Alzheimer Disease: Au R

Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA. · Lipid Metabolism Laboratory, Jean Mayer US Department of Agriculture Human Nutrition REsearch Center on Aging, Tuffs University, Boston, MA 02111, USA. · Arch Neurol. · Pubmed #17101822 links to  free full text

Abstract: BACKGROUND: Docosahexaenoic acid (DHA) is an abundant fatty acid in the brain. In the diet, DHA is found mostly in fatty fish. The content of DHA has been shown to be decreased in the brain and plasma of patients with dementia. OBJECTIVE: To determine whether plasma phosphatidylcholine (PC) DHA content is associated with the risk of developing dementia. Design, Setting, and PARTICIPANTS: A prospective follow-up study in 899 men and women who were free of dementia at baseline, had a median age of 76.0 years, and were followed up for a mean of 9.1 years for the development of all-cause dementia and Alzheimer disease. MAIN OUTCOME MEASURES: Plasma PC fatty acid levels were measured at baseline. Cox proportional regression analysis was used to assess relative risks of all-cause dementia and Alzheimer disease according to baseline plasma levels. RESULTS: Ninety-nine new cases of dementia (including 71 of Alzheimer disease) occurred during the follow-up. After adjustment for age, sex, apolipoprotein E epsilon4 allele, plasma homocysteine concentration, and education level, subjects in the upper quartile of baseline plasma PC DHA levels, compared with subjects in the lower 3 quartiles, had a relative risk of 0.53 of developing all-cause dementia (95% confidence interval, 0.29-0.97; P=.04) and 0.61 of developing Alzheimer disease (95% confidence interval, 0.31-1.18; P=.14). Subjects in the upper quartile of plasma PC DHA levels had a mean DHA intake of 0.18 g/d and a mean fish intake of 3.0 servings per week (P<.001) in a subset of 488 participants. We found no other significant associations. CONCLUSION: The top quartile of plasma PC DHA level was associated with a significant 47% reduction in the risk of developing all-cause dementia in the Framingham Heart Study.

Elias MF, Beiser A, Wolf PA, Au R, White RF, D'Agostino RB. · Department of Mathematics and Statistics, Statistical Consulting Unit, 111 Cummington St, Boston University College of Arts and Sciences, Boston, MA 02215, USA. · Arch Neurol. · Pubmed #10867777 links to  free full text

Abstract: OBJECTIVES: To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD. DESIGN: From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD. SETTING: A community-based center for epidemiological research. PARTICIPANTS: Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing. MAIN OUTCOME MEASURE: Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing. RESULTS: Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years. CONCLUSIONS: The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long. Arch Neurol. 2000.

Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, Wolf PA, Seshadri S. · Department of Medicine, Gerontology Division, Beth Israel Deaconess Medical Center, 110 Francis St, LMOB 1A, Boston, MA 02215, USA. · Arch Intern Med. · Pubmed #18663163 links to  free full text

Abstract: BACKGROUND: Clinical hypothyroidism and hyperthyroidism are recognized causes of reversible dementia, but previous studies relating thyrotropin levels to cognitive performance in clinically euthyroid persons have yielded inconsistent results. METHODS: We related serum thyrotropin concentrations measured at baseline (March 1977-November 1979) to the risk of Alzheimer disease (AD) in 1864 cognitively intact, clinically euthyroid Framingham original cohort participants (mean age, 71 years; 59% women). Sex-specific Cox proportional hazards models were constructed using tertiles of thyrotropin concentration (tertile 2 as the referent) and adjusting for age, apolipoprotein E epsilon4 allele status, educational level, plasma homocysteine level, current smoking, body mass index, prevalent stroke, and atrial fibrillation. RESULTS: During a mean follow-up of 12.7 years (range, 1-25 years), 209 participants (142 women) developed AD. Women in the lowest (<1.0 mIU/L) and highest (>2.1 mIU/L) tertiles of serum thyrotropin concentration were at increased risk for AD (multivariate-adjusted hazard ratio, 2.39 [95% confidence interval, 1.47-3.87] [P < .001] and 2.15 [95% confidence interval, 1.31-3.52] [P = .003], respectively) compared with those in the middle tertile. Thyrotropin levels were not related to AD risk in men. Analyses excluding individuals receiving thyroid supplementation did not significantly alter these relationships. In analyses limited to participants with serum thyrotropin levels of 0.1 to 10.0 mIU/L, the U-shaped relationship between thyrotropin level and AD risk was maintained in women but not when analyses were limited to those with thyrotropin levels of 0.5 to 5.0 mIU/L. CONCLUSION: Low and high thyrotropin levels were associated with an increased risk of incident AD in women but not in men.

