Journal of Alzheimer's Disease - Volume 16, issue 4

Authors: Bierhaus, Angelika | Nawroth, Peter P.

Article Type: Editorial

DOI: 10.3233/JAD-2009-1023

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 673-675, 2009

Authors: Kopf, Daniel | Frölich, Lutz

Article Type: Research Article

Abstract: Diabetes mellitus is an established risk factor of cognitive decline. This excess risk has frequently been attributed to cerebrovascular disease. The contribution of diabetes mellitus to the risk of Alzheimer's disease is less clear. We performed a systematic literature review based on prospective studies that examined the risk of incident Alzheimer's disease in diabetic patients. Fourteen studies in eleven different populations fulfilled the entry criteria. Only one study per population was included by pre-defined criteria, leaving eleven studies for analysis. All studies reported risk ratios greater than one (median 1.59, range 1.15–2.7). In four studies, this excess risk was statistically …significant (median 1.73, range 1.59–1.9); in seven studies the lower border of the 95% confidence interval was below 1.0. Factors associated with significant results were a sample size of 600 or more diabetic subjects, inclusion of patients with mild glycemic dysregulation as assessed by oral glucose tolerance test, and a high proportion of diagnoses of Alzheimer's disease verified by autopsy or magnetic resonance imaging. Diabetes mellitus is likely to increase the risk of Alzheimer's disease. The association of Alzheimer's disease and diabetes mellitus is more clear-cut, if mild cases of diabetes mellitus are included in the analysis. Show more

Keywords: Alzheimer's disease, dementia, diabetes mellitus, hyperinsulinemia, incidence, prospective studies

DOI: 10.3233/JAD-2009-1011

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 677-685, 2009

Authors: Toro, Pablo | Schönknecht, Peter | Schröder, Johannes

Article Type: Research Article

Abstract: Diabetes mellitus type 2 (T2DM) is considered to be an important risk factor for mild cognitive impairment (MCI) and subsequent Alzheimer's disease (AD). The majority of studies relating T2DM to MCI and AD were performed in North America. We investigated the potential impact of T2DM on the development of MCI and AD in the Interdisciplinary Longitudinal Study on Adult Development and Aging which involves a representative birth cohort of subjects born between 1930 and 1932 in Germany. Subjects received a thorough psycho-geriatric examination and neuropsychological testing; particular care was taken to exclude subjects with severe medical or neurological conditions sufficient …to explain the cognitive deficits, or other major psychiatric disorders. When compared to healthy subjects (n = 159), patients with MCI (n = 108) or AD (n = 26) showed a tendency towards increased prevalence rates for T2DM (17% vs. 23%; χ2 = 1.7, p = 0.18). In both patients with MCI and controls, T2DM was associated with psychomotor slowing but not deficits in other cognitive domains typically involved in MCI. Our findings indicate that T2DM is involved in MCI and may aggravate the clinical picture as a concomitant factor. Show more

Keywords: Aging-associated cognitive decline, Alzheimer's disease, diabetes mellitus, Interdisciplinary Longitudinal Study on Adult Development and Aging, mild cognitive impairment

DOI: 10.3233/JAD-2009-0981

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 687-691, 2009

Authors: Luchsinger, José A. | Gustafson, Deborah R.

Article Type: Research Article

Abstract: This manuscript provides a comprehensive review of the epidemiologic evidence linking the continuum of adiposity and type 2 diabetes (T2D) with Alzheimer's disease (AD). The mechanisms relating adiposity and T2D to AD may include hyperinsulinemia, advanced products of glycosylation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of AD but the data on this association in old age is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of AD. Hyperinsulinemia is a risk factor for …T2D, and numerous studies have shown a relation of T2D with higher AD risk. The implication of these associations is that a large proportion of the world population may be at increased risk of AD given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and T2D. However these associations may present a unique opportunity for prevention and treatment of AD. Several studies in the prevention and treatment of T2D are currently conducting, or have planned, cognition ancillary studies. In addition, clinical trials using insulin sensitizers in the treatment or prevention of AD are under way. Show more

Keywords: Adiposity, Alzheimer's disease, cognitive impairment, glucose, hyperinsulinemia, insulin, obesity, overweight, type 2 diabetes

DOI: 10.3233/JAD-2009-1022

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 693-704, 2009

Authors: Tong, Ming | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be associated with cognitive impairment or early neurodegeneration. Previously, we showed that diet-induced obesity with T2DM and NASH results in mild neurodegeneration with some features of AD, including brain insulin resistance. In a companion study, we correlated obesity/T2DM/NASH-associated central nervous system (CNS) abnormalities with increased pro-ceramide gene expression in liver. Since ceramides are neurotoxic and cause insulin resistance, we directly investigated the role of ceramides as mediators of neurodegeneration using an in vitro culture model. We treated PNET2 human CNS neuronal cells with D-erythro-Ceramide analogs (C2Cer:N-acetylsphinganine and C6Cer: N-hexanoylsphinganine), …or the inactive dihydroceramide analog (C2DCer) for 48 h, and probed for changes in genes and proteins that are critical to insulin/IGF signaling, and associated with neurodegeneration. Exposure to C6Cer > C2Cer impaired energy metabolism, viability, and insulin and insulin-like growth factor signaling mechanisms, and resulted in increased levels of AβPP-Aβ and pTau, whereas C2D had no significant effect on these parameters. CNS exposure to neurotoxic ceramides from exogenous sources, including liver, can cause neurodegeneration with impairments in insulin and IGF signaling mechanisms, similar to the findings in experimental models of obesity/T2DM, and NASH. Show more

Keywords: Alzheimer's disease, central nervous system, ceramide, diabetes mellitus, insulin resistance, neurodegeneration, neurons, non-alcoholic steatohepatitis

