Current Alzheimer Research - Volume 4, Issue 2, 2007

There is a worldwide increase in obesity and this increase is of epidemic proportions in the United States [1]. In the last few years, a number of epidemiological studies have pointed to a link between obesity at midlife and the risk of late-life dementia and Alzheimer's disease (AD) [2]. Obesity is a key component of metabolic syndrome which is defined as a clustering of central adiposity, insulin resistance, atherogenic dyslipidemia, hypertension, and endothelial dysfunction. Epidemiological data have also found an association between metabolic syndrome and accelerated cognitive decline in non-demented elderly individuals. This negative impact is further accentuated in individuals with high levels of inflammatory markers in their circulation [3]. Individual components of metabolic syndrome, such as insulin resistance, midlife hypercholesterolemia and hypertension also correlate with increased risk of developing AD [4]. In light of these findings and given the rise in childhood obesity [5] and the prevalence of obesity and metabolic syndrome in the US, there is a need to stimulate research that would examine the possible link between obesity, as well as other components of metabolic syndrome, and AD and to delineate the molecular mechanisms by which disrupted systemic metabolism may influence the transition between normal brain aging and Alzheimer's disease. As a first step towards this goal the National Institute on Aging (NIA) convened a two-day multidisciplinary workshop that brought together basic research scientists, epidemiologists and clinicians from academia as well as from the pharmaceutical industry. The scientific background of the speakers spanned neuroscience,physiology, endocrinology and genetics. In addition to the 21 speakers, the workshop convened about 40 guests from the NIA, the National institute of Neurological Disorders and Stroke, National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Dietary Supplements, and other relevant organizations such as the Alzheimer's Association, the Institute for the Study of Aging, the American Diabetes Association, and the Food and Drug Administration.The workshop was co-sponsored by the Office of Dietary Supplements at the National Institute of Health and by the Alzheimer's Association. The participants of this exploratory workshop critically appraised the current state of knowledge on the subject of obesity, metabolic syndrome and cognition as it relates to AD. This Special Issue brings an array of minireviews, position papers and original research articles contributed by the workshop participants and their colleagues. The authors present a number of new ideas as to how this complex subject can be addressed for the purpose of advancing our understanding and treatment of AD. Some of the questions raised at the workshop and in this issue are: . Do obesity and other components of the metabolic syndrome influence normal brain aging and the transition between normal brain aging and AD, and if so, by what mechanisms? . Do individual components of the metabolic syndrome interact to accelerate brain aging and if they do, what mechanisms are involved? . What is the impact of obesity, hypertension, dyslipidemia and systemic proinflammatory state on the cerebrovasculature and the neurovascular unit? . Are there late-life cognitive consequences of overfeeding or underfeeding early in life and during development? . Does early programming play a role in the etiology of sporadic Alzheimer's disease and, if it does, which epigenetic mechanisms are involved? . Do the hypothalamic-pituitary axis and glucocorticoids have a role in translating the disruption in systemic metabolic homeostasis to AD-related neurodegeneration and, if so, by what mechanisms? . If certain components of the metabolic syndrome are in the causal pathway to AD or contribute to its progression what are the new therapeutic targets and modalities that we can address?.......

The increasing prevalence of obesity world-wide has an expected consequent increase in diabetes and cardiovascular disease. Less attention has been paid to the effect of obesity on dementia. This overview discusses methodological issues related to the epidemiologic study of obesity and dementia, reviews results of long-term prospective studies, and briefly considers possible mechanisms for an obesity-dementia association. At least six cohort studies of 18 to 32 years duration confirm that overweight middle-aged or older adults are at increased risk of dementia in later life. In many of these studies, the association persisted after adjusting for classical cardiovascular risk factors. A few epidemiologic studies (and more laboratory studies not reviewed here) suggest biomarkers such as C-reactive protein, interleukin 6, and leptin may explain part of the obesity-dementia connection. If any of these factors are in the causal pathway to dementia, their reversal or prevention by weight control would have huge public health importance.

