Biomedical subjects

J A Schneider

Publications and source records attributed to J A Schneider.

At least 19 recordsLinked to original sources

PubMed2006

Body mass index in older persons is associated with Alzheimer disease pathology.

OBJECTIVE: We examined the extent to which body mass index (BMI) in older persons is associated with common age-related neuropathologies known to contribute to dementia including Alzheimer disease (AD) pathology, cerebral infarction, and Lewy body disease. METHODS: We studied brain autopsies from 298 deceased Catholic clergy participating in the Religious Orders Study, a longitudinal clinical-pathologic investigation. BMI was assessed at annual clinical evaluations during an average follow-up of 4.9 years (SD = 2.7 years). Each person's average BMI, derived from all evaluations, was used in analyses. Multiple regression analyses were used to examine the relation of common postmortem neuropathologic findings to average BMI prior to death. RESULTS: Mean age at death was 85.7 years (SD = 6.8 years), and average BMI during the course of the study was 26.0 (SD = 5.1). A series of linear regression models was performed with average BMI as the outcome and controlling for age, sex, and education. Level of AD pathology was associated with BMI proximate to death (estimate = -1.15; SE = 0.42; p = 0.007). However, Lewy body pathology (estimate = -0.45; SE = 0.73; p = 0.53) and cerebral infarctions (estimate = -0.10; SE = 0.61; p = 0.88) were not associated with average BMI. The association of AD pathology with BMI was unchanged after controlling for dementia, chronic diseases, and physical activity. CONCLUSION: Body mass in old age is associated with Alzheimer disease pathology in persons with and without dementia.

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PubMed2006

Diabetes is related to cerebral infarction but not to AD pathology in older persons.

OBJECTIVE: To examine the potential relation of diabetes to common neuropathologic causes of dementia, cerebral infarction and Alzheimer disease (AD) neuropathology. METHODS: Subjects were 233 older Catholic clergy in the Religious Orders Study, who underwent detailed annual evaluations, including neuropsychological testing, and brain autopsy at time of death (mean age 86 years, 45% men). Diabetes was identified by annual direct medication inspection and history. Cognitive function proximate to death was summarized into five cognitive domains, based on 19 neuropsychological tests. Macroscopic cerebral infarctions were recorded from 1 cm coronal slabs. Neuritic plaques, diffuse plaques, and neurofibrillary tangles were counted in Bielschowsky silver-stained sections and summarized to yield composite measures of neuritic plaques, diffuse plaques, tangles, and overall AD pathology. We also used immunohistochemistry with antibodies to amyloid-beta and PHF-tau to obtain quantitative measures of amyloid burden and neurofibrillary tangle density. Multiple logistic and linear regression analyses were used to examine the relation of diabetes to cerebral infarctions and AD pathology, controlling for age, sex, and education. RESULTS: AD pathology was related to all five cognitive domains (p < 0.01) and infarctions were related to perceptual speed (p < 0.001). Diabetes (present in 15% subjects) was associated with an increased odds of infarction (OR = 2.47, 95% CI: 1.16, 5.24). Diabetes was not related to global AD pathology score, or to specific measures of neuritic plaques, diffuse plaques or tangles, or to amyloid burden or tangle density. CONCLUSION: We found a relation between diabetes and cerebral infarction but not between diabetes and Alzheimer disease pathology in older persons.

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PubMed2006

Memory complaints are related to Alzheimer disease pathology in older persons.

OBJECTIVE: To study the relationship between Alzheimer disease (AD) pathology and memory complaints proximate to death. METHODS: A group of 90 older persons underwent detailed clinical evaluations and brain autopsy at death. The evaluations included administration of questions on subjective memory complaints and clinical classification of dementia and AD. On postmortem examination, neuritic plaques, diffuse plaques, and neurofibrillary tangles in tissue samples from five cortical regions were counted, and a summary measure of overall AD pathology was derived. In addition, amyloid load and tau tangles were quantified in eight regions. RESULTS: In multiple linear regression models adjusted for age, sex, and education, memory complaints were associated with AD pathology, including both amyloid and tau tangles. Subsequent analyses demonstrated that the relationship between memory complaints and AD pathology was present in those with and without dementia, and could not be explained by the potentially confounding effects of depressive symptoms or coexisting common chronic health problems. CONCLUSION: Memory complaints in older persons may indicate self awareness of a degenerative process.

