The aim of the proposed study is to gain more information about functional and anatomical changes very early in the course of Alzheimer's Disease (AD). One of the obstacles to such studies is the difficulty of identifying individuals with very early AD before their impairments become clinically significant. The approach taken here is to recruit a group of nondemented subjects considered to be at risk for developing AD by virtue of age and a positive history of AD in one or more first-degree relatives. Sixty family history negative (FH-) and 40 matched family history positive (FH+) subjects with normal scores on dementia rating scales will be followed in the ADRC with the core neuropsychological battery; and will be examined annually with a high-resolution MRI protocol. Morphometric analysis will be employed to estimate the volumes of mesial temporal lobe (MTL) structures, temporal neocortex, and prefrontal neocortex. Since parenchymal volume loss is often accompanied by increased volume of adjacent CSF spaces, it is possible that peri- hippocampal fluid volume will be a more sensitive index of MTL loss than will the volume of the remaining tissue. Therefore, the volume of the fissures and sulci surrounding the mesial temporal lobe structures will also be measured. The model guiding the study design can be summarized as follows: In the earliest years after the onset of the disease, AD is characterized by rapid degeneration in mesial temporal lobe structures, with more gradual degeneration in neocortical association areas. During this stage of the illness, memory impairment is relatively isolated and manifests primarily in a decreasing ability to discriminate recently studied from unstudied items, and in an increasing propensity to make intrusion errors in free recall. In the later stages of the illness, the onset of clinically significant dementia coincides with an increasing rate of degeneration in neocortical association areas. Based on this model, the following primary hypotheses are advanced: 1. Nondemented subjects with a positive family history for AD will show loss in mesial temporal lobe structures, over five years, relative to matched subjects without a family history for AD. 2. Furthermore, the loss over time in the MTL of FH+ subjects will be significantly greater than losses in neocortical regions. 3. MTL losses over the study period will be specifically related to worsening performance on sensitive measures of memory function.
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