Prior work has suggested that obesity and overweight as measured by body mass index (BMI) increases risk of dementia. It is unknown if there is a difference in the risk of developing Alzheimer disease (AD) versus vascular dementia (VaD) associated with high body weight. The goal of this study was to examine the association between midlife BMI and risk of both AD and VaD an average of 36 years later in a large (N= 10,136) and diverse cohort of members of a health care delivery system. Participants aged 40-45 participated in health exams between 1964 and 1968. AD and VaD diagnoses were obtained from Neurology visits between January 1, 1994 and June 15, 2006. Those with diagnoses of general dementia from primary care providers were excluded from the study. BMI was analyzed in WHO categories of underweight, overweight and obese, as well as in subdivisions of WHO categories. All models were fully adjusted for age, education, race, sex, marital status, smoking, hyperlipidemia, hypertension, diabetes, ischemic heart disease and stroke. Cox proportional hazard models showed that compared to those with a normal BMI (18.5-24.9), those obese (BMI > 30) at midlife had a 3.10 fold increase in risk of AD (fully adjusted model, Hazard Ratio=3.10, 95% CI 2.19-4.38), and a five fold increase in risk of VaD (fully adjusted model, HR=5.01, 95% CI 2.98-8.43) while those overweight ( BMI > 25 and <30) had a two fold increase in risk of AD and VaD (fully adjusted model, HR=2.09, 95% CI 1.69-2.60 for AD and HR=1.95, 95% CI 1.29-2.96 for VaD). These data suggest that midlife BMI is strongly predictive of both AD and VaD, independent of stroke, cardiovascular and diabetes co morbidities. Future studies need to unveil the mechanisms between adiposity and excess risk of AD and VaD.

Background: Obesity has been related to the incidence of dementia but its impact on cognitive performance in persons without dementia is less clear. We hypothesized that mid-life obesity may modulate the impact of conventional cardiovascular risk factors (CVRF) on cognitive impairment. We tested this hypothesis in the community-based Framingham Offspring Study sample. Methods: At Examination cycle 4 (1988-90) of the Offspring Cohort, indices of obesity (BMI and Waist-Hip Ratio [WHR]) and baseline CVRF levels were ascertained in 1,814 men and women, aged 40-69 years. Obesity and hypertension were related to the score on each of 8 neurocognitive tests measured at Examination 8, 12 years later (1999-2002). Results: Midlife measures of central obesity (WHR in the uppermost quartile- Q4) and of hypertension (BP≥140/≥90 or use of anti-hypertensive medication) were each significantly related to poorer performance on executive function & visuomotor skills (Trails B, Visual Reproductions-Immediate and Delayed Recall). Further, the relation of hypertension to neurocognitive performance was significantly modified by WHR; hypertension was not associated with neurocognitive performance in WHR Q1-Q3, but was associated with a marked adverse performance in Q4 WHR. Neither HTN nor obesity was individually or synergistically related to verbal memory (immediate or delayed recall). Conclusions: Executive function and visuomotor skills were differentially affected by the combined presence of midlife hypertension and Q4 WHR while measures of verbal memory function were not related to these risk factors in our sample, a pattern consistent with vascular cognitive impairment. Control of mid-life elevated blood pressure and central obesity may be strategies to reduce cognitive decline with age.

