P-153

Posters: P-152 strating stress-induced amelioration of estradiol effects on cognition. Objective: To evaluate whether estradiol-induced effects on cognitive function will be disturbed when cortisol levels are exogenously elevated in older postmenopausal women, and the effects of this manipulation on blood levels of beta-amyloid (A␤40 & A␤42) and insulin-like growth factors (IGFs). Methods: Forty subjects (56-84 yrs) were enrolled into a placebo-controlled, double blind, parallel-group design study and randomized to receive 0.10 mg/day of transdermal ␤-estradiol or a placebo skin patch for 8 weeks. In the last 4 days of the trial, subjects were also randomized to receive 90 mg/day (30 mg TID) of oral hydrocortisone or matched placebo. Cognitive test scores and blood levels of estradiol, cortisol, insulin-like growth factors, and beta-amyloid (A␤40 A␤42) were quantified at baseline, and at weeks 4 and 8. Results: Estradiol and cortisol levels attained confirmed compliance. Relative to baseline, performance on the Stroop improved when estradiol was administered alone, and worsened when cortisol was administered alone. Co-administration obliterated each of these effects. For tasks of working memory and visual memory, estradiol alone benefited performance while co-administration of estradiol and cortisol had a deleterious effect. Verbal declarative memory improved with estradiol, regardless of whether cortisol was also administered. Cortisol increased plasma levels of IGF-I and A␤42, but only when administered without estradiol. For A␤40, estradiol administered alone increased levels, cortisol administered alone decreased levels and again, the combined regimen altered each of these effects. Conclusions: This is the first clinical study to document that elevated cortisol levels do in fact modulate biological and cognitive response to estradiol. The cognitive findings, with associated changes in beta-amyloid levels, begin to unmask an influential factor that might very well detract from a salutary response to estradiol for older postmenopausal women, and thereby account for inconsistent findings in estradiol intervention trials. P-152

HUMAN BRAIN MYELINATION AND AMYLOID BETA DEPOSITION IN ALZHEIMER’S DISEASE

George Bartzokis, Po H. Lu, Jim Mintz, UCLA, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: The extensive scope of myelination is the single-most unique aspect in which the human brain differs from that of other species. In this “myelin model” of human evolution and development, our brain’s extensive myelination accounts for the high processing speeds underlying our higher cognitive and behavioral functions as well as our unique susceptibility to develop Alzheimer’s Disease (AD). In older age the breakdown of myelin integrity likely underlies both the trajectory of age-related decline in cognitive functions as well as the “age risk factor” for the increasing protein deposits that have been used to define the pathology of AD. Objective: To test the hypothesis that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte- and myelin-associated iron thus promoting amyloid beta (A␤) oligomerization, its associated toxicity, and the deposition of oligomerized A␤ and iron in neuritic plaques observed in AD. Methods and Results: The model was tested using published maps of cortical myelination from year 1901 and recent in vivo imaging maps of A␤ deposits in humans. The data show that in AD, radio labeled ligands detect A␤ deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the failure of imaging ligands to bind A␤ in animal models is consistent with their much lower levels of myelin and associated iron levels when compared to humans. Conclusions: The hypotheses derived from the myelin model of the human brain are testable with current imaging methods that can measure myelin integrity, brain iron levels, and protein deposits in vivo. The myelin model of the human brain has important implications for preventive and therapeutic interventions and suggests that such interventions should be expanded to include novel targets such as oligodendrocytes, myelin, and brain iron.

P-153

S147 ANTIOXIDANT SUPPLEMENT USE AND RISK OF DEMENTIA AND ALZHEIMER’S DISEASE IN OLDER ADULTS

John C. S. Breitner1,2, Shelly L. Gray3, Melissa L. Anderson4, Paul K. Crane5, Wayne McCormick5, James Bowen6, Linda Teri7, Eric B. Larson4, 1GRECC (S-182) VA Puget Sound Health Care System, Seattle, WA, USA; 2Dept of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; 3University of Washington, Seattle, WA, USA; 4Center for Health Studies, Group Health Cooperative, Seattle, WA, USA; 5Dept of Medicine, University of Washington, Seattle, WA, USA; 6Dept of Neurology, University of Washington, Seattle, WA, USA; 7Dept of Psychosocial & Community Health, University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Oxidative pathways may have an important role in the etiology of Alzheimer’s disease (AD) and vascular dementia. Studies of dietary or supplemental antioxidant vitamins as potential interventions for prevention of dementia have produced conflicting results. Objective(s): To examine whether use of vitamins C or E, alone or in combination, is associated with reduced incidence of dementia and AD in a community-based prospective cohort study. Methods: 2969 members of the Group Health Cooperative, Seattle, Washington, aged 65 or older, were recruited as participants in the Adult Changes in Thought study. Participants were without evidence of cognitive impairment at enrollment. They were then examined biennially to identify incident dementia and Alzheimer’s disease diagnosed by standard criteria. At each examination participants were asked whether they had taken vitamins C, E, or multivitamins (MVI) for at least one week during the preceding month (“users”). Results: During a mean follow-up of 6.4 (SD 2.3) years, 405 participants developed dementia (289 attributed to Alzheimer’s disease). Use of vitamin E was not associated with dementia (adjusted hazard ratio [aHR] 0.98, 95% confidence interval [CI] 0.77-1.25) or AD (aHR 1.04, CI 0.78-1.39). Comparable results were noted for vitamin C alone (dementia aHR 0.90, CI 0.71-1.13; AD aHR 0.95, CI 0.72-1.25) and for concurrent use of vitamins C and E (dementia aHR 0.93, CI 0.72-1.20; AD aHR 1.00, CI 0.73-1.35) or E with MVI (dementia aHR 1.01, CI 0.57-1.81; AD aHR 1.03, CI 0.44-2.39). Similar results were found when we excluded participants with low screening scores at baseline (who might therefore have begun using vitamins to slow progression of prodromal symptoms). Conclusions: These data provide no evidence that use of supplemental vitamins E or C, either alone or in combination, is associated with reduced risk of dementia or AD over 6 years of follow-up. The contrast of these results with others may reflect different population nutritional intake, or dosage of supplements, or methods of exposure classification. P-154

DEPRESSION AS A RISK FACTOR FOR DEMENTIA

Jessica A. Brommelhoff1, Margaret Gatz1,2, Nancy L. Pedersen2,1, 1 University of Southern California, Los Angeles, CA, USA; 2Karolinska Institutet, Stockholm, Sweden. Contact e-mail: [email protected] Background: Studies have shown that depression and dementia frequently coexist, but whether depression is a risk factor or prodrome of dementia remains controversial. Objective: This study tested whether history of depression was associated with significantly increased risk of developing dementia, and whether those with a greater time difference between the age of onset of depressive episodes and onset of dementia were at greater risk for developing dementia compared with those who had a first depressive episode occurring closer in time to dementia onset. Methods: Dementia was clinically diagnosed by an assessment team using DSM-IV criteria, with age of onset estimated by using both informant reporting and medical records. Depression information, including occurrence and age of onset, was collected from four sources: 1) a national inpatient discharge registry, 2) a national psychiatric hospital discharge registry, 3) medical history for cases and co-twin controls, as reported by an informant, and 4) medical records for cases and co-twin controls. This study used two designs_case-control and co-twin control. In the case-control design, twins diagnosed with dementia were compared