Kristoffer Rhoads

Differential modulation of plasma β-amyloid by insulin in patients with Alzheimer disease

Background: Hyperinsulinemia and insulin resistance are risk factors for memory impairment and Alzheimer disease (AD). Insulin regulates levels of the amyloid β-peptide (Aβ) in vitro in neuronal cultures and in vivo in the CSF of normal older adults. Objective: To determine whether insulin affected plasma Aβ levels and whether such effects differed for patients with AD compared with normal older adults. Methods: Fifty-nine patients with AD and 50 healthy older adults each received infusions of saline and of insulin (1.0 mU · kg−1 · min−1) with accompanying dextrose to maintain euglycemia. A subset of participants (19 AD, 12 normal) received two additional conditions, in which insulin was infused at a lower (0.33 mU · kg−1 · min−1) and higher (1.67 mU · kg−1 · min−1) rate. Plasma insulin and Aβ were measured after 120 minutes of infusion. Results: Adults with AD had higher plasma insulin vs normal adults at the two higher infusion rates, despite receiving comparable amounts of insulin. For normal adults, insulin reduced plasma Aβ levels at the middle (1.0 mU · kg−1 · min−1) dose, with attenuated effects at lower and higher doses. In contrast, for patients with AD, insulin raised plasma Aβ levels at the two higher doses (1.0 and 1.67 mU · kg−1 · min−1). Conclusions: These results suggest that patients with Alzheimer disease (AD) have reduced insulin clearance and insulin-provoked plasma amyloid β-peptide (Aβ) elevation. Abnormal regulation of peripheral Aβ by insulin may contribute to AD risk.

Use of Spoken and Written Japanese Did Not Protect Japanese-American Men From Cognitive Decline in Late Life

OBJECTIVES Spoken bilingualism may be associated with cognitive reserve. Mastering a complicated written language may be associated with additional reserve. We sought to determine if midlife use of spoken and written Japanese was associated with lower rates of late life cognitive decline. METHODS Participants were second-generation Japanese-American men from the Hawaiian island of Oahu, born 1900-1919, free of dementia in 1991, and categorized based on midlife self-reported use of spoken and written Japanese (total n included in primary analysis = 2,520). Cognitive functioning was measured with the Cognitive Abilities Screening Instrument scored using item response theory. We used mixed effects models, controlling for age, income, education, smoking status, apolipoprotein E e4 alleles, and number of study visits. RESULTS Rates of cognitive decline were not related to use of spoken or written Japanese. This finding was consistent across numerous sensitivity analyses. DISCUSSION We did not find evidence to support the hypothesis that multilingualism is associated with cognitive reserve.

Midlife use of written Japanese and protection from late life dementia

Background: The cognitive reserve hypothesis would predict that use of written Japanese should confer protection against dementia because of the complexity of its ideograms compared with written English. We sought to test this hypothesis in analyses from a longitudinal study of Japanese-American men. Methods: Participants were second-generation Japanese-American men (Nisei) on the island of Oahu, Hawaii, who were seen in 1965 and in subsequent examinations to detect dementia beginning in 1991–1993. Use of spoken and written Japanese was self-reported in 1965 (Analyses 1 and 2), and midlife use of written Japanese and written English was self-reported in 1994–1996 (Analysis 3). We analyzed prevalent dementia outcomes in 1991–1993 (Analysis 1, n = 3139) using logistic regression, and incident dementia outcomes in 1994–2002 (Analysis 2, n = 2299) and in 1997–2002 (Analysis 3, n = 1655) using Cox proportional hazards regression. Dementia outcomes included all-cause dementia, probable and possible Alzheimer disease, and probable vascular dementia. We adjusted models for probable and possible confounders. Results: Participants who reported proficiency with written Japanese were older and had lower incomes. For Analysis 1, there were 154 prevalent cases of dementia, 74 of Alzheimer disease, and 43 of vascular dementia; for Analysis 2, 236 incident cases of dementia, 138 of Alzheimer disease, and 45 of vascular dementia; and for Analysis 3, 125 incident cases of dementia, 80 of Alzheimer disease, and 20 of vascular dementia. There was no relationship in adjusted models between self-reported proficiency with written Japanese and any dementia outcomes. Conclusions: Proficiency with written Japanese does not appear to be protective for dementia.