Adipose tissue is the largest endocrine gland in the body, yet only recently has its role in neurodegenerative disease been considered. Prospective population level evidence has emerged to show that both obesity and overweight, is associated with an increased risk of all cause dementia, Alzheimer's disease (AD), and underlying neurodegenerative changes. Weight loss in late life however is associated with dementia, and those categorized as underweight are also at a greater risk of dementia. Given the current epidemic of obesity, and the expected age-related increase in dementia incidence, even a small association between these two diseases has far reaching public health implications. However, due to the effects of both AD-associated weight loss and age-related changes in body composition, there are methodological challenges in appropriately evaluating obesity as a risk factor for developing dementia. There is a need to take a ‘life course approach’ and to consider the role of risk factors prior to the onset of old age. Our work has shown that both obesity and overweight, as measured by body mass index and skinfold thickness, in middle-age are strongly associated with an increased risk of all cause dementia, Alzheimer disease & Vascular dementia, independent of the development of diabetes and cardiovascular-related morbidities. There is also value in assessing regional body shape distributions of adiposity, particular the role of abdominal obesity. Mechanistic pathways such as adipocyte secreted proteins and hormones, and inflammatory cytokines could explain the association between obesity and increased risk of dementia.

Over 33% of women and 20% of men aged 65 and older will develop dementia during their lifetime, and many more will develop a milder form of cognitive impairment. Given the anticipated exponential increase in both the incidence and prevalence of cognitive impairment in the next century, it is critical to identify preventative strategies to thwart this critical public health issue. The metabolic syndrome is comprised of five cardiovascular risk factors that include abdominal obesity, hypertriglyceridemia, low high density lipoprotein (HDL) levels, hypertension, and hyperglycemia. The prevalence of the metabolic syndrome, similar to that for cognitive disorders, increases dramatically with age. While several of the individual components of the metabolic syndrome have been linked to risk of developing dementia and cognitive impairment, few studies have looked at the components of the metabolic syndrome as a whole. We found, in two separate studies involving elders of different ethnicities, that the metabolic syndrome is a risk factor for accelerated cognitive aging. This was especially true for elders with the metabolic syndrome and with elevated serum level of inflammation. Several possible mechanisms may explain the association between the metabolic syndrome and cognitive decline including micro- and macro-vascular disease, inflammation, adiposity and insulin resistance. If metabolic syndrome is associated with increased risk of developing cognitive impairment, regardless of mechanism, then early identification and treatment of these individuals might offer avenues for disease course modification.

The objective of this manuscript is to provide a comprehensive review of the relation between adiposity and Alzheimer's disease (AD), its potential mechanisms, and issues in its study. Adiposity represents the body fat tissue content. When the degree of adiposity increases it can be defined as being overweight or obese by measures such as the body mass index. Being overweight or obese is a cause of hyperinsulinemia and diabetes, both of which are risk factors for AD. However, the epidemiologic evidence linking the degree of adiposity and AD is conflicting. Traditional adiposity measures such as body mass index have decreased validity in the elderly. Increased adiposity in early or middle adult life leads to hyperinsulinemia which may lead to diabetes later in life. Thus, the timing of ascertainment of adiposity and its related factors is critical in understanding how it might fit into the pathogenesis of AD. We believe that the most plausible mechanism relating adiposity to AD is hyperinsulinemia, but it is unclear whether specific products of adipose tissue also have a role. Being overweight or obese is increasing in children and adults, thus understanding the association between adiposity and AD has important public health implications.

Brain imaging has played a major role in exploring abnormalities of brain structure and function in aging and dementia. Recently, with reports linking obesity to cognitive decline and dementia, magnetic resonance imaging has been used to investigate how brain structure may be altered with obesity. These studies have convincingly demonstrated both generalized and regional brain atrophy and changes in white matter in association with obesity. These results do not appear to be simply explained by links to cardiovascular disease. However, the mechanisms underlying these alterations are unclear and could be accounted for by a number of different processes that are known to alter brain structure and which could also be related to obesity. Application of additional imaging methods could help to establish the pathway through which obesity produces cognitive decline and dementia.

Epidemiologic studies have provided important clues about the etiology, prognosis and options for prevention and treatment of AD, and sub-clinical changes in cognition and brain structure. A brief review is given of what we have learned from epidemiologic studies of risk factors and natural history. This is followed by a discussion of how these findings could inform the design of basic research strategies that may further the translation of bench science to the clinic and public health arena.

