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Adiposity hormones and dementia
Journal of the Neurological Sciences 299 (2010) 30–34
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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j n s
Adiposity hormones and dementia Deborah R. Gustafson ⁎ From the Section for Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit at the Sahlgrenska Academy, University of Gothenburg, Sweden Departments of Neurology and Medicine, Section for NeuroEpidemiology, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
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Article history: Received 30 April 2010 Received in revised form 19 August 2010 Accepted 22 August 2010 Available online 27 September 2010 Keywords: Adipose Leptin Adiponectin All cognitive disorders/dementia Alzheimer's disease Risk factors Epidemicology Endocrine
a b s t r a c t Adipose tissue is an endocrine and paracrine organ that contributes to both metabolic and vascular homeostasis. Overweight and obesity due to excess adipose tissue, are cornerstones of vascular risk and increase risk for late-onset dementia. Vascular risk does not exist in isolation, and is accompanied by alterations in hormonal metabolism and metabolic syndromes. Thus, while vascular risk is highlighted as a primary mechanism for elevated dementia occurrence due to obesity, hormonal risk states may also precede or result from underlying dementia-related neuropathologies and direct neuronal toxicity. This is exemplified during the prodromal phase of dementia, as vascular and metabolic parameters decline in relation to dementia development, and potentially in a way that is different from ‘normal’ aging. In this review will be presented a review of the epidemiology of adiposity and dementia; adipose tissue biology; and two major hormones produced by adipose tissue, leptin and adiponectin, that interact directly with the brain. In addition, a synthesis related to other lines of supporting evidence for the role of adipose hormones in dementia will be provided. Understanding the role of adipose tissue in health of the brain is pivotal to a deeper understanding of dementia processes. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Overweight and obesity are cornerstones of vascular risk, and increase risk for late-onset, sporadic dementia and Alzheimer's disease (AD), as well as corresponding risk factors such as hypertension, diabetes, and cardiovascular and cerebrovascular diseases. [1] While vascular pathologies are highlighted as a primary mechanism for increased dementia and AD occurrence due to overweight and obesity, [1] vascular pathologies are concurrent with neurodegenerative pathologies. Together, they may exacerbate each other; [2] vascular processes may augment neurodegeneration; or neurodegenerative processes may be vascular. [3,4] Irrespective of the direction and temporality of the associations, vascular and neurodegenerative pathologies in the brain against the background of peripheral overweight and obesity, may contribute to metabolic risk states characterized by alterations in adipose tissue hormone levels and subsequent feedback loops. These alterations may also lead to direct neuronal toxicity perhaps due to an altered blood brain barrier. [5] Vascular pathology includes white matter lesions, lacunar infarcts, hypoperfusion, blood vessel inflammation, and cerebrovascular disease. Hallmark neuropathology in dementia and AD include amyloid plaques and neurofibrillary tangles, and markers of neuro-
⁎ Institute for Neuroscience and Physiology, Section for Psychiatry and Neurochemistry, Wallinsgatan 6, 431 41 Mölndal, Sweden. Tel.: + 46 31 343 8646, + 1 718 270 1581; fax: + 46 31 776 04 03, + 1 718 270 3840. E-mail addresses: [email protected], [email protected]. 0022-510X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.08.036
degeneration such as cerebral atrophy and synaptic dysfunction. In addition, combined neurovascular mechanisms must be considered. [6] For example, nearly every neuron in the brain has its own capillary, there is a reduction and loss of integrity in the 20 m2 of capillary surface area in the AD brain, [3] amyloid precursor protein (APP) exists in platelets and plays a role in the clotting cascade, [7] and almost all persons with AD have cerebral amyloid angiopathy (CAA). [3] Thus adipose tissue may play multiple roles in the aging brain, and in the aging brain at risk for or possessing dementia-related pathologies (Fig. 1). Hormones are metabolic parameters of interest that are related to AD. New genetic findings enrich the evidence base for the vascular and metabolic etiology of AD, as well as provide a broader evidence base for potential involvement of peripheral metabolism in health of the brain. Major endocrine axes link brain with periphery. Data suggest that neuropathological changes in AD brains alter endocrine axis regulation. The hypothalamic-pituitary-adrenal, hypothalamicpituitary-thyroid, and hypothalamic-pituitary-gonadal axes have all shown peripheral and central affectation in dementia. A hypothalamic-pituitary-adipose axis or ‘Fat Brain’ axis has been suggested [8] given the range of central and peripheral metabolic implications associated with higher adiposity. 2. Epidemiology of adiposity and dementia Body fat measures, such as body mass index (BMI), over the life course are related to dementia. [9,10] Published reports can broadly
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Fig. 1. Mechanisms whereby overweight and obesity may increase risk for cognitive impairment and dementia. Epidemiologic studies show that overweight and obesity are associated with cognitive impairment and dementia, as well as other brain outcomes. Overweight and obesity also increase risk for vascular diseases and blood vessel events that independently increase risk for dementia. While vascular processes have been touted as primary mechanisms of action, neurodegeneration and metabolic alterations are concomitant. Adipose tissue is also a source of hormones and other metabolic factors that have been related to dementia and dementia processes.