Effects of Insulin and Octreotide on Memory and Growth Hormone in Alzheimer's Disease

Both insulin alone and the somatostatin analogue octreotide alone facilitate memory in patients with Alzheimers disease (AD). Since octreotide inhibits endogenous insulin secretion, the cognitive effects of insulin and octreotide may not be independent. This study tested the individual and interactive effects of insulin and octreotide on memory and plasma growth hormone (GH) levels in older adults. Participants were 16 memory-impaired (AD = 7, amnestic mild cognitive impairment = 9; apolipoprotein E [APOE] epsilon4- [no epsilon4 alleles] = 9, epsilon4+ [1-2 epsilon4 alleles] = 7), and 19 cognitively-intact older adults (APOE epsilon4- = 17, epsilon4+ = 1). On separate days, fasting participants received counterbalanced infusions of: 1) insulin (1 mU.kg(-1).min(-1)) and dextrose to maintain euglycemia; 2) octreotide (150 microg/h); 3) insulin, dextrose, and octreotide; or 4) saline. Story recall was the principal endpoint. Insulin alone facilitated delayed recall for epsilon4- patients, relative to epsilon4+ patients (P = 0.0012). Furthermore, epsilon4- patients with higher Mattis Dementia Rating Scale (DRS) scores had greater octreotide-induced memory facilitation (P = 0.0298). For healthy adults, octreotide facilitated memory (P = 0.0122). Unexpectedly, hyperinsulinemia with euglycemia increased GH levels in healthy controls (P = 0.0299). Thus, insulin and octreotide appear to regulate memory in older adults. APOE epsilon4 genotype modulates responses to insulin and octreotide. Finally, insulin may regulate GH levels during euglycemia.

Statin Users Without an APOE-ε4 Allele have Increased Insulin Resistance

The present study examined the relationships among statin use, APOE genotype, and insulin resistance as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) in healthy older adults. APOE epsilon4- (i.e., not having an epsilon4 allele) statin users had higher HOMA-IR values compared with epsilon4+/statin users (p=0.0169), and with non-users who were epsilon4- (p=0.0003) or epsilon4+ (p=0.0006). These results suggest that statin use may modulate insulin levels for individuals without an APOE epsilon4 allele.

P3-134: Assessment of Japanese- and English-language equivalence of the cognitive abilities screening instrument (CASI) among Japanese-Americans in two large epidemiological studies

memory, the Neuropsychological Assessment Battery (NAB) List Learning (LL) test (Stern & White, 2003) is a promising tool for the assessment of older adults due to its relative simplicity, excellent psychometric validation, equivalent forms, and extensive normative data in older individuals. This study examined the diagnostic utility of the NAB LL test in differentiating cognitively normal, MCI, and AD participants. Methods: Extant data from the Boston University Alzheimer’s Disease Center Registry was retrospectively analyzed for 153 participants (57-94 years, 74 8 years; 61% women) diagnosed by a consensus team as cognitively normal (n 98), amnestic MCI (single or multiple domain; n 29), or AD (n 26). Diagnoses were made independent of NAB LL performance. To determine classification accuracy, receiver operating characteristics analyses were conducted for seven NAB LL variables (List A Immediate Recall, List B Immediate Recall, Short Delay Recall, Long Delay Recall, Percent Retention, and Recognition Hits and False Alarms). In addition, ordinal multiple regression was used to create a model to predict group membership based on a combination of the NAB LL variables. Results: The sensitivities and specificities of the NAB LL test variables were good to excellent, yielding positive likelihood ratios ranging from 1.8 to 30.2 (Mdn 4.2). The ordinal regression produced a model that predicted group membership with an overall accuracy of 85%. The model was most accurate at classifying controls (97%), followed by AD (74%) and MCI (52%), which indicates that it can very accurately rule out the latter two diagnoses. Conclusions: Both the regression-based model and the individual NAB LL variables were highly accurate in differentiating cognitively normal controls, MCI, and AD groups. Compared to published data, the classification accuracy statistics presented here appear to match or exceed those reported for other common list learning tests (e.g., HVLT-R, CERAD, CVLT) in this population.