Emerging evidence suggests that components of the metabolic syndrome either in isolation or in aggregate may impact the onset or severity of neurodegenerative processes, including those physiologic changes that lead to Alzheimer's Disease (AD). Several animal models that were originally designed to interrogate the metabolic syndrome are readily available. These models can now be used to support studies that may provide new mechanistic links between the metabolic syndrome and neurodegeneration. In addition, animal strains currently being generated and phenotyped through the efforts of an array of NIDDK-supported projects are likely to provide novel and better tools to advance Alzheimer's disease research in the near future.

Insulin modulates cognition and other aspects of normal brain function. Insulin resistance is characterized by chronic peripheral insulin elevations, and it is accompanied by reduced brain insulin levels and insulin activity. Obesity, type 2 diabetes mellitus and hypertension are strongly associated with insulin resistance. In addition, insulin resistance increases the risk of age-related memory impairment and Alzheimer's disease. Possible mechanisms through which these risks are increased include the effects of peripheral hyperinsulinemia on memory, CNS inflammation, and regulation of the β-amyloid peptide. We have shown that raising plasma insulin in humans to levels that characterize patients with insulin resistance increases the levels of Aβ and inflammatory agents in brain. These convergent effects may impair memory and induce AD pathology. Therapeutic strategies focused on preventing or correcting insulin abnormalities may thus benefit a subset of adults with age-related memory impairment and AD.

Identification of genes and pathways that alter lifespan has allowed for new insights into factors that control the aging process as well as disease. While strong molecular links exist between aging and metabolism, we hypothesize that targeting the mechanisms involved in aging will also give rise to therapeutics that treat other devastating age-related diseases, such as neurodegeneration, cancer, inflammation and cardiovascular disease. Insulin sensitivity, glycemic control and adiposity are not only hallmarks of the major metabolic diseases, type 2 diabetes and obesity, but they also represent significant risk factors for the development of Alzheimer's Disease and cognitive impairment. Insulin/IGF-1 signaling is an important pathway regulating aging and disease in a variety of species, including mammals. Here we describe an important role for the gut-derived peptide ghrelin in upstream signaling through the insulin/IGF-1 pathway and exemplify modulation of ghrelin signaling as an approach to mechanistic treatment of multiple age-related diseases by virtue of its ability to regulate key metabolic functions.

Alzheimer's disease (AD) is a devastating neurodegenerative disease for which there are no highly effective therapies. A novel therapeutic approach to the treatment of AD is the use of agonists of the nuclear receptor, peroxisome proliferators-activated receptor gamma (PPARγ). PPARγ is a ligand activated transcription factor whose best described roles are to regulate lipid metabolism and inflammation. Agonists of PPARγ have been shown to ameliorate AD-related pathology in animal models of AD and improve cognition. A number of potential mechanisms have been advanced to account for these effects. PPARγ agonists act as insulin sensitizers, facilitating insulin action. In addition, PPARγ agonists have been shown to inhibit inflammatory gene expression, alter A β homeostasis and exhibit neuroprotective effects. Importantly, recent clinical trials of FDA approved PPARγ agonists have been shown to improve cognition and memory in AD patients. Thus, PPAR agonists represent a new and potentially efficacious treatment of AD.

Mounting evidence suggests that copper may influence the progression of Alzheimer's disease by reducing clearance of the amyloid beta protein (Aß) from the brain. We propose that Aβ is cleared from the brain by tagging along with cholesterol/ApoE in traversing the BBB, with subsequent incorporation into HDL for delivery of the toxin to the liver. It is suggested that either ABC-A1 or LRP, or both are involved in Aβ transport across the BBB, as well as normal cholesterol efflux. We have previously shown that addition of only 0.12 PPM copper (one-tenth the Environmental Protection Agency Human consumption limits) to distilled water was sufficient to precipitate the accumulation of Aß in the brains of cholesterol-fed rabbits. Here we show that in a setting of elevated cholesterol levels, overproduced Aβ is cleared to the blood and can simultaneously be identified in the liver if copper ion is absent from the animal's drinking water, but if trace levels copper (0.12 PPM) are added to the drinking water Aβ accumulates in the brain, while the levels in the liver are greatly reduced.

