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tent with epidemiological studies indicating that TC is a risk factor for AD. These results suggest that factors associated with lipid metabolism may be important in the development of AD even at very old ages. These findings are consistent with our recent observations of an association between AD-neuropathological lesions density and coronary artery disease. Supported by NIA grant PO-AG02219 (VH), Dextra Baldwin McGonagle Foundation, Joseph and Norma Saul Foundation (GTL and LSL), and NIA grant K01 AG023515 (MSB). P1-205

FOLATE LEVELS AND COGNITIVE PERFORMANCE. THE ROTTERDAM SCAN STUDY.

Lonneke M. de Lau1, Helga Refsum2,3, A. David Smith2, Carole Johnston2, Monique M. Breteler1, 1Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands; 2Oxford Centre for Gene Function, Oxford, United Kingdom; 3Institute of Basic Biomedical Sciences, University of Oslo, Oslo, Norway. Contact e-mail: [email protected] Background: Elevated homocysteine concentrations are associated with cerebral small vessel disease, hippocampal atrophy, worse cognitive performance and an increased risk of dementia. It is unclear whether these associations are due to effects of homocysteine itself, or rather to other factors involved in homocysteine metabolism, such as folate. Recent evidence suggests that folate may have beneficial effects on cognition, independent from its effects on homocysteine levels. Objective(s): To examine the independent association of plasma folate levels with cognitive performance, and to evaluate to what extent this effect is through vascular mechanisms. Methods: In the population-based Rotterdam Scan Study, 1,033 non-demented participants aged 60-90 years underwent extensive cognitive testing and brain imaging. We constructed compound scores for psychomotor speed, memory function, and global cognitive function and scored white matter lesions and hippocampal atrophy on brain MRI scans. We evaluated the relation between folate levels and cognitive performance by means of multivariate linear regression, with plasma folate as a continuous variable (expressed per standard deviation increase) and in quintiles. To examine the role of vascular mechanisms, we also evaluated the association between folate levels and white matter lesions and hippocampal atrophy. Results: Increasing folate levels were associated with higher scores for psychomotor speed and global cognitive function (adjusted difference in test score per standard deviation increase in folate for psychomotor speed 0.07 (95% confidence interval (CI), 0.02-0.12), for global cognitive function 0.04 (95% CI, 0.00-0.08)), but not with memory function. Analyses in quintiles suggested a linear relationship. Higher folate levels were associated with a lower prevalence of severe white matter lesions (adjusted Odds Ratio per standard deviation increase 0.82 (95% CI, 0.69-0.98)). Adjustment for homocysteine levels only slightly diminished these associations. No relation was seen between folate levels and hippocampal atrophy. Conclusions: Higher plasma concentrations of folate are associated with better cognitive performance, in particular psychomotor speed, regardless of homocysteine level. A significant inverse association between folate levels and presence of severe white matter lesions was found, while no association was observed for hippocampal atrophy. These findings suggest that the effect of folate on cognition is mediated through vascular mechanisms. P1-206

THE SEARCH FOR A SUCCESSFUL COGNITIVE AGING ENDOPHENOTYPE IN THE OFFSPRING OF VERY ELDERLY (90ⴙ) NONDEMENTED PROBANDS IN A FOUNDER POPULATION

Steven D. Edland1, Michal Schnaider-Beeri2, Henriette Raventos3, Daniel Valerio Aguilar3, Luis Emilio Corrales Campos3,