be divided into mid-life and late-life results. Mid-life overweight and obesity, measured as total adiposity (body mass index, BMI) or central adiposity (waist circumference or waist-to-hip ratio) measured decades before dementia onset has been linked to higher risk of dementia in late life. [11–15] In late-life, individuals with dementia, on average, have a lower body weight or BMI than those without dementia. [15,16] However, during the prodromal phase of dementia, the relationship is less clear, as greater body weight or BMI decline among those developing dementia has been shown, [16–18] as well as risky effects of high BMI as late as in the eighth decade of life. [19,20]. Observations of overweight and obesity increasing risk for AD follow consistent reports in the epidemiological literature over the past 20 years illustrating the importance of vascular factors in AD. Data from the Gothenburg Birth Cohort Studies in Sweden, are some of the first reported on vascular factors in AD [15,21] and global awareness increases. Despite the clustering of vascular and metabolic risk factors, epidemiological studies report independent associations of individual factors, such as BMI, with AD, indicating the contribution of multiple potential biological processes in dementia pathogenesis. BMI and central obesity are also related to underlying brain pathologies, such as temporal atrophy, [22–24] white matter changes, [24,25] and blood brain barrier disturbance, [5] which are more pronounced in late-life and AD. BMI and central obesity have also been related to brain structure and function in mid-life, pointing to earlier influences of higher adiposity on brain health [24]. Interestingly, there are also signs of classical AD pathology in peripheral adipose tissue, such as amyloid precursor protein (APP) production, APP upregulation in obesity, and a positive correlation between APP expression and insulin resistance and adipocyte cytokine expression levels [26] (Fig. 1). 3. Adipose tissue biology Adipose tissue is a metabolically active tissue and source of a variety of hormones, such as leptin and estrone, adiponectin and other
components of complement, pro-inflammatory cytokines, and components of the Renin Angiotensin System (RAS). [10] The metabolic implications of adipose are wide ranging, and knowledge related to this phenomenon is far from complete. In mammals, total body fat can be divided into various compartments. There is total fat; subcutaneous fat, which is both superficial and deep; and internal fat, which is comprised of visceral (within chest, abdomen, pelvis), nonvisceral (intramuscular, perimuscular), and other fat (e.g., lipoma). [27] Adipocytes originate from mesenchymal (multipotetent) stem cells in bone marrow. [28] These cells migrate to adipose tissue itself where they form the underlying stroma or supportive connective tissue, and are functional. The stroma is highly vascularized and contains the progenitor cells that give rise to the adipose cell. Preadipocytes are immature fat cells that have not yet accumulated lipid. Fully differentiated fat cells contain lipid. While BMI is a marker of total body fat stores, most of which are subcutaneous, there is also fat surrounding internal organs, such as the heart or pancreas. Visceral fat depots within close proximity to target organs, may have more to do with and be a more sensitive indicator of the potential physiological impact of adipose on human health [29]. Locally produced hormones, inflammatory cytokines, and oxidative end products released from adipose tissue directly surrounding these organs play, as yet, not fully characterized roles. 4. Adipose hormones 4.1. Leptin Leptin is a 16 kDa protein hormone discovered in 1994. While deemed to be the putative obesity hormone in the mid-1990s, [30,31] with effects possibly mediated by an impaired BBB, [32] it did not become the answer to the current obesity epidemic as originally hoped. Amount of adipose tissue is positively related to blood leptin levels, as adipose is the major source of this hormone. [33,34] The Prospective Study of Women in Gothenburg, Sweden show mid-life
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correlations of r = 0.67, and late-life correlations of r = 0.61 between BMI and blood leptin levels (unpublished). Classical functions of leptin include signalling inadequate energy stores through the regulation of food intake, regulation of energy expenditure, improving insulin sensitivity, facilitating lipolysis, inhibiting lipogenesis, and reducing intracellular lipids [35,36]. In addition, leptin plays a permissive role in neuroendocrine immune function [35]. Leptin has numerous effects on brain development [37] and potentially on brain health in cognition and aging. Leptin affects hypothalamic function, and learning and memory processes controlled by the hippocampus [38]. Experimental data show that leptin, and other adipose tissue compounds, interact directly with hypothalamic nuclei, such as the arcuate nucleus, and regulate energy expenditure and food intake through production of orexigenic (NPY, agrp) and anorectic (aMSH) peptides [39,40]. In addition, leptin appears to facilitate pre- and postsynaptic transmitter release and sensitivity, respectively, in hippocampal CA1 neurons [41]. This translates to improved performance related to spatial learning and memory function. Leptin may even shape the hypothalamus in the earliest stages of development and enhance cognition [37]. Leptin reduces beta-secretase, increases