Studies, ranging from epidemiological to in vitro and in vivo experimental settings have provided convincing evidence that different aspects of brain lipid metabolism may influence Alzheimer disease pathogenesis through effects on β-amyloid deposition and clearance. It has been demonstrated that transcription factors called nuclear liver X receptors (LXR) and their responsive genes provide natural regulatory mechanisms and influence AD pathogenesis through their modulatory effects on intracellular cholesterol content, cholesterol efflux and possibly via anti-inflammatory mechanisms. Here, we provide a brief summary of the approaches undertaken by different groups that lead to the nowadays working model of LXR and ABCA1 regulatory role in brain amyloidogenesis and amyloid clearance and we highlight the therapeutic potential of LXR agonists.

Liver X receptors (LXRα and LXRβ ) are oxysterol receptors that function as master transcription factors mediating cholesterol homeostasis in the periphery. LXRs regulate the levels of the ABCA1 and ABCG1 cholesterol transporters as well as apolipoproteins (apoE and apoC) in various cells thereby affecting cholesterol transport and metabolism. In the brain, LXRs regulate ABCA1 in both neurons and glia resulting in cholesterol efflux from these cells. In addition, the expression of apolipoprotein E (apoE), synthesized primarily by astrocytes and microglia, is also upregulated by LXR agonists. As both apoE and the ABCA1 transporter are intimately involved in amyloid-β peptide (Aβ ) transport and clearance, activation of these genes by LXR agonists in brain may have a significant impact on Aβ deposition and amyloid/ neuritic plaque formation. Furthermore, LXR activation has been shown to have significant anti-inflammatory properties. Taken together, these findings suggest that brain-penetrable LXR agonists or modulators may be useful therapeutic agents for the treatment and (or) prevention of Alzheimer's disease.

Alzheimer disease (AD) includes inflammatory processes in the senile plaques and surrounding glia, with increased expression of acute phase proteins such as C-reactive protein (CRP) and IL-6. Increased IL-6 expression during normal brain aging suggests a link of age-related inflammation to the onset of AD during aging. Blood levels of CRP and IL-6 are also associated with higher risk of Alzheimer disease and cognitive decline during aging. Some infections are known to induce inflammation and amyloid deposits. For example, HIV induces the deposition of the same beta-amyloid as in Alzheimer disease. The ApoE4 allele may increase HIV-associated dementia, in addition to its well-known effect on accelerating the onset age of AD. Many other adverse effects of apoE4 are recognized, which suggested the hypothesis that apoE4 persists in human populations because of balancing selection (Charlesworth-Martin hypothesis). The apoE4 allele was acquired during human evolution and may have conferred initial advantages in pathogen resistance. As evidence for this hypothesis, apoE4 carriers have less severe liver damage during hepatitis C infections. As human lifespan lengthened and cognitive and cardiovascular health became more important, the apoE3 allele spread, while the E4 allele was maintained in all populations by balancing selection.