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PubMed2006

The relationship between cerebral Alzheimer's disease pathology and odour identification in old age.

BACKGROUND: Olfactory dysfunction is common in old age, but its basis is uncertain. OBJECTIVE: To test the hypothesis that difficulty in identifying odours in old age is related to the accumulation of Alzheimer's disease pathology. METHODS: As part of the Rush Memory and Aging Project, participants completed the 12-item Brief Smell Identification Test, a standard measure of odour identification. During a mean (standard deviation (SD)) of 2.2 (1.2) years of follow-up (range 0.2-4.9), 166 people died, with brain autopsies performed on 129 (77.7%) people and neuropathological examinations completed on 77 (mean (SD) age at death 87.5 (5.9) years; median postmortem interval 6.1 h). From a uniform postmortem examination of multiple brain regions, summary measures of plaque and tangle pathology were derived on the basis of silver staining, and those of amyloid beta burden, tangle density and Lewy bodies on the basis of immunohistochemistry. RESULTS: Odour identification performance ranged from 0 to 12 correct (mean (SD) 8.0 (2.6)). In analyses adjusted for age, sex and education, a composite measure of plaques and tangles accounted for >12% of the variation in odour identification. The association remained after controlling for dementia or semantic memory. Density of tau tangles was inversely related to odour identification. A similar effect for amyloid burden was attenuated after controlling for tangles. The association with odour identification was robust for tangles in the entorhinal cortex and CA1/subiculum area of the hippocampus, but not for tangles in other cortical sites. Lewy bodies, identified in 12.5%, were not related to odour identification, probably partly due to to their relative infrequency. CONCLUSION: The results suggest that difficulty in identifying familiar odours in old age is partly due to the accumulation of neurofibrillar pathology in central olfactory regions.

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PubMed2006

Neuropathology of older persons without cognitive impairment from two community-based studies.

OBJECTIVE: To examine the relation of National Institute on Aging-Reagan (NIA-Reagan) neuropathologic criteria of Alzheimer disease (AD) to level of cognitive function in persons without dementia or mild cognitive impairment (MCI). METHODS: More than 2,000 persons without dementia participating in the Religious Orders Study or the Memory and Aging Project agreed to annual detailed clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. A total of 134 persons without cognitive impairment died and underwent brain autopsy and postmortem assessment for AD pathology using NIA-Reagan neuropathologic criteria for AD, cerebral infarctions, and Lewy bodies. Linear regression was used to examine the relation of AD pathology to level of cognitive function proximate to death. RESULTS: Two (1.5%) persons met NIA-Reagan criteria for high likelihood AD, and 48 (35.8%) met criteria for intermediate likelihood; 29 (21.6%) had cerebral infarctions, and 18 (13.4%) had Lewy bodies. The mean Mini-Mental State Examination score proximate to death was 28.2 for those meeting high or intermediate likelihood AD by NIA-Reagan criteria and 28.4 for those not meeting criteria. In linear regression models adjusted for age, sex, and education, persons meeting criteria for intermediate or high likelihood AD scored about a quarter standard unit lower on tests of episodic memory (p = 0.01). There were no significant differences in any other cognitive domain. CONCLUSIONS: Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory.

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PubMed2005

Education modifies the association of amyloid but not tangles with cognitive function.

The authors quantified amyloid and tau tangles in Religious Orders Study participants. In separate analyses, amyloid and tangles were related to level of cognition. When terms for education's interaction with amyloid and tangles were added, education dampened the association of amyloid with level of cognition (p = 0.02) but not the association of neurofibrillary tangles with level of cognition, suggesting that education is related to factors that reduce the effect of amyloid on cognition.

Activities of Daily Living↗

PubMed2005

The apolipoprotein E epsilon4 allele increases the odds of chronic cerebral infarction [corrected] detected at autopsy in older persons.

