Neocortical beta-amyloid area, but not CERAD plaque stage, is associated with dementia status and Apolipoprotein E (APOE) genotype in the oldest old

Oral O3-01 Epidemiology: Prevalence and Biomarkers O3-01-04

THE ALZRISK DATABASE: WEB-BASED CATALOGUE AND META-ANALYSIS OF FINDINGS FROM EPIDEMIOLOGIC STUDIES OF NON-GENETIC RISK FACTORS FOR ALZHEIMER’S DISEASE

Jennifer Weuve1,2, Matthew B. McQueen3, Meredith Harrington4, Jacqueline O’Brien4, Shanshan Li4, Melinda Power4,2, Maile Ray4, Colin Knep5, June Kinoshita5, Deborah Blacker6,4, 1Rush Institute for Healthy Aging, Rush University, Chicago, IL, USA; 2Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA; 3 Department of Psychology and Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA; 4Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; 5Alzheimer Research Forum (www.alzforum.org), Cambridge, MA, USA; 6Gerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Contact e-mail: [email protected] Background: Alzheimer disease (AD) is a disorder of complex etiology. The AlzGene database documents putative genetic risk factors for AD, but there is no centralized source of summary information for non-genetic risk factors. Associations for some risk factors have been replicated across studies, while others have not. Modeled on AlzGene but modified to accommodate the greater complexity of exposure timing and levels for non-genetic risk factors, the AlzRisk database (www.alzrisk.org) aims to provide a comprehensive, unbiased, centralized, publicly available and regularly updated summary of epidemiologic reports on non-genetic risk factors for AD. Methods: We identify eligible publications through systematic literature review, including only those published or in press in English in peer-reviewed journals. Studies must have been conducted in large, well-defined cohorts (allowing for inclusion of studies that follow conventional longitudinal and nested case-control designs), and must offer sufficient details on design and findings, which must be adjusted at least for age and sex. For each risk factor, we aggregate information from the studies into tables (grouped to maximize homogeneity in the exposure) that include data on the cohort, distribution of the risk factor, analytic methods, and effect size/statistical significance of the observed association. We also offer a text summary of critical issues and findings for each risk factor, and conduct meta-analyses where comparable data are available in at least four samples. Results: Currently, AlzRisk includes 28 studies of four risk factors from 15 cohorts. We were able to meta-analyze data for diabetes, which indicated an overall adverse association with AD (summary hazard ratio [HRS] ¼ 1.52, 95% CI: 1.31-1.73), and for vitamin E supplement use, which indicated no association with AD (HRS ¼ 0.96 [0.80-1.15]). Data for physical activity, which generally indicated reduced risk with higher levels of activity, were not meta-analyzable, nor were those for blood-based inflammation biomarkers, which showed complex patterns and no clear associations. Work on five additional risk factors (blood pressure/hypertension, homocysteine, obesity, postmenopausal hormone use, and vitamin C intake) is underway. Conclusions: As the volume of reports on AD is expected to expand substantially in the coming years, tools, such as AlzRisk, that organize and summarize relevant findings will become increasingly valuable. O3-01-05

CSF MARKERS AS PREDICTORS FOR ALZHEIMER’S DISEASE IN SUBJECTS WITH MCI: EFFECT OF APOE GENOTYPE-ADJUSTED CUT OFFS

Leah Burns1, Ineke van Rossum2, Pablo Lapuerta1, Frans Verhey3, Wiesje van der Flier2, Lars-Olof Wahlund4, Magda Tsolaki5, Lennart Minthon6, Katharina Buerger7, Harald Hampel8, Tuula Pirtilla9, Hilkka Soininen9, Marcel Verbeek10, Luiza Spiru11, Marinus Blankenstein2, Kaj Blennow12, Philip Scheltens2, Pieter Jelle Visser3,2, 1Bristol - Myers Squibb, Wallingford, CT, USA; 2VU University Medical Center, Amsterdam, Netherlands; 3Maastricht University, Maastricht, Netherlands; 4Karolinska Institute, Stockholm, Sweden; 5Aristotle University of Thessaloniki, Thessaloniki, Greece; 6Lund University, Malmo, Sweden; 7Ludwig-Maximilian University, Munich, Germany; 8University of Frankfurt, Frankfurt, Germany; 9 University of Kuopio, Kuopio, Finland; 10Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 11‘‘Carol Davila’’ University of