Mariana Pereira Castro3, Gary W. Angelo2, Hillel T. Grossman2, Irina N. Bespalova2, Mary Sano2, Jeremy M. Silverman2, 1University of California at San Diego, San Diego, CA, USA; 2Mount Sinai School of Medicine, New York, NY, USA; 3University of Costa Rica, San Jose, Costa Rica. Contact e-mail: [email protected] Background: Ascertaining families with demonstrable successful cognitive aging might help reveal rare genes associated with good cognitive functioning into very late old age. Given the genetic complexity of this desirable condition, however, validated cognitive endophenotypes (i.e., traits lying midstream between a gene and a genetically complex condition of interest) will be required for open ended gene finding strategies. Delayed recall in particular is a promising candidate endophenotype because it has shown strong heritability in AD proband families and delayed recall impairment has predicted the development of AD. Objective(s): To identify cognitive endophenotypes for successful cognitive aging in a founder population. Methods: Delayed recall, along with other tests of cognitive functions, were assessed in 27 very elderly (age 90⫹) nondemented (VEND) probands and 47 of their aged 60⫹ offspring. The families were ascertained from the Central Valley of Costa Rica (CVCR), a founder population. Two sets of CVCR comparison groups were also assessed: 1) Very elderly (aged 90⫹) demented (VED) probands (n⫽13) and their age 60⫹ offspring (n⫽28); 2) Young (aged 60-70) nondemented elderly (YND; n⫽15) and their age 60⫹ siblings (n⫽17). Results: VEND offspring, VED offspring, and YND sibling groups did not significantly differ with respect to age, sex, or years of education. Using a random effects model controlling for sex and education, delayed recall was significantly better among VEND offspring than YND siblings(P⬍0.005) and VED offspring (P⬍0.05). In addition, there were significant group by education interactions such that fewer years of education was associated with lower delayed recall scores in the YND siblings (P⬍0.005) and VED offspring (P⬍0.05), but education had no effect on VEND offspring. Similar albeit nonsignificant relationships were observed with age. Conclusions: The VEND offspring had higher levels of delayed recall than the VED offspring and YND siblings. In addition, whereas low education was associated with poorer performance in delayed recall in two comparison groups, no such association was present in VEND offspring. These results are consistent with the hypothesis that delayed recall in VEND offspring is a state independent trait and might be a useful endophenotype for successful cognitive aging. P1-207

INCIDENT DEMENTIA IN WOMEN IS PRECEDED BY WEIGHT LOSS BY AT LEAST A DECADE

David S. Knopman1, Walter A. Rocca1, Steven D. Edland2, Ruth H. Cha1, Ronald C. Petersen1, 1Mayo Clinic College of Medicine, Rochester, MN, USA; 2University of California San Diego, San Diego, CA, USA. Contact e-mail: [email protected] Background: Several studies have shown that weight loss precedes dementia. Objective(s): To study the association between antecedent height and body weight and dementia using a case-control design. Methods: Cases of incident dementia in the 5 year period of 1990 to 1994 were identified in Rochester MN. We also identified age (⫾ 1 year) and sex matched controls from the same community who were free of dementia in their matched case’s year of onset (index year). Dementia and Alzheimer disease (AD) were defined using the criteria of DSM-IV. Weights were abstracted from the medical record for time periods of 1-2, 3-4, 5-6, 7-8, 9-10, 11-20, 21-30 and ⬎ 30 years prior to the index year. We also recorded height at age 40 years. Results: We identified 481 incident cases of primary dementia (AD, vascular dementia or another neurodegenerative disorder), of whom 345 were diagnosed as AD. There were 350 women and 131 men; 60.2% were age 80 and 4.6% were ⬍65 at onset. For both primary dementia and AD, there were no significant differences in height between cases and controls at age 40. In addition, there were no differences in weight between cases and controls 21-30 years prior to the index year. However, women with primary dementia were nearly 6 lb lighter than

Poster Presentations P1 controls by 11-20 years prior to the index year (p⫽ .01). By the index year, cases were over 13 lb lighter than controls (p⬍ .0001). Although male cases were lighter than controls by about 5 lb at the index year, the difference was not significant then or at any earlier time point. Conclusions: Substantial weight loss precedes the diagnosis of primary dementia or AD in women. The weight changes were only modest in men. At no time in the decades preceding the index year did cases ever significantly exceed controls in weight. The cause of weight loss is unclear but could include increasing apathy and loss of initiative; hypothalamic involvement by neurodegeneration; anosmia making food less appealing; alterations in systemic metabolism involving insulin levels or tissue insulin sensitivity; or subclinical gastrointestinal disorders. P1-208

