Search

Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid beta-protein (Abeta). We demonstrate in vitro that LRP mediates the clearance of both Abeta40 and Abeta42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Abeta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Abeta, this work provides the first in vivo evidence that the LRP pathway may modulate Abeta deposition and AD susceptibility by regulating the removal of soluble Abeta.

We have prospectively followed over a 5-year period 434 volunteers who were at intake ambulatory, functional, presumably nondemented, and between 75 and 85 years of age. Fifty-six (an incidence of 3.53 per 100 person-years at risk) developed a progressive dementia: 32 met diagnostic criteria for Alzheimer's disease (AD) (an incidence of 2.0 per 100 person-years at risk), 15 had vascular or mixed dementia, and 9 had other disorders or remain undiagnosed. New cases of dementia were as common as myocardial infarction and twice as common as stroke. Risk factors for both dementia and AD were age (over 80) and gender (female); other reported risk factors such as family history, prior head injury, thyroid disease, maternal age, and smoking were not risk factors for AD in this elderly cohort. Prior stroke was the major risk factor for vascular or mixed dementia; diabetes and left ventricular hypertrophy but not a history of hypertension per se were also risk factors for vascular dementia. The major predictor of the development of AD was the mental status score on entry. The 58.5% of the cohort who made zero to two errors on a 33-item mental status test had a less than 0.6% per year chance of developing AD, whereas the 16% of the cohort with five to eight errors on this test developed AD at a rate of over 12% per year. Thus, it is possible to identify a large cohort of 80-year-olds who are at low risk for AD and a smaller cohort at very high risk.

The gathering of reliable data on dementia presents a difficult challenge to public health officials. Not only are there serious difficulties in diagnosis, but there are also problems in achieving a reliable and representative sample of patients for study. Some of these problems may be circumvented by choosing a sample of elderly individuals from the general community without evidence of dementia and then providing long-term follow-up. This eliminates some selection bias as new cases of dementia emerge from within a previously selected group. Such a study was performed on a cohort of 157 men and 285 women between 75 and 85 years of age. During the follow-up period of up to seven years, 75 cases of dementia emerged within the study group. At least 47 percent of the cases were attributed to Alzheimer's disease. Overall, the incidence of dementia in the study group was about 3.1 per 100 subjects per year, a rate which is comparable to other published studies of the elderly. This rate is greater than the incidence for heart attacks and stroke for this population. The study also found that women were three times more likely than men to suffer dementia, and that this disparity could not be accounted for by sampling error or sex differences for other risk factors in the study. A similar predisposition of women to dementia has been reported in other studies as well. However, another association was identified which has not been previously reported. Women with a history of heart attacks had over five times the likelihood of dementia. A similar trend was not observed among men. The physiological basis for this striking interaction between female sex and heart attacks in the development of dementia has not yet been identified. (Consumer Summary produced by Reliance Medical Information, Inc.)

Particular pathological features of cells seen under the microscope tend to be associated with particular clinical disorders. Therefore, when a pathologist examines brain tissue from a patient with Alzheimer's disease, he should expect to observe neurofibrillary tangles (tangles of nerve cells) and deposits of amyloid, which are the characteristic findings for that disease. Similarly, Lewy bodies might be anticipated from the brain a patient with Parkinson's disease. Lewy bodies are tiny structures which seem to be accumulating within the cell bodies of nerve cells. In patients with Parkinson's disease, they are most common in the substantia nigra and the locus ceruleus, two areas of the brain important in dopamine regulation. A careful examination of the brain tissues of 36 patients with Alzheimer's disease has revealed that Lewy bodies may be present in this disorder more commonly than has been previously suspected. Thirteen of the patients were found to have Lewy bodies in the cerebral cortex upon microscopic examination of tissue from that region. Twelve of these 13 patients also had Lewy bodies in the substantia nigra and at least one other structure beneath the cerebral cortex. Furthermore, a review of the case records of the patients with the Lewy bodies suggests that perhaps such patients may constitute a distinct type of Alzheimer's disease. The patients with the Lewy bodies were found to have greater deficits in attention, linguistic fluency, and the processing of visual and spatial information. While there was an increase in tremor, mild neck rigidity, and slow movement in the Lewy body patients, there were no symptoms which had the severe character associated with Parkinson's disease. Curiously, the brains of nine of the Lewy body patients also had signs of spongiform degeneration in the cortex; this degeneration gets its name from the hole-filled 'spongy' appearance of the tissue. It is suspected that Lewy bodies may be often overlooked in the brains of patients with Alzheimer's disease, since they are more difficult to recognize than other more readily observable features (such as senile plaques). The presence of Lewy bodies in the brains of patients with Alzheimer's disease may constitute a distinct subtype of this neurological disorder. (Consumer Summary produced by Reliance Medical Information, Inc.)

Although all patients with Alzheimer's disease (AD) experience an inexorable deterioration of mental capacities, this deterioration progresses at widely varying rates in different individuals. Recently, pathological examination was performed on the brain of a patient with an especially rapidly progressive case of Alzheimer's disease. The patient was a 65-year-old woman who was first examined after a six-month history of problems with short-term memory and becoming lost while driving. Curiously, it was found that the patient had lost her sense of smell two years previously, and it is tempting to speculate that this might have been the first indication that important brain centers were failing. Over the next three months, the patient deteriorated especially rapidly, and she could not remember a short list of items and did not know who was the US President. The patient was then transferred to a nursing facility, and she died within a month. Postmortem examination of the brain revealed the presence of neurofibrillary tangles and senile plaques, the neuropathological hallmarks of Alzheimer's disease. Other features were also observed, however, which might have contributed to the especially rapid downward course seen in this patient. Lewy bodies were observed in both the cerebral cortex and in brain structures beneath the cortex. Lewy bodies are tiny abnormal structures in the cytoplasm of nerve cells which are common in patients with Parkinson's disease in a part of the brain called the substantia nigra. Some authors believe that the observation of Lewy bodies in a patient with AD is merely an indication of coexisting Parkinson's disease, while others believe there is a variant of AD which has these structures. Also observed in the brain of this patient were areas of spongiform degeneration in a region called the entorhinal cortex and the amygdala. Such degeneration is typical of Creutzfeldt-Jakob disease, a disorder in which patients usually deteriorate more rapidly than those with AD. However, it was not possible to find any of the laboratory features which might indicate that the present patient actually had Creutzfeldt-Jakob disease. (Consumer Summary produced by Reliance Medical Information, Inc.)