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Medicine and Pharmacy, Bucarest, Romania; 12Sahlgrenska University Hospital, Molndal, Sweden. Contact e-mail: [email protected] Background: Decreased Ab1-42 and increased levels of tau and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) are key markers for Alzheimer’s disease (AD). Previous studies showed that the concentration of these markers correlate with the apolipoprotein E (APOE) genotype. The aim of the present study was to investigate whether correction for APOE genotype could improve the predictive accuracy of CSF markers for AD in subjects with mild cognitive impairment (MCI). Methods: Subjects with MCI for which data were available on CSF markers, APOE genotype, and followup were selected from the ADNI study (n ¼ 198), DESCRIPA study (n ¼ 98), and VU University medical center (n ¼ 96). Subjects aged <55 years and with obvious causes for MCI were excluded. Follow-up was performed every 6-12 months up to 3 years. CSF markers were analyzed using xMAP technology (INNO-BIA AlzBio3, ADNI) or ELISA (Innotest Ab1-42, hTAUAg, Phospho-tau [181P], other cohorts). For each assay the cut-off was determined that maximized the area under the curve (AUC) for the distinction between subjects with and without AD at follow-up. Results: At baseline, subjects (n ¼ 391) had a mean age of 72 years, MMSE score of 26.6, and 13.2 years of education. 204 Subjects (52%) were carriers of at least 1 APOE-e4 allele. Average follow-up was 2.4 years and 146 subjects (37%) converted to AD. At baseline, the APOE-e4 allele was associated lower Ab1-42 and higher tau and ptau levels (p < 0.0001). Without correction for APOE genotype, the AUC ranged from 0.63 (ptau) to 0.66 (tau). Compared to the optimal cut-off for subjects without APOE-e4 allele, the cut-off for APOE-e4 allele carriers was lower for Ab1-42 (15% to 26%; the lower estimate applies to xMAP, the higher estimate to ELISA) and higher for tau (24% to 48%) and ptau (48% to 54%). When APOE-e4 allele-corrected cut-offs were used, the AUC for the prediction of AD remained the same or decreased compared to cut-offs without correction for APOE genotype. Conclusions: While APOE-e4 allele has a strong effect on Ab1-42, tau, and ptau levels in CSF, correction for APOE genotype may not improve the predictive accuracy for AD. O3-01-06

NEOCORTICAL BETA-AMYLOID AREA, BUT NOT CERAD PLAQUE STAGE, IS ASSOCIATED WITH DEMENTIA STATUS AND APOLIPOPROTEIN E (APOE) GENOTYPE IN THE OLDEST OLD

Daniel J. Berlau1, Maria M. Corrada1, John Robinson2, Felix Geser2, Steven Arnold2, Virginia M.-Y. Lee2, Claudia H. Kawas1, John Q. Trojanowski2, 1University of California, Irvine, Irvine, CA, USA; 2 University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: Evidence suggests that APOE4 is a risk factor for clinical Alzheimer’s disease (AD) and AD neuropathology whereas APOE2 is protective. It is suggested that APOE2 carriers are protected because they have reduced levels of cortical beta-amyloid. However, in the oldest-old, we have found that APOE2 is associated with increased CERAD plaque stage, even with preserved cognition. We obtained a measure of percent of cortical area burdened by beta-amyloid and compared different measures of beta-amyloid pathology across APOE genotypes in the oldest-old, and their relationship with all-cause dementia. Methods: The study included 68 genotyped participants from The 90+ Study who came to autopsy. All-cause dementia (DSM-IV) diagnoses were made by consensus conference using all available information. Neuropathological examination included CERAD staging for amyloid plaques and beta-amyloid cortical percent area defined as the maximal area occupied by nab228 antibody-stained frontal or temporal cortex. Results: Participants’ mean age at death was 97.2 years. APOE2 was present in 10.3% of participants and APOE4 in 19.1%. Dementia was present in 28.6% of APOE2 carriers and 76.9% of APOE4 carriers. Both APOE2 and APOE4 carriers had high CERAD plaque staging (>50% with stage B or C), and were significantly higher than APOE3/3 carriers (P < 0.05). APOE4 carriers had significantly greater beta-amyloid area levels than APOE3/3 carriers (P < 0.01). Surprisingly, however, APOE2 carriers had lower beta-amyloid area levels than APOE3/3 carriers.