POINT AND FIVE-YEAR PERIOD PREVALENCE OF NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA: THE CACHE COUNTY STUDY

Martin Steinberg1, Huibo Shao2, Peter Zandi2, JoAnn Tschanz3, Kathleen Welsh-Bohmer4, Maria Norton3, John CS Breitner5, David Steffens4, Constantine Lyketsos1, 1Johns Hopkins School of Medicine, Baltimore, MD, USA; 2Johns Hopkins School of Public Health, Baltimore, MD, USA; 3Utah State University, Logan, UT, USA; 4 Duke University School of Medicine, Durham, NC, USA; 5University of Washington School of Medicine, Seattle, WA, USA. Contact e-mail: [email protected] Background: Neuropsychiatric symptoms are nearly universal in dementia, affecting up to 90% of patients. In a previously published study from the prevalence wave of the population-based Cache County Study on Memory, Health and Aging, 61% exhibited at least one neuropsychiatric symptom. Most common were apathy (27%), depression (24%) and agitation/aggression (24%); least common were disinhibition (9%) and elation (1%). Little is known about the longitudinal course of symptoms in the community setting. Objective: We extend our previous work and examine the point and five-year period prevalence of neuropsychiatric symptoms in an incident sample of 441 dementia participants from the Cache County Study. Methods: The Neuropsychiatric Inventory (NPI) was used to assess symptoms in participants at baseline (N⫽ 441) and at the following mean follow-up intervals: 1.5 years (N⫽ 234), 3.0 years (N⫽ 113), 4.1 years (N⫽ 65), and 5.3 years (N⫽ 38). The point and period prevalence at each time point was estimated for the following symptoms: delusions, hallucinations, agitation/aggression, depression, apathy, elation, anxiety, disinhibition, irritability, and aberrant motor behavior. Results: Over five years, period prevalence was greatest for depression (76%), apathy (73%), and anxiety (61%); lowest for elation (5%), disinhibition (30%), and hallucinations (36%). Point prevalence for delusions was 18% at baseline and 35-37% during the last three visits; hallucinations, 10% at baseline and 19-23% at all subsequent visits; agitation/aggression fluctuated between 14% and 22%; depression 29% at baseline and 41-46% subsequently; apathy gradually increased from 20% at baseline to 54% at 5.3 years; elation never rose above 1%; anxiety 14% at baseline and 25-31% subsequently; disinhibition fluctuated between 2% and 15%; irritability fluctuated between 16% and 27%; aberrant motor behavior gradually increased from 7% at baseline to 28% at 5.3 years. Conclusions: At some point over the course of dementia, participants were most likely to develop depression, apathy or anxiety, and least likely to develop elation, hallucinations or disinhibition. The trend for most symptoms is to increase in prevalence over five years. However, they often fluctuate within this time period, and, with the exception of delusions, apathy, and aberrant motor behavior, these increases tend to be modest. P1-209

RELATIONS OF SERUM INFLAMMATORY MARKERS AND MONOCYTE PRODUCTION OF CYTOKINES TO THE RISK FOR ALZHEIMER’S DISEASE: THE FRAMINGHAM STUDY

Zaldy S. Tan1, Sudha Seshadri2, Alexa Beiser3, Ronenn Roubenoff4, Charles Dinarello5, Tamara Harris6, Emelia Benjamin7, Rhoda Au7, Douglas P. Kiel8, Ramachandran S. Vasan7, Philip A. Wolf2, 1Harvard