BACKGROUND AND PURPOSE: Studies investigating the relation of the apolipoprotein E (apoE) epsilon4 allele to clinical stroke and to vascular changes on magnetic resonance imaging have been conflicting. Little data are available regarding the relation of apoE epsilon4 to cerebral infarctions documented on postmortem examination. METHODS: We studied the apoE epsilon4 allele in 214 deceased members of the Religious Orders Study, a longitudinal clinical-pathologic study of aging and Alzheimer disease. The apoE genotype was determined using DNA from lymphocytes. Brains were removed a median of 5 hours (interquartile range, 5.5) after death. At postmortem examination, age, location, and size of macroscopic chronic cerebral infarctions were recorded from 1-cm coronal slabs after paraformaldehyde fixation. We also examined 20-microm paraffin-embedded sections of midfrontal and calcarine cortex for amyloid angiopathy on a scale of 1 to 4. RESULTS: Subjects included 96 males and 118 females with a mean age at death of 86 years (SD, 7). Sixty-five subjects (30.4%) had at least 1 apoE epsilon4 allele and 76 (35.5%) exhibited cerebral infarctions. More than 74% of the subjects exhibited amyloid angiopathy with a mean score of 1.4+/-1.2. After controlling for age and sex, apoE epsilon4 increased the odds of cerebral infarction by 2.3-fold (95% CI, 1.2 to 4.2). apoE epsilon4 increased the odds of cortical 3.2-fold (95% CI, 1.3 to 7.7) and subcortical infarctions 2.3-fold (95% CI, 1.2 to 4.5). The effect was unchanged after accounting for amyloid angiopathy. CONCLUSIONS: apoE epsilon4 increases the odds of chronic cerebral infarction detected at autopsy in older persons.

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PubMed2005

Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions.

OBJECTIVES: To examine the extent to which persons with mild cognitive impairment have intermediate levels of Alzheimer disease (AD) pathology, cerebral infarcts, and Lewy body disease. METHODS: A total of 180 Catholic clergy participating in the Religious Orders Study underwent annual detailed evaluation and brain autopsy. Blocks of midfrontal, superior temporal, medial temporal lobe, inferior parietal, entorhinal cortex, hippocampus, and substantia nigra were paraffin embedded, and sectioned at 6 mum. Cortical neuritic plaques, diffuse plaques, and neurofibrillary tangles were visualized with Bielschowsky silver stain, and counted and summarized to yield a Braak stage, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) diagnosis, National Institute on Aging (NIA)-Reagan diagnosis, and composite measure of AD pathology. The authors recorded the number and location of all gross chronic cerebral infarctions. Lewy bodies were identified with antibodies to alpha-synuclein. Multiple regression analyses were used to examine the relation of AD pathology and cerebral infarctions to clinical diagnosis proximate to death, controlling for age, sex, and education. RESULTS: A total of 37 had mild cognitive impairment, 60 did not have cognitive impairment, and 83 had dementia proximate to death. Nearly all persons had at least some AD pathology. Cerebral infarctions were present in 35.2%, and 15.6% had Lewy body disease. Persons with mild cognitive impairment were intermediate in terms of Braak stage and CERAD and NIA-Reagan neuropathologic criteria for AD compared to the other two groups. In multiple regression analyses, persons with mild cognitive impairment had intermediate levels of AD pathology from those without cognitive impairment and those with dementia (test for trend, F = 45.2, p < 0.001). Further, the relation between cognition and AD pathology in persons with mild cognitive impairment did not differ significantly from the relation between cognition and AD pathology in persons with dementia or those without cognitive impairment. Persons with mild cognitive impairment also had intermediate levels of cerebral infarctions (test for trend, p = 0.04). Only 3 (8.1%) persons with mild cognitive impairment had Lewy body disease. CONCLUSION: These data suggest that mild cognitive impairment may be the earliest clinical manifestation of common age-related neurologic diseases.

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PubMed2005

Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people.

BACKGROUND: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. OBJECTIVE: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. METHODS: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. RESULTS: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. CONCLUSION: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.

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PubMed2004

Diabetes mellitus and progression of rigidity and gait disturbance in older persons.

