Journal of Alzheimer's Disease - Volume 30, issue s2

Authors: Frisardi, Vincenza | Imbimbo, Bruno P.

Article Type: Introduction

DOI: 10.3233/JAD-2012-120811

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S1-S4, 2012

Authors: Stranahan, Alexis M. | Mattson, Mark P.

Article Type: Review Article

Abstract: Mild cognitive impairment (MCI) and Alzheimer's disease (AD) represent points on a continuum of cognitive performance in aged populations. Cognition may be impaired or preserved in the context of brain aging. One theory to account for memory maintenance in the context of extensive pathology involves ‘cognitive reserve’, or the ability to compensate for neuropathology through greater recruitment of remaining neurons. In this review, we propose a complementary hypothesis of ‘metabolic reserve’, where a brain with high metabolic reserve is characterized by the presence of neuronal circuits that respond adaptively to perturbations in cellular and somatic energy metabolism and thereby protects …against declining cognition. Lifestyle determinants of metabolic reserve, such as exercise, reduced caloric intake, and intake of specific dietary components can promote neuroprotection, while pathological states arising from sedentary lifestyles and excessive caloric intake contribute to neuronal endangerment. This bidirectional relationship between metabolism and cognition may be mediated by alterations in central insulin and neurotrophic factor signaling and glucose metabolism, with downstream consequences for accumulation of amyloid-β and hyperphosphorylated tau. The metabolic reserve hypothesis is supported by epidemiological findings and the spectrum of individual cognitive trajectories during aging, with additional data from animal models identifying potential mechanisms for this relationship. Identification of biomarkers for metabolic reserve could assist in generating a predictive model for the likelihood of cognitive decline with aging. Show more

Keywords: Brain-derived neurotrophic factor (BDNF), caloric restriction, diabetes, diet, exercise, insulin, metabolic syndrome, neurodegeneration

DOI: 10.3233/JAD-2011-110899

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S5-S13, 2012

Authors: Lahiri, Debomoy K. | Maloney, Bryan

Article Type: Review Article

Abstract: Diabetes, cardiovascular disease, hypertension, and other disorders have been unified within the metabolic syndrome. Recently, it has been proposed that Alzheimer's disease (AD) and other degenerative, age-related neurological disorders may also be etiologically linked to the metabolic syndrome in a metabolic-cognitive syndrome. We review current evidence in the field for this unification. In addition, we describe how the latent early-life associated regulation (LEARn) model provides specific mechanisms to predict genetic targets for both metabolic disorders, e.g., diabetes, and neurodegenerative disorders, e.g., AD. The LEARn model is based on environmental induction of latent epigenetic misregulation, which develops into disease upon suffering …additional environmental insults. We review structural differences between gene sequences that are and are not susceptible to LEARn misregulation. In addition to suggesting research targets such as the IDE and SORCS1 genes, which are implicated in both AD and diabetes, LEARn suggests specific mechanisms for pre-disease remediation, based on nutritional adjustment of aberrant DNA methylation and oxidation. The possibility of a single metabolic-cognitive disorder opens up the possibility of unified preventative treatments that reduce monetary and social costs of disease. LEARn suggests specific, testable pathways within the large theory. Show more

Keywords: Epigenetic, epigenomic, gene regulation, idiopathic disease, metabolic-cognitive syndrome, sporadic disease, two-hit

DOI: 10.3233/JAD-2012-120373

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S15-S30, 2012

Authors: Panza, Francesco | Solfrizzi, Vincenzo | Logroscino, Giancarlo | Maggi, Stefania | Santamato, Andrea | Seripa, Davide | Pilotto, Alberto

