Neuropathology of Aging

Alzheimer's disease (AD) is characterized by extensive, yet selective, neuron death in the cerebral neocortex leading to dramatic decline in cognitive abilities and memory. A more modest disruption of memory occurs frequently in normal aging, in humans and in animal models. Significant neuron death does not appear to be the cause of such age-related memory deficits, but in AD, hippocampal and long association corticocortical circuits are devastated. Evidence from rodent and nonhuman primate models reveals that these same circuits exhibit subtle age-related changes in neurochemical phenotype, dendritic and spine morphology, and synaptic integrity that correlate with impaired function. Molecular alterations of synapses, such as shifts in expression of excitatory receptors, also contribute to these deficits. These brain regions are also responsive to circulating estrogen levels. Interactions between reproductive senescence and brain aging may affect cortical synaptic transmission, implying that certain synaptic alterations in aging may be reversible. As such, integrity of spines and synapses may reflect age-related memory decline, whereas the loss of select cortical circuits is a crucial substrate for functional decline in AD.