Alzheimer Disease: Vasan RS

Tan ZS, Vasan RS. · Division of Aging, Brigham and Women's Hospital, Boston, MA 02160, USA. · J Alzheimers Dis. · Pubmed #19276542 No free full text.

Abstract: Thyroid dysfunction has been implicated as a cause of reversible cognitive impairment and as such, the thyroid stimulating hormone has long been part of the screening laboratory test for dementia. Recently, several population-based studies demonstrated an association between hypo- or hyperthyroidism and Alzheimer's disease. This review discusses the role of thyroid hormone in the normal development and regulation of central nervous system functions and summarizes the studies that have linked thyroid function and dementia risk. Finally, it explores possible biological mechanisms to explain this association, including the direct effects of thyroid hormone on cerebral amyloid processing, neurodegeneration and thyrotropin-mediated mechanisms and vascular mediated enhancement of Alzheimer's disease risk.

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.

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.