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Oral O3-02: Neuropsychology

Additionally, beta-amyloid area levels were highly associated with clinical dementia (P < 0.005), whereas CERAD plaque scores were not (P ¼ 0.22) Conclusions: In the oldest-old, APOE2 was associated with increased CERAD plaque staging, but not increased beta-amyloid percent area. This lower level of percent area may reflect lower total beta-amyloid and may be responsible for the APOE2 carriers’ decreased risk of dementia, despite high CERAD plaque staging. Conversely, APOE4 carriers have both increased CERAD plaque staging and total beta-amyloid, which may be associated with their increased risk of clinical dementia. Therefore, findings from APOE2 carriers highlight the poor relationship between CERAD staging and cognition, and suggest that other measures of total beta-amyloid are more related to cognition in this age group. Consequently, the neuropathological criteria for AD may need to be reevaluated in this age group. O3-01-07

RATE OF DECLINE IN ADNI NORMAL CONTROLS WITH EVIDENCE OF AMYLOID BURDEN

Michael Donohue1, Anthony Gamst1, Ron Thomas1, Jim Brewer1, Michael Weiner2, Paul Aisen1, 1University of California San Diego, San Diego, CA, USA; 2University of California San Diego, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Amyloid beta 1-42 peptide (Abeta) has been shown to differentiate normal elderly controls (NC) from Alzheimer’s Disease (AD). We explore whether changes in measures of volumetric MRI, resting glucose metabolism (FDG-PET), or cognitive or functional assessments within NCs are also predicted by evidence of amyloid deposition in the brain. We explore the feasibility of randomized interventions in amyloid positive (Abeta+) NCs to detect a 50% improvement in 2-year amyloid specific decline. Methods: We stratify the ADNI NC cohort by established PIB and CSF Abeta cutoffs, and estimate the 2-year rate of change in vMRI hippocampus, vMRI entorhinal cortex, FDG-PET posterior cingulated, RAVLT, FAQ, and MMSE. Using the difference between Abeta+ and Abeta- change from baseline as estimates of Abeta related decline, we estimate the required sample size necessary to detect a 50% improvement in a proof-of-concept randomized study in an Abeta+ cognitively normal cohort. We use linear mixed-models to estimate rates change. Results: The Abeta- group was slightly younger (75.13 (SD ¼ 5.27) vs 76.83 (5.23) years, p ¼ 0.086), so age was included as a covariate. A low proportion of Abeta- were ApoE4 carriers (7/76 ¼ 9% versus 21/46 ¼ 46%; p < 0.001), and a lower proportion converted to MCI within 2-years (2/76 ¼ 3% vs 4/46 ¼ 9%; p ¼ 0.133). The effect of Abeta on decline was significant for MMSE (p ¼ 0.007), hippocampus (p ¼ 0.010), and FAQ (p ¼ 0.026); and the rate of decline in Abeta+ was significant for hippocampus (p < 0.001), entorhinal (p < 0.001), MMSE (p ¼ 0.024), and FAQ (p ¼ 0.025). It would require N ¼ 187 (hippocampus), N ¼ 279 (MMSE), and N ¼ 613 (FAQ) subjects per arm to achieve 80% power (5% alpha) to detect a 50% reduction in amyloid specific decline in a hypothetical 2-year randomized, placebo controlled study in Abeta+ NCs (6-month visit intervals). Conclusions: There was a highly significant rate of vMRI change in Abeta+. Change in FDG-PET was not as pronounced. Surprisingly, we also found a significant (p < 0.05) rate of FAQ and MMSE change. Furthermore, the difference between amyloid+ and amyloid- was significant for hippocampus, FAQ and MMSE (p < 0.05), while the difference in entorhinal and FDG-PET was not.

O3-01-08

FAMILY HISTORY, DEMOGRAPHICS, AND GENETIC CHARACTERISTICS OF SYMPTOMATIC AND NON-SYMPTOMATIC SUBJECTS WITH NEUROPATHOLOGICAL ALZHEIMER’S DISEASE IN THE NATIONAL ALZHEIMER’S COORDINATING CENTER (NACC) DATASETS