BACKGROUND: Parkinsonian-like signs, including rigidity, gait disturbance, and bradykinesia, are common and progressive in old age and are associated with morbidity and mortality. Few risk factors for these signs have been identified. Diabetes mellitus, also a common chronic condition in old age and known to be associated with physical and neurologic disability, may be associated with parkinsonian-like signs. OBJECTIVE: To examine the relation of diabetes to four parkinsonian-like signs. METHODS: Participants were 822 older Catholic clergymen and women who were without clinically diagnosed Parkinson disease or dementia at baseline. For up to 9 years, they had uniform annual evaluations, which included a modified version of the motor portion of the Unified Parkinson's Disease Rating Scale, from which previously established measures of four specific parkinsonian-like signs were derived. Participants were evaluated for the presence of diabetes, based on direct medication inspection and history. RESULTS: Diabetes was present in 128 (15.6%) participants. In random effects models controlling for age, sex, and education, diabetes was associated with worsening rigidity (p < 0.01) and gait (p < 0.05), over an average of 5.6 years of follow-up, but not with change in bradykinesia or tremor. The presence of stroke did not substantially affect the association of diabetes with rigidity but reduced the association of diabetes with gait to a trend (p = 0.08). CONCLUSION: Diabetes may be a previously unrecognized risk factor for progression of parkinsonian-like signs in older persons.

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PubMed2004

Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology.

BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia. The effect of cerebral infarctions on the likelihood of dementia from AD pathology is not well understood. METHODS: The study included 153 deceased Catholic clergy who participated in the Religious Orders Study. Annual evaluations, including 19 tests of cognitive function, were performed to determine a diagnosis of dementia and level of cognitive abilities proximate to death. At autopsy, neuritic and diffuse plaques and neurofibrillary tangles were counted and combined into a standardized summary measure of AD pathology. Number, volume, side, and distribution of old macroscopic infarctions were recorded. Analyses included logistic and linear regression, adjusting for age, sex, and education. RESULTS: The AD pathology score ranged from 0 to 2.93 units, and 54 persons had infarctions. There was no relationship between AD pathology and infarctions (r = 0.04, p = 0.56). Each unit of AD pathology increased the odds of dementia by 4.40-fold (95% CI = 2.33 to 8.32), and this was essentially unchanged after accounting for infarctions. The presence of one or more infarctions independently increased the odds of dementia by 2.80-fold (95% CI = 1.26 to 6.21). There was no interaction between AD pathology and infarctions to further increase the likelihood of dementia (p = 0.39). The number, size, and distribution of infarctions added to the odds of dementia but also did not show an interaction with AD pathology. Similar results were found in analyses with global cognitive function and five different cognitive systems. CONCLUSION: Cerebral infarctions independently contribute to the likelihood of dementia but do not interact with AD pathology to increase the likelihood of dementia beyond their additive effect.

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PubMed2003

Proneness to psychological distress is associated with risk of Alzheimer's disease.

BACKGROUND: Chronic stress is associated with hippocampal damage and impaired memory in animals and humans. OBJECTIVE: To examine this relationship with clinical and pathologic data from the Religious Orders Study. METHODS: Older Catholic clergy members underwent annual clinical evaluations, which included clinical classification of Alzheimer's disease (AD) and detailed cognitive function testing from which composite measures of global cognition and specific cognitive functions were derived. At the baseline evaluation, participants completed a measure of the tendency to experience psychological distress, a stable personality trait that served as an indicator of susceptibility to negative emotional states across the life span. More than 90% of participants who died underwent a uniform postmortem examination of the brain from which summary measures of AD pathology were derived. The association of distress proneness with incident AD and cognitive decline and with measures of AD pathology was examined in analyses adjusted for selected demographic and clinical variables. RESULTS: During a mean of 4.9 years of follow-up, 140 persons developed AD. Those high in distress proneness (90th percentile) had twice the risk of developing AD than those low in distress proneness (10th percentile). Distress proneness was related to decline in episodic memory but not in other cognitive domains, with a >10-fold increase in episodic memory decline in those high in distress proneness compared with those low in the trait. Among those who died, however, distress proneness was not related to common measures of AD pathology. CONCLUSION: Proneness to experience psychological distress is a risk factor for AD, an effect independent of AD pathologic markers such as cortical plaques and tangles.

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PubMed2003

Depressive symptoms, clinical AD, and cortical plaques and tangles in older persons.

