Alzheimer's disease (AD) is a chronic progressive fatal disorder that accounts for 20 percent of the deaths after age seventy-five as well as most of the cases of 'senility' (dementia) in late life. During the past twelve years my colleagues and I at the UCSD Alzheimer Disease Research Center (ADRC) have sought to understand the nature and etiology of AD with the eventual goal of learning enough about the disorder to be able to prevent and treat it.
At the ADRC we follow a large cohort of AD patients, together with age matched non-demented volunteers, studying clinical, neuropsychological and genetic findings and the course of AD, and correlating these findings with changes observed in the brain obtained at autopsy.
One of the clinical puzzles in AD is that a subset of patients present with mild Parkinsonian findings. We have shown that these patients have the characteristic neuropathological features of AD (b-amyloid plaques and neurofibrillary tangles) and a pathological feature associated with Parkinson's disease (PD) - an intraneuronal inclusion (Lewy body) - but present primarily in cerebral cortex rather than in the subcortical neurons as usually found in PD, so that we consider this condition to be the Lewy body variant of Alzheimer's disease (LBV). We are now studying the many ways in which LBV patients differ from AD patients clinically and neuropsychologically so that we may be able to diagnose this condition reliably during life. This is important since there is evidence that LBV patients may respond differently to drugs developed to treat AD.
During the past several years, a number of genes have been identified, in which inheritance of specific forms predisposed to AD. We have found that our LBV patients often have both a gene that predisposes to AD (the apolipoprotein E 4 allele) and a gene that may predispose to PD (the CYP2D6B allele). NACP is a synaptic protein discovered and cloned by our late colleague, Tsunao Saitoh; it is also a component of the amyloid plaque in the AD brain. We are interested in the question of whether alterations in this protein may also predispose to AD. The goal is to identify and understand the mode of action of AD susceptibility genes, so that we will be able to develop strategies to block this action of these genes.
During normal aging, one loses synapses (the connections between nerve cells) in the cerebral cortex and perhaps also a limited number of large neurons. We have found that the presence of a larger reserve of neocortical synapses and neurons delays the clinincal onset of AD. An interesting extension of this work has been an epidemiological study carried out in Shanghai China in collaboration with the Shanghai Mental Health Centre. During the past decade we have followed over 5000 elderly in the Jing-An district of Shanghai. Over a quarter of this cohort did not have the opportunity to attend school when they were children. These non- educated individuals are at a much greater risk of developing AD and other dementing illnesses than those who attended school. We are now trying to determine if this finding is due to a reduction in brain reserve in those who did not have the stimulus of education as children or whether differences in life style resulting from their illiteracy is involved. In addition, we are involved in determining whether genes predisposing to AD in western populations also are important in this Chinese population.
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