Chat, Ache, and Cholinergic Neurons in Aging and Alzheimer's
Our working hypothesis is that over 50 percent of typical late onset Alzheimer's disease (AD) is linked to genetic determinants that increase the concentration of amyloid beta protein (Abeta42) in a way that can be detected in plasma. Our data indicate that these determinants, which do note the coding region of the genes linked to early onset familial AD, cause plasma Abeta42 to be elevated in approximately 34 percent of first-degree AD relatives. We find that plasma A642 increases with aging in control subjects over the age of 65, that plasma Abeta42 is not elevated in most symptomatic patients with typical late onset AD, and that plasma Abeta decreases in the Tg2576 model of AD coincident with cerebral Abeta deposition. Thus we postulate that the typical profile of many AD patients is one in which plasma Abeta42 is elevated or high normal, increases further with aging, and then declines toward or into the normal range as Abeta deposition begins and the symptoms of AD develop. Since declining plasma Abeta appears to be linked to Abeta deposition in brain and Abeta42 is deposited in the brain of everyone who develops AD, plasma Abeta42 may decline in everyone who develops AD, even those whose plasma Abeta42 is in the normal range. This means that the simple, annual measurement of plasma Abeta42 may be an excellent way to identify many of those who are destined to develop AD, much as measurements of plasma lipoproteins and cholesterol identify those at risk for atherosclerotic heart disease. We plan to examine this possibility by following 500 first-degree AD relatives, 400 over age 65 and 100 between the ages of 45 and 65. Plasma Abeta and cognitive performance will be analyzed annually to determine (1) how plasma Abeta changes with aging in this cohort of AD relatives and (2) if elevated and/or declining plasma Abeta are important risk factors for typical late onset AD or memory decline.
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