Aging and Alzheimer disease lead to alterations in calcium homeostasis. The concentration of cytosolic free calcium in cultured skin fibroblasts during aging and Alzheimer disease was determined with the calcium-sensitive fluorescent dyes quin-2 and fura-2. The Alzheimer donors showed a decline of 70% when compared to age-matched controls (P less than 0.001) and 81% when compared to cells from young adult donors (P less than 0.001). This reduction in quin-2-calcium fluorescence does not appear to be due to quenching by heavy metals or alterations in intracellular pH. Similar decreases in free cytosolic calcium were observed with fura-2. In addition, cells from aged and Alzheimer donors spread more slowly than those from young donors, and this deficit can be partially reversed by treatment with the calcium ionophore A23187. These studies agree with accumulating evidence that, at the cellular level, Alzheimer disease is a systemic, as well as cerebral, disease. The precise molecular basis of the decreased cytosolic calcium in fibroblasts is unknown, but there is evidence that it may be pathophysiologically important.