Cerebrovascular dysfunction contributes to the cognitive decline and dementia in Alzheimer's disease (AD), and may precede cerebral amyloid angiopathy and brain accumulation of the Alzheimer's neurotoxin, amyloid β-peptide (Aβ). The blood-brain barrier (BBB) is critical for brain Aβ homeostasis and regulates Aβ transport via two main receptors, the low density lipoprotein receptor related protein 1 (LRP1) and the receptor for advanced glycation end products (RAGE). According to the neurovascular hypothesis of AD, faulty BBB clearance of Aβ through deregulated LRP1/RAGE-mediated transport, aberrant angiogenesis and arterial dysfunction may initiate neurovascular uncoupling, Aβ accumulation, cerebrovascular regression, brain hypoperfusion and neurovascular inflammation. Ultimately these events lead to BBB compromise and chemical imbalance in the neuronal ‘milieu’, and result in synaptic and neuronal dysfunction. Based on the neurovascular hypothesis, we suggest an array of new potential therapeutic approaches that could be developed for AD to reduce neuroinflammation, enhance Aβ clearance and neurovascular repair, and improve cerebral blood flow. RAGE-based and LRP1-based therapeutic strategies have potential to control brain Aβ in AD, and possibly related familial cerebrovascular β-amyloidoses. In addition, we have identified two vascularly restricted genes, GAX (growth arrest-specific homeobox), which controls LRP1 expression in brain capillaries and brain angiogenesis, and MYOCD (myocardin), which controls contractility of cerebral arterial smooth muscle cells and influences cerebral blood flow. These findings provide insights into new pathogenic pathways for the vascular dysfunction in AD and point to new therapeutic targets for AD.

In mammals, glucocorticoid actions appear to have evolved to maintain and enhance energy stores to be used for life-saving gluconeogenesis. They act on the brain to stimulate search behaviors, palatable feeding and emotionally relevant memories, and they act on the body to mobilize stored peripheral energy and direct it to central depots that serve the substrate needs of the liver. Our work in rats shows that searching and intake of palatable foods (sucrose, saccharin and lard) are stimulated by corticosterone in a dose-related fashion. Adrenalectomized rats gain weight poorly, have low fat content, increased sympathetic neural and hypothalamo-pituitary-adrenal outflow, and altered behaviors. Replacement with corticosterone reverses these effects. Surprisingly, when such rats are provided with 30% sucrose to drink, in addition to saline, all of the usual effects of adrenalectomy are corrected without corticosterone. We hypothesize that there is a metabolic feedback system that decreases stress-responsiveness. Although we have not yet identified the signal associated with sucrose drinking, the weight of mesenteric fat correlates inversely with hypothalamic corticotropin-releasing factor (CRF). When rats eat lard and sucrose ad libitum, fat stores increase and CRF, ACTH and corticosterone responses are reduced. During stress, chow intake decreases but intake of lard and sucrose does not. Our current working model suggests that palatability signals and neural signals from fat stores act on brain to reduce activity in the central stress response system. Correlative results from a clinical study support the powerful role of small changes in glucocorticoids in type 2 diabetes.

The original glucocorticoid (GC) hypothesis of brain aging and Alzheimer's disease proposed that chronic exposure to GCs promotes hippocampal aging and AD. This proposition arose from a study correlating increasing plasma corticosterone with hippocampal astrocyte reactivity in aging rats. Numerous subsequent studies have found evidence consistent with this hypothesis, in animal models and in humans. However, several results emerged that were inconsistent with the hypothesis, highlighting the need for a more definitive test with a broader panel of biomarkers. We used microarray analyses to identify a panel of hippocampal gene expression changes that were aging-dependent, and also corticosterone- dependent. These data enabled us to test a key prediction of the GC hypothesis, namely, that the expression of most target biomarkers of brain aging should be regulated in the same direction (increased or decreased) by both GCs and aging. This prediction was decisively contradicted, as a majority of biomarker genes were regulated in opposite directions by aging and GCs, particularly inflammatory and astrocyte-specific genes. Thus, the initial hypothesis of simple positive cooperativity between GCs and aging must be rejected. Instead, our microarray data suggest that in the brain GCs and aging interact in more complex ways that depend on the cell type. Therefore, we propose a new version of the GC-brain aging hypothesis; its main premise is that aging selectively increases GC efficacy in some cell types (e.g., neurons), enhancing catabolic processes, whereas aging selectively decreases GC efficacy in other cell types (e.g., astrocytes), weakening GC anti-inflammatory activity. We also propose that changes in GC efficacy might be mediated in part by cell type specific shifts in the antagonistic balance between GC and insulin actions, which may be of relevance for Alzheimer's disease pathogenesis.