Nicotinic Receptors in Subjects at Risk for Alzheimer's

Project Summary

The brain's nicotinic receptor is indeed the site where nicotine in cigarettes has its psychological effects. However, this receptor is also extremely important for many other things, including learning and memory. Many kinds of evidence suggest that nicotinic receptor levels are reduced early in the course of Alzheimer's disease and that these reductions are strongly related to the cognitive impairment that occurs in the disease. However, it remains unclear whether these nicotinic receptor deficits occur at a preclinical stage-before the individual actually has clear symptoms of the disease. It is conceivable that these receptor losses could serve as a clinical marker that would allow the early diagnosis of Alzheimer's disease and initiation of appropriate medication treatment-before irreversible brain damage and cognitive deterioration occurred.

The proposed research will test the hypotheses that people in middle age at high risk for developing Alzheimer's disease (by virtue of either having significant memory loss or of carrying the major genetic risk factor for Alzheimer' disease-2 copies of the ApoE4 gene) will already show evidence of nicotinic receptor losses in the brain similar to those that occur in people with Alzheimer's disease. This research will also examine whether the extent of nicotinic receptor losses is related to the extent of cognitive deterioration in these "at risk" individuals.

Four groups of subjects (twelve in each group) will be recruited for brain scanning: I) people with significant memory loss but without evidence of dementia ("Mild Cognitive Impairment"), 2) a comparison group of healthy older people without significant memory loss, 3) middle-aged people with a positive family history of Alzheimer's disease who also carry 2 copies of the ApoE4 gene, and 4) a comparison group of middle-aged people with a positive family history of Alzheimer's disease who do not carry the ApoE4 gene. All subjects will have two different brain scans: a SPECT scan to measure the nicotinic receptor levels in several areas of the brain, and an MRI scan to help in identifying the brain anatomy in the SPECT scan. Subjects will also have a battery of psychological tests in order to relate the extent of nicotinic receptor losses to the extent of cognitive deterioration in these "at risk" individuals.

If either group of individuals at risk for developing Alzheimer' disease is found to have lower levels of nicotinic receptors than their comparison group (i.e., the group at lower risk), then this study will provide the first evidence for a nicotinic abnormality in the pre-clinical "at risk" stages of Alzheimer's disease. This research could thus yield a clinical marker that would facilitate the early diagnosis of Alzheimer's disease. It would also provide a rational foundation for the early initiation of cholinergic and other pharmacotherapy, prior to irreversible neuronal loss and cognitive decline.