Sun X, Steffens DC, Au R, Folstein M, Summergrad P, Yee J, Rosenberg I, Mwamburi DM, Qiu WQ. · Department of Psychiatry, Tufts-New England Medical Center, Campus Box 1007, 750 Washington St, Boston, MA 02111, USA. · Arch Gen Psychiatry. · Pubmed #18458206 links to  free full text

Abstract: CONTEXT: A high ratio of plasma amyloid-beta peptide 40 (Abeta(40)) to Abeta(42), determined by both high Abeta(40) and low Abeta(42) levels, increases the risk of Alzheimer disease. In a previous study, we reported that depression is also associated with low plasma Abeta(42) levels in the elderly population. OBJECTIVE: To characterize plasma Abeta(40):Abeta(42) ratio and cognitive function in elderly individuals with and without depression. DESIGN: Cross-sectional study. SETTING: Homecare agencies. PARTICIPANTS: A total of 995 homebound elderly individuals of whom 348 were defined as depressed by a Center for Epidemiological Studies Depression score of 16 or greater. MAIN OUTCOME MEASURES: Cognitive domains of memory, language, executive, and visuospatial functions according to levels of plasma Abeta(40) and Abeta(42) peptides. RESULTS: Subjects with depression had lower plasma Abeta(42) levels (median, 14.1 vs 19.2 pg/mL; P = .006) and a higher plasma Abeta(40):Abeta(42) ratio (median, 8.9 vs 6.4; P < .001) than did those without depression in the absence of cardiovascular disease and antidepressant use. The interaction between depression and plasma Abeta(40):Abeta(42) ratio was associated with lower memory score (beta = -1.9, SE = 0.7, P = .006) after adjusting for potentially confounders. Relative to those without depression, "amyloid-associated depression," defined by presence of depression and a high plasma Abeta(40):Abeta(42) ratio, was associated with greater impairment in memory, visuospatial ability, and executive function; in contrast, nonamyloid depression was not associated with memory impairment but with other cognitive disabilities. CONCLUSION: Amyloid-associated depression may define a subtype of depression representing a prodromal manifestation of Alzheimer disease.

Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB, Benjamin EJ, Au R, Kiel DP, Wolf PA, Seshadri S. · Department of Medicine, Institute for Aging Research, Hebrew Senior Life, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02131, USA. · Neurology. · Pubmed #17536046 No free full text.

Abstract: OBJECTIVE: To examine whether serum cytokines and spontaneous production of peripheral blood mononuclear cell (PBMC) cytokines are associated with the risk of incident Alzheimer disease (AD). METHODS: We followed 691 cognitively intact community-dwelling participants (mean age 79 years, 62% women) and related PBMC cytokine production (tertiles of spontaneous production of interleukin 1 [IL-1], IL-1 receptor antagonist, and tumor necrosis factor alpha [TNF-alpha]) and serum C-reactive protein and interleukin 6 (IL-6) to the risk of incident AD. RESULTS: Adjusting for clinical 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-alpha were at increased risk of developing AD (multivariable-adjusted hazard ratio [HR] for IL-1 T2 = 2.84, 95% CI 1.09 to 7.43; p = 0.03 and T3 = 2.61, 95% CI 0.96 to 7.07; p = 0.06; for TNF-alpha, adjusted HR for T2 = 1.30, 95% CI 0.53 to 3.17; p = 0.57 and T3 = 2.59, 95% CI 1.09 to 6.12; p = 0.031]) compared with those in the lowest tertile (T1). Interpretation: Higher spontaneous production of interleukin 1 or tumor necrosis factor alpha by peripheral blood mononuclear cells may be a marker of future risk of Alzheimer disease (AD) in older individuals. These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD.

