Alzheimer's disease (AD) is defined by degeneration of specific populations of neurons and the presence of insoluble aggregates of cytoskeletal proteins and amyloid beta-peptide (A beta) within affected brain regions. Alzheimer's disease does not appear to result from a single alteration, but in some cases of inherited AD a specific genetic defect can precipitate the disease. In this article, metabolic compromise, altered metabolism of the beta-amyloid precursor protein (beta APP), and an excitotoxic form of neuronal injury are considered central to the pathogenesis AD. The hypothesis is forwarded that destabilization of neuronal Ca2+ homeostasis underlies neuronal degeneration and that multiple age-associated and/or genetic alterations contribute to the loss of Ca2+ homeostasis. Recent studies showed that the secreted forms of beta APP (APPss) stabilize intracellular free calcium levels ([Ca2+]i) and protect neurons against excitotoxic insults. In contrast, A beta which arises from alternative processing of beta APP forms free radical peptides and aggregates that destabilize [Ca2+]i and make neurons vulnerable to metabolic insults. Increased expression (eg, Down's syndrome) or altered processing (eg, beta APP mutations) of beta APP may increase the A beta/APPs ratio. The death of neurons in AD most likely has an excitotoxic component because: the vulnerable neurons possess high levels of glutamate receptors; experimentally induced excitotoxicity shows several features similar to those of neurofibrillary tangles; and A beta can destabilize [Ca2+]i homeostasis and render neurons vulnerable to neurofibrillary degeneration. Selective vulnerability may result from cell type-specific differences in expression of proteins involved in regulating [Ca+]i. In addition, many intercellular signals are involved in determining whether a neuron is able to maintain [Ca2+]i within a range of concentrations conducive to cell survival and adaptive plasticity. In this regard, it was recently shown that several growth factors can stabilize [Ca]i and protect neurons against excitotoxic injury and A beta toxicity. Age-related changes in the brain (eg, ischemic conditions, reduced glucose uptake, and increased glucocorticoid levels) may compromise the mechanisms that normally regulate [Ca2+]i adaptively.