BACKGROUND: Depressive symptoms in old age have been associated with risk of Alzheimer disease (AD), but it is uncertain whether they are an independent risk factor for disease or an early clinical sign of its underlying pathology. METHODS: A group of 130 older Catholic nuns, priests, and brothers underwent detailed annual clinical evaluations and brain autopsy at death. The evaluations included administration of a modified 10-item Center for Epidemiologic Studies Depression Scale (CES-D) and 19 cognitive performance tests and clinical classification of dementia and AD. On postmortem examination, neuritic plaques, diffuse plaques, and neurofibrillary tangles in tissue samples from four cortical regions were counted, and a previously established composite measure of cortical plaque and tangle density (range 0 to 2.98) was derived. All analyses were adjusted for age, sex, and education. RESULTS: Participants reported a mean 1.5 depressive symptoms (SD 1.6) on the CES-D scale averaged across evaluations. In a logistic regression model, the odds of clinically diagnosed AD proximate to death increased by 1.33 (95% CI 1.01 to 1.76) for each depressive symptom and by 8.41 (95% CI 3.49 to 20.26) for each unit on the composite measure of pathology. In subsequent analyses, depressive symptoms were not related to level of pathology and did not modify the relation of pathology to clinical AD. In a series of linear regression models that controlled for pathology, depressive symptoms were related to level of cognitive function proximate to death and did not modify the association of pathology with cognition. CONCLUSION: The association of depressive symptoms with clinical AD and cognitive impairment appears to be independent of cortical plaques and tangles.

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PubMed2003

Education modifies the relation of AD pathology to level of cognitive function in older persons.

OBJECTIVE: To test the hypothesis that years of formal education modifies the relation of AD pathology to level of cognitive function. METHODS: A total of 130 older Catholic clergy participating in the Religious Orders Study underwent annual cognitive function testing and brain autopsy at the time of death. Individual cognitive function tests were z-scored and averaged to yield a global measure of cognitive function and summary measures of five different cognitive abilities. Neuritic and diffuse plaques and neurofibrillary tangles were counted in separate 1 mm(2) areas of maximal density. Counts were converted to standard scores by dividing by their SD, and combined to yield a global AD pathology score and summary scores of each postmortem index. Linear regression was used to examine the relation of education and AD pathology scores to level of cognitive function proximate to death, controlling for age and sex. Subsequent analyses tested the interaction between education and each AD pathology score to determine whether education modified the relation of AD pathology to level of cognitive function. Additional analyses examined these associations on five specific cognitive abilities. RESULTS: Both years of formal education (regression coefficient = 0.073, p = 0.0001) and the global AD pathology score (regression coefficient = -0.689, p < 0.0001) were related to level of cognitive function. When an interaction term between education and AD pathology was added to the model, the association between a unit of AD pathology and level of cognitive function was 0.088 (p = 0.0078) standard unit less for each year of education than the level predicted from the model without the interaction term. Whereas neuritic plaques, diffuse plaques, and neurofibrillary tangles were all strongly related to cognitive function, education only modified the relation of neuritic plaques (p = 0.002) and diffuse plaques (p = 0.03) to cognition, but not neurofibrillary tangles. In analyses examining five different cognitive abilities, the interaction between education and the neuritic plaque score was strongest for perceptual speed and weakest for episodic memory. CONCLUSIONS: These data provide strong evidence that the relation between senile plaques and level of cognitive function differs by years of formal education.

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PubMed2003

Gender, cognitive decline, and risk of AD in older persons.

BACKGROUND: Cross-sectional studies suggest gender differences in cognitive function and risk of AD in older persons. However, longitudinal studies comparing change in cognitive function and risk of AD in men and women have had mixed results. The authors investigated gender differences in rate of decline for different cognitive systems and for risk of developing AD. METHODS: Participants were from the Religious Orders Study, a longitudinal, clinical-pathologic study of aging and AD in older Catholic nuns, priests, and brothers. Longitudinal data were available from 577 older women and 271 older men, who completed an average of 5.8 annual evaluations with more than 95% follow-up participation in survivors. The evaluations included 21 neuropsychological tests, from which summary measures of global cognitive function and 5 functional domains were formed, and clinical classification of AD. RESULTS: Random effects models were used to analyze change in cognitive function, and proportional hazards models were used to assess risk of incident AD. On average, men and women declined in all abilities during the 8-year period but did not differ in annual rates of change in analyses that controlled for age, education, and initial level of cognitive function. Risk of incident AD did not differ between men and women. Furthermore, results were unchanged after controlling for possession of the apolipoprotein-epsilon4 allele. Duration of estrogen use was related to rate of global cognitive decline and visuospatial abilities in women but did not influence comparisons between men and women in cognitive decline. CONCLUSIONS: The results suggest that patterns of cognitive decline and incidence of AD are similar in older men and women.