Jefferson AL, Massaro JM, Wolf PA, Seshadri S, Au R, Vasan RS, Larson MG, Meigs JB, Keaney JF, Lipinska I, Kathiresan S, Benjamin EJ, DeCarli C. · Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA. · Neurology. · Pubmed #17389308 No free full text.

Abstract: BACKGROUND: Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]). METHODS: MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures. RESULTS: In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals. CONCLUSIONS: Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.

Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, Wolf PA, Seshadri S. · Department of Medicine, Morehouse School of Medicine, Atlanta, GA, USA. · Arch Neurol. · Pubmed #17101823 links to  free full text

Abstract: BACKGROUND: Diabetes mellitus (DM) could increase the risk of Alzheimer disease (AD) through several biologically plausible pathways, but the relationship between DM and the development of AD remains uncertain. OBJECTIVE: To compare the risk of developing AD in subjects with and without DM. DESIGN: Prospective community-based cohort study. PARTICIPANTS: Framingham Study Original cohort participants who were dementia free and attended the 16th biennial examination (n = 2210 persons, 1325 women; mean age, 70 years). MAIN OUTCOME MEASURES: Relative risk of incident AD (criteria from the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association) associated with baseline DM (casual plasma glucose >or=200 mg/dL [>or=11.1 mmol/L] or use of insulin or a hypoglycemic drug) in overall group and within subgroups defined by apolipoprotein E genotype and plasma homocysteine levels; models were adjusted for age, sex, and cardiovascular risk factors. RESULTS: At baseline, 202 participants (9.1%) had DM. During the follow-up period (mean, 12.7 years; range, 1-20 years), 17 of 202 persons with DM (8.4%) and 220 of 2008 persons without DM (11.0%) developed AD, yielding a relative risk of 1.15 (95% confidence interval, 0.65-2.05). Among subjects without an apolipoprotein E epsilon4 allele or elevated plasma homocysteine levels, 44 of 684 persons (6.4%) developed AD; relative risk for AD comparing diabetic patients with nondiabetic patients was 2.98 (95% confidence interval, 1.06-8.39; P = .03). The effect was strongest in persons aged 75 years or older with a relative risk of 4.77 (95% confidence interval, 1.28-17.72; P = .02). CONCLUSION: Diabetes mellitus did not increase the risk of incident AD in the Framingham cohort overall; however, DM may be a risk factor for AD in the absence of other known major AD risk factors.

McKee AC, Au R, Cabral HJ, Kowall NW, Seshadri S, Kubilus CA, Drake J, Wolf PA. · Department of Neurology and Pathology, Boston University School of Medicine, Bedford Veterans Administration Medical Center, MA 01730, USA. · J Neuropathol Exp Neurol. · Pubmed #16783172 No free full text.

Abstract: The transition from normal aging to mild cognitive impairment to Alzheimer disease (AD) is often indistinct. Imaging studies suggest early changes in posterior brain regions, including posterior temporoparietal and occipital cortex, but pathologic studies show initial changes in the medial temporal lobe with progressive neocortical involvement as cognition deteriorates. We evaluated the regional distribution of AD pathology in 41 elderly brain donors from the Framingham Heart Study who were cognitively intact, mildly impaired, or demented on the basis of probable AD. We found that 52% of the cognitively intact subjects, and all subjects with mild cognitive impairment or dementia, had dense neurofibrillary tangles (NFTs), neuropil threads, and tau-immunoreactive neurites surrounding neuritic plaques (NPs) in visual association cortex Brodmann area 19. All cognitively intact subjects with area 19 NFTs also had dense core NP and beta amyloid (Abeta) angiopathy in area 19. Area 19 pathology was occasionally present in the absence of substantial pathology in the hippocampus or entorhinal cortex and was not correlated with medial temporal lobe pathology. Dense AD pathology in area 19 is present in some cognitively intact subjects with preclinical AD. The unique metabolic, connectional, and vascular features of this region may confer enhanced vulnerability to neurodegeneration.

Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, Wolf PA. · Department of Neurology, School of Medicine, Boston University, Boston, MA 02118-2526, USA. · Stroke. · Pubmed #16397184 links to  free full text

Abstract: BACKGROUND AND PURPOSE: The lifetime risk (LTR) of stroke has not been reported for the United States population; such data would assist public education and health planning. METHODS: Framingham Original cohort participants (n=4897) who were stroke- and dementia-free at 55 years of age were followed biennially for up to 51 years (115 146 person years). We estimated the sex-specific 10-, 20-, and 30-year risks and LTR of developing a stroke by baseline age and blood pressure (BP) and compared it with the risk of developing Alzheimer disease (AD). RESULTS: A total of 875 participants (522 women) developed a first-ever stroke; 749 (448 women) had an ischemic stroke. LTR of stroke was high and remained similar at ages 55, 65, and 75 years, approximating 1 in 5 for women and 1 in 6 for men. Participants with a normal BP (<120/80 mm Hg) had approximately half the LTR of stroke compared with those with high BP (> or =140/90 mm Hg). The LTR of AD at age 65 (292 participants; 211 women) approximated 1 in 5 for women and 1 in 10 for men. The LTR of developing either stroke or dementia approximated 1 in 3 in both sexes. CONCLUSIONS: The LTR of stroke in middle-aged adults is 1 in 6 or more, which is equal to or greater than the LTR of AD. Women had a higher risk because of longer life expectancy. BP is a significant determinant of the LTR of stroke, and promotion of normal BP levels in the community might be expected to substantially reduce this risk.

Tan ZS, Seshadri S, Beiser A, Zhang Y, Felson D, Hannan MT, Au R, Wolf PA, Kiel DP. · Division on Aging, Harvard Medical School, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02215, USA. · Arch Neurol. · Pubmed #15642856 links to  free full text

Abstract: BACKGROUND: Some, but not all, studies have suggested that estrogen replacement therapy has a beneficial effect on cognition in postmenopausal women. Bone mineral density (BMD) is a potential surrogate marker for cumulative estrogen exposure and has been associated with cognitive performance and risk of cognitive deterioration. OBJECTIVE: To examine whether low BMD in elderly individuals is associated with an increased risk of developing Alzheimer disease (AD). DESIGN, SETTING, AND PARTICIPANTS: Community-based prospective cohort study of 987 subjects (610 women) who were cognitively intact and had baseline BMD measured at the femoral neck, the trochanter, and the radial shaft between 1988 and 1989. MAIN OUTCOME MEASURES: Incidence of AD and all-cause dementia during an 8-year follow-up period. RESULTS: Women in the lowest quartile of femoral neck BMD had more than twice the incidence of AD (hazard ratio, 2.04; 95% confidence interval, 1.11-3.75) and all-cause dementia (hazard ratio, 2.01; 95% confidence interval, 1.16-3.49) compared with those in higher quartiles after adjusting for age, sex, apolipoprotein E epsilon4, baseline homocysteine level, education, estrogen use, smoking, and stroke. A similar but statistically nonsignificant relationship was observed between BMD of the femoral trochanter and AD, while no such relationship was seen between radial BMD and AD or all-cause dementia. In men, there was a trend toward an inverse relationship between BMD and the risk of AD, but the relationship was not statistically significant at any of the 3 sites. CONCLUSIONS: Low femoral neck BMD was associated with approximately 2 times the risk of AD and all-cause dementia in women but not men, suggesting the possibility that cumulative estrogen exposure may influence the risk of developing AD. Additional studies are needed to confirm this correlation.