unclear when this environmental stress may occur. Therefore it is important to identify an environmental trigger(s) and to pinpoint the period during which such factors pose the greatest risk. Recently, we reported that developmental exposure of rats to the xenobiotic metal lead (Pb) resulted in a delayed overexpression (20 months later) of the amyloid precursor protein (APP) and its amyloidogenic Aβ product. Similarly, aged monkeys exposed to Pb as infants also responded in the same way. These data suggest that environmental influences occurring during brain development predetermine the expression and regulation of APP later in life, potentially influencing the course of amyloidogenesis, and argue for both an environmental trigger and a developmental origin of AD. In this review, we present evidence for the developmental basis of neurodegeneration and discuss mechanisms that may explain how perturbations during development can have long-term or delayed consequences in the aging brain.