Article Type: Review Article

Abstract: In the last decade, cumulative epidemiological evidence suggested that vascular- and metabolic-based risk factors may be important in the development of mild cognitive impairment and dementia. Epidemiological and basic research have also proposed a model of cognitive impairment linked to metabolic syndrome (MetS) and metabolic disorders, suggesting for research purposes a “metabolic-cognitive syndrome” (MCS) in patients with MetS plus cognitive impairment of degenerative or vascular origin. In particular, MetS has been associated with the risk of age-related cognitive decline and vascular dementia, but contrasting findings also existed on the possible role of MetS in overall dementia and Alzheimer's disease. Among …metabolic determinants of cognitive impairment, a better approach to the understanding of mechanisms could be to hypothesize a continuum leading to various degrees of late-life cognitive disorders in older subjects with metabolic-based risk factors. The MCS model could help us to explain the complex relationship between metabolic disorders and cognitive disturbances and the boundaries between normal and pathological conditions, with a better understanding of clinical and neuropathological features of these metabolic-based cognitive disorders. Strategies toward early and effective risk factor management could be of value in reducing the risk of MCS, so delaying the onset or preventing the progression of predementia syndromes. In the near future, clinical trials could be undertaken to determine if addressing MetS and metabolic-based risk factors, including inflammation, through lifestyle modification holds out the possibility of slowing down or ameliorating the cognitive aging process itself. Show more

Keywords: Alzheimer's disease, body mass index, dementia, diabetes mellitus, frailty, HDL cholesterol, hypertension, hypertriglyceridemia, insulin resistance, metabolic syndrome, mild cognitive impairment, obesity, predementia syndromes, vascular dementia, vascular risk factors

DOI: 10.3233/JAD-2012-111496

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S31-S75, 2012

Authors: Crichton, Georgina E. | Elias, Merrill F. | Buckley, Jonathan D. | Murphy, Karen J. | Bryan, Janet | Frisardi, Vincenza

Article Type: Review Article

Abstract: Obesity, hypertension, dyslipidemia, and insulin resistance have been associated with an increased risk of cognitive impairment or dementia. Together, these risk factors cluster as metabolic syndrome (MetS). The first aim of this systematic review was to identify and critically review studies assessing associations between MetS and cognition, with consideration given both to early cognitive changes and the severe endpoint of dementia. The second aim was to identify and discuss limitations in the literature and subsequent difficulties in drawing conclusions from research to date. Nine studies that assessed cognitive performance and ten studies that estimated incidence of dementia in relation to …MetS were identified and appraised. Limitations in the literature include the lack of standardized nomenclature for cognitive variables, the use of multiple MetS definitions, and the difficulty in differentiating the adverse effects of multiple risk factors on cognition. Show more

Keywords: Alzheimer's disease, cognition, dementia, metabolic syndrome

DOI: 10.3233/JAD-2011-111022

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S77-S87, 2012

Authors: Sellbom, Kelly Stanek | Gunstad, John

Article Type: Review Article

Abstract: Obesity is a significant contemporary health concern that carries wide-ranging implications for society, as well as for individual health and well-being. In particular, the neuropsychological sequelae of obesity carry wide ranging functional implications. While research in this area is growing, our knowledge of obesity-related cognitive dysfunction and brain alterations has not yet been synthesized. The present review integrates the recent literature regarding patterns of obesity-related cognitive dysfunction and brain alterations and also indicates potential mechanisms for these neuropathological changes. The review culminates in a preliminary model of obesity-related cognitive dysfunction and suggestions for future research, including the potential reversibility of …these changes with weight-loss. Show more

Keywords: Cognitive decline, cognitive function, dementia, obesity

DOI: 10.3233/JAD-2011-111073

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S89-S95, 2012

Authors: Gustafson, Deborah R.

Article Type: Review Article

Abstract: Level of adiposity is linked to manifest dementia and Alzheimer's disease in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. The role of adiposity during the period of cognitive decline is, as yet, not understood; however, some hypotheses relating adipose tissue to brain can be drawn. This review focuses on potential, varied mechanisms whereby adipose tissue may influence or interact with the brain and/or dementia risk during …the dynamic period of life characterized by both body weight and cognitive decline. These mechanisms relate to: a) adipose tissue location and cell types, b) body composition, c) endocrine adipose, and d) the interplay among adipose, brain structure and function, and genes. This review will illustrate that adipose tissue is a quintessential, multifunctional tissue of the human body. Show more

Keywords: Adiponectin, adipose, all cognitive disorders/dementia, Alzheimer's disease, endocrine, epidemiology, ghrelin, leptin, risk factors

DOI: 10.3233/JAD-2012-120487

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S97-S112, 2012

Authors: Elias, Merrill F. | Goodell, Amanda L. | Waldstein, Shari R.