Leslie E. Phillips1, Dawn P. Gill1, Catherine M. Roe2, Thomas D. Koepsell1, Walter A. Kukull1, John C. Morris2, 1National Alzheimer’s Coordinating Center, Seattle, WA, USA; 2Washington University in St. Louis, St. Louis, MO, USA. Contact e-mail: [email protected] Background: Greater education and older age have been associated with decreased cognitive impairment in the presence of neuropathology consistent

with Alzheimer’s disease (AD). To date, no published studies have sought to comprehensively characterize the family history, demographics, and genetic characteristics of persons who were not clinically-demented in life but who showed neuropathological features consistent with Alzheimer’s disease (AD) at autopsy. Methods: We studied 2,033 subjects who had neuropathologic features consistent with AD. We compared 126 subjects without clinically-detectable dementia (NONDEM) to the remaining 1,907 subjects with dementia (DEM). Deaths occurred within 18 months of subjects’ clinical evaluation at one of 32 Alzheimer’s Disease Centers in the U.S. All subjects had AD-consistent neuropathology, defined as one or more of the following neuropathologic features: Braak Stage >¼ 3 plus frequent neuritic plaques, NIA/Reagan intermediate or high, CERAD or Khachaturian consistent with AD, and/or primary pathologic diagnosis of AD. We conducted a stratified analysis using Mantel-Haenszel (M-H) odds ratios (OR) to control for ADC and identify characteristics that differentiate DEM subjects (those with both clinical dementia and neuropathological signs of AD) from NONDEM subjects (those with only neuropathological signs of AD). Results: Compared to NONDEM subjects, DEM subjects were more like to carry the APOE4 allele (M-H OR ¼ 2.94;95% CI, 1.85 to 4.66), more likely to have a first-degree relative with a history of dementia (M-H OR ¼ 1.79; 95% CI, 1.16 to 2.77), less likely to have completed a high school or greater education (M-H OR ¼ 0.33; 95% CI, 0.21 to 0.55), and were less likely to be age 82 years or older at last clinical assessment (M-H OR ¼ 0.28; 95% CI, 0.18 to 0.44). We observed no significant differences between NONDEM and DEM subjects by subject’s sex. Conclusions: The degree to which patients express clinical manifestations of AD neuropathology may be influenced by several demographic characteristics as well as family history and APOE status. Identifying demographic and genetic characteristics associated with clinical robustness to neuropathologic changes may advance understanding of factors that influence the slope of cognitive decline and help identify potential interventions aimed at slowing cognitive impairment. Funding: National Institute on Aging Grant (U01 AG016976) to National Alzheimer’s Coordinating Center

TUESDAY, JULY 13, 2010 ORAL O3-02 NEUROPSYCHOLOGY O3-02-01

SUBJECTIVE MEMORY COMPLAINERS IN THE AIBL COHORT: HYPERVIGILANCE AMONGST THE WORRIED WELL, OR INDIVIDUALS AT INCREASED RISK OF ALZHEIMER’S DISEASE?

Jonathan Foster1, Uma Jha2, Belinda Brown1, Greg Savage3, Kathryn Ellis4, David Darby5, Nicola Lautenschlager4, Paul Maruff4, Cassandra Szoeke4, Kevin Taddei1, Vanessa Ward1, Mark Rodrigues1, Rebecca Lachovitzki1, Mira Rimajova1, Nat Lenzo6, Andrew Campbell7, Christopher Rowe4, Victor Villemagne8, Tania Taddei1, James Lui1, Colin Masters4, David Ames4, Ralph Martins1, 1Edith Cowan University, Joondalup, Australia; 2Shenton College, Shenton Park, Australia; 3Macquarie University, Sydney, Australia; 4University of Melbourne, Melbourne, Australia; 5University of Mebourne, Melbourne, Australia; 6Notre Dame University, Fremantle, Australia; 7Royal Perth Hospital, Perth, Australia; 8University of Melbourne, Melbourne, Australia. Contact e-mail: [email protected] Background: The significance of subjective memory complaints in older adults is controversial. We sought to clarify this issue in this study. Methods: We examined the relationship between memory complaints, neuropsychological capacity, mood, diagnostic status and clinically significant brain amyloid deposition (PIB PET) in the Australian Imaging, Biomarker and Lifestyle (AIBL) cohort (Ellis et al., 2009) of 1112 participants over the age of 60 studied i) at baseline and ii) 18 months later. We focused on subjective memory complainers (MCs: n ¼ 318) and subjective non-memory complainers (NMCs: n ¼ 311) from among the healthy controls enrolled at baseline in this cohort. Results: Statistically significant differences in neuropsychological capacity were observed at baseline between MC and NMC