O1-01-04: Midlife proficiency with written Japanese and late life dementia risk among Japanese-American men. The Honolulu-Asia aging study

was to investigate the possible effect modification of the apoE e4 allele for several lifestyle related risk factors for dementia and AD. Methods: Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1449 (73%) aged 65 to 79 years were reexamined in 1998. Results: The apoE e4 allele was an independent risk factor for dementia even after adjustments for lifestyle and vascular factors (OR 2.83, 95% CI 1.61-4.97). Physical inactivity, alcohol drinking, and smoking at midlife increased the risk of dementia and AD particularly among the apoE e4 carriers. Further, among the apoE e4 carriers low to moderate dietary intake of polyunsaturated fats at midlife, as well as moderate to high intake of saturated fats were associated with increased risk of dementia and AD. Also the summarized effect of the lifestyle related factors was more pronounced among the apoE e4 carriers. Conclusions: Physical inactivity, dietary fat intake, alcohol drinking, and smoking at midlife are associated with the risk of dementia and AD, especially among the apoE e4 carriers. The apoE e4 carriers may be more vulnerable for various lifestyle related factors. Thus, especially the carriers of the apoE e4 allele might benefit from adopting a healthy and moderate lifestyle.

P-206: Pioglitazone modulates plasma levels of β-amyloid in glucose intolerant older adults

not available. S164 Plenary: PL1: Primary Risk and Prevention

P-184: APOE-e4 carriers treated with statins have greater insulin-mediated glucose disposal

analysis demonstrated that age (odds ratio (OR) 1.079; 95% confidence interval (CI) 1.011-1.150), GDS 15 scores (OR 1.139; 95% CI 1.045-1.243), serum albumin (OR 0.336; 95% CI 0.174-0.745), and history of cerebrovascular disease (OR 3.011; 95% CI 1.578-5.748) were the variables significantly associated with having lower MMSE scores. Conclusion: Based on the results obtained in the current crosssectional assessment, the prevention of cerebrovascular disease may be a primary way of preventing cognitive decline in elderly DM subjects. An investigation of how lower serum albumin levels are associated with DM-related cognitive impairment may lead to the development of effective strategies for the prevention or treatment of this decline.

42 ACCULTURATION AND ALZHEIMER DISEASE RISK AMONG JAPANESE-AMERICAN ELDERLY: THE KAME STUDY.

Background Cross-cultural studies of Alzheimer disease (AD) in genetically similar populations have been designed to detect possible environmental risk factors. It may be possible to perform similar analyses on a single population by examining acculturation, which is the extent to which individuals moving into a host society adapt to changes in lifestyle. Our objective was to determine whether acculturation to Western society was a risk factor for developing AD in an elderly population of Japanese-Americans. Study Design and Methods A cohort of 1,622 dementia-free individuals with baseline acculturation scores was followed for 8 years with biennial cognitive screening assessments using the Cognitive Abilities Screening Instrument. Individuals scoring < 88 were given a full physical and neuropsychological evaluation. Diagnoses of dementia and AD were obtained by consensus agreement using criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Item response theory was used to combine 20 questionnaire responses to generate acculturation scores. Scores were divided into quartiles for analysis. Hazard ratios were calculated using the Cox proportional hazards model to determine the risk of AD for participants in high quartiles of acculturation versus those in low quartiles. We adjusted models for cardiovascular disease risk factors and demographic characteristics such as primary language and income. Results In unadjusted models, the relative hazard associated with higher levels of acculturation was 0.6 (95% CI 0.4-0.97). With adjustments for demographic characteristics, the relative hazard associated with higher levels of acculturation was 1.84 (95% CI 0.5-6.6). With further adjustments for vascular disease risk factors and apolipoprotein E genotype, the relative hazard associated with higher levels of acculturation was 1.83 (95% CI 0.4-8.5). Conclusion Japanese-Americans in the highest acculturation group appear to have an increased risk for acquiring AD, though the confidence interval includes the null value. This finding suggests further research to determine a biological rationale.