The transition from age-associated memory impairment (AAMI) to the dramatic loss of cognitive abilities accompanying Alzheimer's disease (AD) requires progressive development of neocortical pathology that results in neuron death. The selective vulnerability of this neuron death is reflected in the characteristics of cortical pyramidal neurons that are prone to form neurofibrillary tangles. Loss of the neurons that form long corticocortical projections in the association neocortex emerges as the pathological outcome most directly related to the dementia observed in AD. AAMI likely involves alterations of neuronal spines and synapses without neuron death. Interestingly, the same circuits that are vulnerable to degeneration in AD are vulnerable to synaptic alterations short of neuron death. These synaptic alterations likely impact cognitive function in normal aging in a manner consistent with the more modest cognitive decline typically seen in aging. Estrogen levels affect spine density on pyramidal neurons in the prefrontal cortex; these neurons may provide many of the same circuits implicated in AAMI. This association demonstrates an important interface between reproductive and neural senescence and suggests that the synaptic alterations prevalent in normal aging may be responsive to therapy.