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PubMed2003

Relation of cerebral infarctions to dementia and cognitive function in older persons.

BACKGROUND: Cerebral infarctions are common in older persons but their relationship with dementia and cognitive function remains controversial. METHODS: Participants were 164 older Catholic nuns, priests, and brothers who underwent annual clinical evaluation and brain autopsy at death. The authors quantified number and volume of old cerebral infarctions on postmortem examination and determined the association with dementia and cognitive function proximate to death. Analyses controlled for age, sex, and education. RESULTS: A total of 58 (35.4%) subjects had cerebral infarctions: 29 had one infarction and 29 had multiple infarctions. In logistic regression analyses, infarctions increased the odds of dementia twofold (OR 2.12; 95% CI 1.06 to 4.25). The odds of dementia increased by 2.67-fold for multiple infarctions (95% CI 1.08 to 6.61), whereas the odds of dementia with single infarctions increased by 69% (95% CI 0.70 to 4.09). In linear regression analyses, there was a trend for multiple infarctions to be associated with lower global cognitive scores (-0.44 standard units, p = 0.057). Multiple infarctions were related to perceptual speed, visuospatial skills, and working memory, but not to episodic or semantic memory. The authors found similar results with infarction volume. In secondary analyses, only infarctions that were clinically evident during life were associated with dementia and cognitive function. CONCLUSION: Cerebral infarctions are associated with a twofold increase in odds of dementia. Odds are higher in persons with multiple, large, or clinically evident infarctions. In addition, cerebral infarctions do not affect all cognitive systems equally, showing the strongest association with perceptual speed and the weakest with episodic memory.

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PubMed2003

Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer's disease.

OBJECTIVE: To test the hypothesis that the APOE epsilon4 allele is associated with the clinical manifestations of AD through an association with the pathologic hallmarks of disease. METHODS: Participants were older Catholic nuns, priests, and brothers who agreed to annual neurologic and neuropsychological evaluation for AD and other common neurologic conditions and brain autopsy at the time of death. There were 77 persons without dementia and 51 with probable AD; 38 participants had one or more epsilon4 alleles. RESULTS: In logistic regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with the likelihood of clinical AD (odds = 3.46, 95% CI = 1.44 to 8.33). However, controlling for the effect of AD pathology, the association of the epsilon allele with clinical AD was reduced by >50% and was no longer significant (odds = 1.58, 95% CI = 0.56 to 4.43). Similarly, in linear regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with level of cognitive function proximate to death (regression coefficient = -0.477, p = 0.005). However, after controlling for the effect of AD pathology, the association of the epsilon4 allele with level of cognition was reduced by >80% and was no longer significant (regression coefficient = -0.093). Similar results were found in analyses using separate measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles, and in analyses of five different cognitive systems (episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability). CONCLUSIONS: The APOE epsilon4 allele appears to be associated with the clinical manifestations of AD through an association with the pathologic hallmarks of AD rather than another mechanism.

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PubMed2003

A multicentre randomised double masked clinical trial of a new formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis.

AIM: To evaluate the safety and efficacy of a new topical cysteamine formulation, stable at room temperature, for the treatment of corneal cystine crystals in cystinosis. METHODS: 20 study subjects were enrolled in the safety study and 16 in the efficacy study. Both studies were randomised and double blind. The primary outcome for the safety study was the occurrence of predefined serious adverse reactions over 6 months and for the efficacy study the reduction of corneal cystine crystal score (CCCS) by 1.00 or more units on photographs graded by a reading centre using a standardised protocol. RESULTS: No study subject developed any serious adverse reactions. In the efficacy study, 47% of eyes receiving the standard formulation experienced a reduction in the CCCS of >/=1.00 after 1 year, while 7% of eyes on the new formulation experienced such a decrease (p=0.04). CONCLUSION: Although no serious adverse reactions were observed with either formulation, the new formulation was not as effective as the standard formulation.

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