DOI: 10.3233/JAD-2009-0983

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 705-714, 2009

Authors: Lyn-Cook Jr., Lascelles E. | Lawton, Margot | Tong, Ming | Silbermann, Elizabeth | Longato, Lisa | Jiao, Ping | Mark, Princess | Wands, Jack R. | Xu, Haiyan | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be complicated by cognitive impairment and neurodegeneration. Experimentally, high fat diet (HFD)-induced obesity with T2DM causes mild neurodegeneration with brain insulin resistance. Since ceramides are neurotoxic, cause insulin resistance, and are increased in T2DM, we investigated the potential role of ceramides as mediators of neurodegeneration in the HFD obesity/T2DM model. We pair-fed C57BL/6 mice with a HFD or control diet for 4–20 weeks and examined pro-ceramide gene expression in liver and brain and neurodegeneration in the temporal lobe. HFD feeding gradually increased body weight, but after 16 weeks, liver …weight surged (P < 0.001) due to lipid (triglyceride) accumulation (P < 0.001), and brain weight declined (P < 0.0001-Trend analysis). HFD feeding increased ceramide synthase, serine palmitoyl transferase, and sphingomyelinase expression in liver (P < 0.05 – P < 0.001), but not brain. In HFD fed mice, temporal lobe levels of ubiquitin (P < 0.001) and 4-hydroxynonenal (P < 0.05 or P < 0.01) increased, and tau, β-actin, and choline acetyltransferase levels decreased (P < 0.05 – P < 0.001) with development of NASH. In obesity, T2DM, or NASH, neurodegeneration with brain insulin resistance may be mediated by excess hepatic production of neurotoxic ceramides that readily cross the blood-brain barrier. Show more

Keywords: Alzheimer's disease, amyloid, diabetes mellitus, high fat diet, insulin resistance, neurodegeneration, non-alcoholic steatohepatitis, obesity

DOI: 10.3233/JAD-2009-0984

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 715-729, 2009

Authors: Tezapsidis, Nikolaos | Johnston, Jane M. | Smith, Mark A. | Ashford, J. Wesson | Casadesus, Gemma | Robakis, Nikolaos K. | Wolozin, Benjamin | Perry, George | Zhu, Xiongwei | Greco, Steven J. | Sarkar, Sraboni

Article Type: Research Article

Abstract: Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin …levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients. Show more

Keywords: AICAR, AMP-activated kinase, amyloid-β, glycogen synthase kinase-3, leptin, tau

DOI: 10.3233/JAD-2009-1021

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 731-740, 2009

Authors: Moreira, Paula I. | Duarte, Ana I. | Santos, Maria S. | Rego, A. Cristina | Oliveira, Catarina R.

Article Type: Research Article

Abstract: The processes underlying the pathogenesis of Alzheimer's disease involve several factors including impaired glucose/energy metabolism, mitochondrial dysfunction, oxidative stress and altered insulin-signaling pathways. This review is mainly devoted to discuss evidence supporting the notion that mitochondrial dysfunction and oxidative stress are interconnected and intimately associated with the development and progression of Alzheimer's disease. Furthermore, the review explores the role of insulin signaling in the pathophysiology of the disease. Indeed, several studies have begun to find links between insulin and mechanisms with clear pathogenic implications for this disorder. Understanding the key mechanisms involved in the etiopathogenesis of Alzheimer's disease may provide …opportunities for the design of efficacious preventive and therapeutic strategies. Show more

Keywords: Alzheimer's disease, glucose metabolism, insulin, mitochondria, oxidative stress

DOI: 10.3233/JAD-2009-0972

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 741-761, 2009

Authors: Reddy, V. Prakash | Zhu, Xiongwei | Perry, George | Smith, Mark A.

Article Type: Research Article

Abstract: Oxidative stress plays a major role in diabetes as well as in Alzheimer's disease and other related neurological diseases. Intracellular oxidative stress arises due to the imbalance in the production of reactive oxygen/reactive nitrogen species and cellular antioxidant defense mechanisms. In turn, the excess reactive oxygen/reactive nitrogen species mediate the damage of proteins and nucleic acids, which have been shown to have direct and deleterious consequences in diabetes and Alzheimer's disease. Oxidative stress also contributes to the production of advanced glycation end products through glycoxidation and lipid peroxidation. The advanced glycation end products and lipid peroxidation products are ubiquitous to …diabetes and Alzheimer's disease and serve as markers of disease progression in both disorders. Antioxidants and advanced glycation end products inhibitors, either induced endogenously or exogenously introduced, may counteract with the deleterious effects of the reactive oxygen/reactive nitrogen species and thereby, in prevention or treatment paradigms, attenuate or substantially delay the onset of these devastating pathologies. Show more

Keywords: Advanced glycation end products, AGE inhibitors, Alzheimer's disease, diabetes, glycation, Maillard reaction, oxidative stress, protein crosslinks

DOI: 10.3233/JAD-2009-1013

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 763-774, 2009

Authors: Muhammad, Sajjad | Bierhaus, Angelika | Schwaninger, Markus

Article Type: Research Article

Abstract: A morphological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-β peptide in plaques and along blood vessels. As several lines of evidence suggest that vascular dysfunction contributes to AD, the pathophysiology of diabetic vasculopathy and stroke may cast light on the vascular component of AD. In this review, we compile some recent findings on the role of reactive oxygen species in diabetes-induced vascular dysfunction and the consequent cerebral ischemia and compare them with key findings in AD. Overall, there is compelling evidence that reactive oxygen species play a key role in the pathophysiology of AD. Unfortunately, this insight …has not yet led to a new treatment of AD. Show more

Keywords: Antioxidants, endothelial dysfunction, mitochondrial dysfunction, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-2009-0982

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 775-785, 2009