Alzheimer Disease: Qiu WQ

Qiu WQ, Folstein MF. · Department of Psychiatry, New England Medical Center and Tufts University School of Medicine, 150 Harrison Avenue, Rm 234, Boston, MA 02111, USA. · Neurobiol Aging. · Pubmed #16399206 No free full text.

Abstract: Clinical and epidemiological studies have found that type 2 diabetes, and hyperinsulinaemia, increased the risk of developing Alzheimer's disease (AD) in the elderly. The link between hyperinsulinaemia and AD may be insulin-degrading enzyme (IDE). This enzyme degrades both insulin and amylin, peptides related to the pathology of type 2 diabetes, along with amyloid-beta peptide (Abeta), a short peptide found in excess in the AD brain. We review the current evidence, which suggests that hyperinsulinaemia may elevate Abeta through insulin's competition with Abeta for IDE. Genetic studies have also shown that IDE gene variations are associated with the clinical symptoms of AD as well as the risk of type 2 diabetes. The deficiency of IDE can be caused by genetic variation or by the diversion of IDE from the metabolism of Abeta to the metabolism of insulin. It is intriguing to notice that both hyperinsulinaemia and IDE gene variations are related to the risk of AD when the Apolipoprotein E4 (ApoE4) allele, the major risk factor of late-onset AD, is not present. Further studies of the role of IDE in the pathogenesis of AD, which may uncover potential treatment target, are much needed.

Okereke OI, Xia W, Irizarry MC, Sun X, Qiu WQ, Fagan AM, Mehta PD, Hyman BT, Selkoe DJ, Grodstein F. · Division of Aging, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. · J Alzheimers Dis. · Pubmed #19221417 No free full text.

Abstract: Identifying biomarkers of Alzheimer's disease (AD) risk will be critical to effective AD prevention. Levels of circulating amyloid-beta (Abeta) 40 and 42 may be candidate biomarkers. However, properties of plasma Abeta assays must be established. Using five different protocols, blinded samples were used to assess: intra-assay reproducibility; impact of EDTA vs. heparin anticoagulant tubes; and effect of time-to-blood processing. In addition, percent recovery of known Abeta concentrations in spiked samples was assessed. Median intra-assay coefficients of variation for the assay protocols ranged from 6-24% for Abeta(40), and 8-14% for Abeta(42). There were no systematic differences in reproducibility by collection method. Plasma concentrations of Abeta (particularly Abeta(42) appeared stable in whole blood kept in ice packs and processed as long as 24 hours after collection. Recovery of expected concentrations was modest, ranging from -24% to 44% recovery of Abeta(40), and 17% to 61% of Abeta(42). In conclusion, across five protocols, plasma Abeta(40) and Abeta(42) levels were measured with generally low error, and measurements appeared similar in blood collected in EDTA versus heparin. While these preliminary findings suggest that measuring plasma Abeta(40) and Abeta(42) may be feasible in varied research settings, additional work in this area is necessary.

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.

Qiu WQ, Sun X, Selkoe DJ, Mwamburi DM, Huang T, Bhadela R, Bergethon P, Scott TM, Summergrad P, Wang L, Rosenberg I, Folstein M. · Department of Psychiatry, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA, USA. · Int J Geriatr Psychiatry. · Pubmed #17096467 No free full text.

Abstract: BACKGROUND: Depression often precedes the onset of Alzheimer's disease (AD) before the appearance of cognitive symptoms. Plasma Amyloid-beta peptide 42 (Abeta42) declines before and soon after the onset of AD, yet the relationship between plasma Abeta42 and depression is unclear. METHODS: We used 515 homebound elders aged 60 and older in a population-based, cross-sectional study to investigate associations between plasma Abeta levels and depression with and without cardiovascular co-morbidities. Depression was evaluated by using the Center for Epidemiological Studies Depression (CES-D) scale. Plasma Abeta40 and Abeta42 were measured. RESULTS: The elderly with depression had lower plasma Abeta42 (median: 15.3 vs. 18.9, p = 0.008) than those without depression. The CES-D score was inversely associated with plasma Abeta42 (p = 0.001) in subjects with no cardiovascular disease (CVD); however, in the presence of CVD, this association did not exist. Low plasma Abeta42 (OR = 0.41, p = 0.007) and the presence of CVD (OR = 1.84, p = 0.005) were independently associated with depression after adjusting for the confounders of age, stroke and apolipoprotein E4. CONCLUSIONS: Depressive symptoms are associated with low plasma Abeta42 independently of CVD. Prospective studies are needed to determine whether depression associated with low plasma Abeta42 is a separate depression subtype that could predict the onset of AD.

Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ. · Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · J Neurosci. · Pubmed #10684867 links to  free full text

Abstract: Progressive cerebral accumulation of amyloid beta-protein (Abeta) is an early and invariant feature of Alzheimer's disease. Little is known about how Abeta, after being secreted, is degraded and cleared from the extracellular space of the brain. Defective Abeta degradation could be a risk factor for the development of Alzheimer's disease in some subjects. We reported previously that microglial cells release substantial amounts of an Abeta-degrading protease that, after purification, is indistinguishable from insulin-degrading enzyme (IDE). Here we searched for and characterized a role for IDE in Abeta degradation by neurons, the principal cell type that produces Abeta. Whole cultures of differentiated pheochromocytoma (PC12) cells and primary rat cortical neurons actively degraded endogenously secreted Abeta via IDE. However, unlike that in microglia, IDE in differentiated neurons was not released but localized to the cell surface, as demonstrated by biotinylation. Undifferentiated PC12 cells released IDE into their medium, whereas after differentiation, IDE was cell associated but still degraded Abeta in the medium. Overexpression of IDE in mammalian cells markedly reduced the steady-state levels of extracellular Abeta(40) and Abeta(42), and the catalytic site mutation (E111Q) abolished this effect. We observed a novel membrane-associated form of IDE that is approximately 5 kDa larger than the known cytosolic form in a variety of cells, including differentiated PC12 cells. Our results support a principal role for membrane-associated and secreted IDE isoforms in the degradation and clearance of naturally secreted Abeta by neurons and microglia.