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Medical School/Hebrew SeniorLife/Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Boston University School of Medicine, Department of Neurology, Boston, MA, USA; 3Boston University School of Public Health, Boston, MA, USA; 4Tufts University, Boston, MA, USA; 5University of Colorado Health Sciences Center, Denver, CO, USA; 6National Institutes of Aging, Bethesda, MD, USA; 7Boston University School of Medicine, Boston, MA, USA; 8Hebrew SeniorLife/Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: Substantial experimental and epidemiological evidence implicates inflammation in the pathogenesis of Alzheimer’s disease (AD). However, prior studies relating serum proinflammatory cytokines to the risk of developing AD have yielded conflicting results. The measurement of cytokine production by peripheral blood mononuclear cells (PBMC) may be an attractive alternative marker of the proinflammatory response that antedates AD. Objective(s): To examine whether serum cytokines (interleukin-6 [IL-6]; C-reactive protein [CRP]) and the spontaneous production of proinflammatory interleukin-1 (IL-1), tumor necrosis alpha (TNF-␣) and anti-inflammatory IL-1-receptor antagonist (IL-1RA) by PBMC are associated with the risk of incident AD. Methods: We followed 691 cognitively intact, communitydwelling participants (mean age 79, 62% women) with available measures of PBMC cytokine production and CRP for the development of incident AD.Using Cox proportional hazards regression adjusted for age, gender, ApoE4 allele status, prior stroke, education, homocysteine, smoking, body mass index and statin use, we evaluated the relations of serum cytokines (CRP and IL-6) levels and spontaneous production of IL-1, IL-1RA and TNF-␣ by PBMC to the risk of incident AD. Results: After 10 years of follow-up, 44 participants (25 women) developed AD. After adjusting for all covariates, individuals in the top two tertiles (T2 and T3) of PBMC production of IL-1 or the top tertile (T3) of PBMC production of TNF-␣ were at increased risk of developing AD (multivariable-adjusted hazards ratio [HR] for IL-1 T2⫽2.84, 95% confidence interval [CI] 1.09-7.43; P⫽0.033 and T3⫽2.61, 95% CI 0.96-7.07; P⫽0.059; for TNF-␣, adjusted-HR for T2⫽1.30, 95% CI 0.53-3.17; P⫽0.569 and T3⫽2.59, 95% CI 1.09-6.12; P⫽0.031) compared to those in the lowest tertile (T1).Participants who had 2 out of 3 or all 3 markers of enhanced inflammation (⬎T1 IL-1, ⬎T2 TNF-␣, or ⬍T2 IL-1RA) had an even greater risk of developing AD (adjusted HRs⫽2.85 (1.08-7.50); P⫽0.034 and 3.83 (1.818.09); P⫽⬍0.001, respectively). PBMC production of IL-1RA alone and serum cytokines were not significantly associated with incident AD. Conclusions: Higher spontaneous production of IL-1 or TNF-␣ by PBMC may be a marker of future risk of AD in older individuals.These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD. P1-210

NEUROTICISM AND EXTROVERSION IN RELATION TO INCIDENT COGNITIVE IMPAIRMENT AND DEMENTIA. A COMMUNITYBASED 6-YEAR FOLLOW-UP STUDY

Hui-Xin Wang, Anita Karp, Agneta Herlitz, Bengt Winblad, Laura Fratiglioni, Karolinska Institute, Stockholm, Sweden. Contact e-mail: [email protected] Background: Proneness to psychological distress, as indicated by high scores in neuroticism, has been reported to be associated with a higher risk of Alzheimer disease. Objective(s): To explore whether persons with high neuroticism and introversion were at high risk to develop cognitive impairment and dementia. Methods: A community-based cohort of 507 non-demented people aged 78 years and above from the Kungsholmen project, a populationbased study in Sweden, was followed for an average of 6 years. During the follow-up, 125 subjects were diagnosed with dementia according to the DSMIII-R criteria. Personality traits were assessed using the Eysenck Personality Inventory (EPI) at baseline by self-administered questionnaire. Results: High neurotics (above median) had an elevated relative risk (RR) of cognitive impairment, age, gender and education adjusted RR⫽1.93 (95% confidence interval (CI)⫽1.42-2.64) compared to those who were less neurotic. In contrast, introverts were not at a higher risk of cognitive impairment compared to