Article Type: Review Article

Abstract: The conditions of chronic obesity and overweight status are risk factors for lower cognitive performance, cognitive decline, cognitive deficit, and dementia. But lower cognitive performance early in life itself may be a risk factor for an increase in body weight over time. With this in mind, we review important papers in the literature that advance our knowledge of relations between weight and cognitive functioning, with an emphasis on papers that illustrate methodological and theoretical issues of importance. We describe the evolution in research on weight and cognition with respect to two major features: (a) the move backward in time from …the diagnosis of dementia to the pre-clinical period of dementia in order to better identify risk factors; and (b) the evolution of studies from an earlier emphasis on obesity-related cardiovascular risk factors as major mediators of relations between obesity and cognition to a more recent emphasis on metabolic variables, lifestyle variables, genotype, and other mechanisms that explain relations among weight change, obesity, and cognition. We conclude that: 1) a complete understanding of the causal links between weight and cognitive functioning requires a lifespan perspective; 2) practically speaking, lifespan research may need to amalgamate and integrate research at different segments of the lifespan until such time that we can include the entire life cycle within a single study of weight and cognition; and 3) we need more studies that examine reciprocal relations between weight and cognition, especially early in life. Show more

Keywords: Body mass index, cognition, dementia, obesity, weight

DOI: 10.3233/JAD-2011-111175

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S113-S125, 2012

Authors: Reitz, Christiane

Article Type: Review Article

Abstract: The role of cholesterol in the etiology of Alzheimer's disease (AD) is still controversial. Some studies exploring the association between lipids and/or lipid lowering treatment and AD indicate a harmful effect of dyslipidemia and a beneficial effect of statin therapy on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including apolipoprotein E, apolipoprotein J, and the sortilin-related receptor. Functional cell biology studies support a critical involvement of lipid raft cholesterol in the modulation of amyloid-β protein precursor (AβPP) processing by …β- and γ-secretase resulting in altered amyloid-β production. Contradictory evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk. Additionally, cell biology studies suggest that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits co-localization of BACE1 and AβPP in non-raft membrane domains, thereby increasing generation of plasmin, an amyloid-β-degrading enzyme. The aim of this review is to summarize the findings of epidemiological and cell biological studies to elucidate the role of cholesterol in AD etiology. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β peptides, amyloid-β protein precursor, cholesterol, genetics, neurodegeneration

DOI: 10.3233/JAD-2011-110599

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S127-S145, 2012

Authors: van Vliet, Peter

Article Type: Review Article

Abstract: High cholesterol levels are a major risk factor for cardiovascular disease, but their role in dementia and cognitive decline is less clear. This review highlights current knowledge on the role of cholesterol in late-life cognitive function, cognitive decline, and dementia. When measured in midlife, high cholesterol levels associate with an increased risk of late-life dementia and cognitive decline. However, when measured in late-life, high cholesterol levels show no association with cognitive function, or even show an inverse relation. Although statin treatment has been shown to associate with a lower risk of dementia and cognitive decline in observational studies, randomized controlled …trials show no beneficial effect of statin treatment on late-life cognitive function. Lowering cholesterol levels may impair brain function, since cholesterol is essential for synapse formation and maturation and plays an important role in the regulation of signal transduction through its function as a component of the cell membrane. However, membrane cholesterol also plays a role in the formation and aggregation of amyloid-β. Factors that influence cholesterol metabolism, such as dietary intake, are shown to play a role in late-life cognitive function and the risk of dementia. In conclusion, cholesterol associates with late-life cognitive function, but the association is strongly age-dependent. There is no evidence that treatment with statins in late-life has a beneficial effect on cognitive function. Show more

Keywords: Amyloid-β, cholesterol, cognitive function, dementia, statins

DOI: 10.3233/JAD-2011-111028

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S147-S162, 2012