APOE-dependent Abeta uptake in vitro, and via lipolytic mechanisms, affects Abeta turnover [42]. Understanding interactions between leptin and insulin in the brain may weave together the interrelationship of adiposity and diabetes in AD. Not only leptin, as aforementioned, but insulin, interacts directly with hypothalamic nuclei, and it appears that both are necessary characters in the insulin resistance story. The pro-opiomelanocortin (POMC) neurons in the hypothalamus express both leptin and insulin receptors and regulate energy balance and glucose homeostasis. Experimental mouse models lacking both leptin and insulin receptors in POMC neurons, display systemic insulin resistance, which is distinct from what occurs with the single deletion of either receptor. These mice also show alterations in sex hormone levels that reduce fertility. Thus, direct action of both insulin and leptin on POMC neurons appears required to maintain normal glucose homeostasis and reproductive function [43]. It has also been proposed that cross talk between leptin and insulin occurs within a network of cells rather than within individual POMC neurons [44]. Limited data in human populations suggest different temporal relationships of leptin on the brain. A report from Gothenburg, Sweden, shows overweight and obesity, but not leptin, to be related to blood-brain barrier integrity after 24 years, from mid- to late-life in women [45]. However, within a median time of 8 years to dementia onset among a subsample of the Framingham cohort (mean age 79 years), higher leptin levels were associated with a lower dementia risk [46]. Leptin was also related to higher brain volume among those not developing dementia. Thus, it appears that change in leptin levels follow changes in BMI with dementia and aging, and may also reflect the influence of underlying dementia neuropathology on the fat-brain axis related to leptin. Effects of overweight and obesity are chronic due to the sustainability of resulting vascular damage, alterations in the metabolic milieu, and adaptive, yet irreversible resetting of regulatory axes. [47] In the case of leptin, a more acute relationship is suggested since the relationship between BMI and brain health appears to change direction over the life course. Markers such as those produced by adipose, may be acute rather than long-term prognostic indicators. This is exemplified by cross-sectional imaging data in younger adults, showing inverse correlations between leptin levels and grey matter volumes [48].
diseases. It is also predictive of type 2 diabetes, and observations appear consistent cross-culturally. Adiponectin exists as complex multimeric isoforms comprised of High Molecular Weight (HMW), hexamers and trimers [49]. HMW adiponectin or HMW adiponectin/ total adiponectin may be better indicators of insulin sensitivity than total adiponectin in obesity, diabetes, and cardiovascular disease [49]. Adiponectin is not only produced by adipose tissue, but by numerous other tissues including the brain. BMI is inversely related to circulating adiponectin. The Prospective Study of Women in Gothenburg, Sweden show late-life correlations of r = −0.29, between BMI and blood adiponectin levels (unpublished). There are no published reports of adiponectin in relationship to dementia or AD (PubMed, August 18, 2010). Total adiponectin was not related to mild cognitive impairment (MCI) in a case-control study in Olmsted County, Minnesota USA, [50]; nor to vascular dementia in a small case-control study in Japan [51] . Given adiponectin's inverse relationship with BMI, one may expect higher adiponectin levels to be related to prevalent dementia and AD, since individuals with dementia tend to have lost weight prior to a clinical diagnosis, and subsequently weigh less than those without dementia [16]. However, this has not been reported. In addition, perhaps total adiponectin levels are not as sensitive as HMW adiponectin or the HMW adiponectin to total adiponectin ratio in relationship to brain health; and while moderately correlated to BMI, adiponectin may be a more sensitive indicator of visceral fat, which is more difficult to quantify and not as strongly correlated to BMI as leptin [52]. Fig. 2 illustrates mechanisms of interaction of leptin and adiponectin with the human brain. 5. Supporting cross-disciplinary evidence The role of adipose tissue, and the metabolic syndromes or milieu it represents, is underscored by Genome Wide Association Study (GWAS) results based on over 16,000 individuals with and without AD [53–55]. These reports [53,54] showed not only a relationship between the major susceptibility gene for AD, APOE, but three other DNA variants (SNPs) within loci encoding for proteins associated with vascular and metabolic health. These include SNPs: 1) in the clustering (CLU, also known as APOJ) gene, located within an intron on chromosome 8; 2) located downstream from PICALM on chromosome 11; and 3) in CR, the gene encoding for complement component receptor 1 on chromosome 1. These genes complement the list of vascular and metabolic susceptibility genes that is maintained at www.alzgene.org. [56] and which includes additional genes such as sortilin-related receptor (SORL1, which is related to the low density lipoprotein receptor, LDLR), angiotensin converting enzyme (ACE), interleukin 8 (IL8), LDLR, and cystatin 3 (CST3). The functional significance of these vascular and metabolic genes is linked to adipose tissue and its downstream effects. A recent report linking the FTO (‘fatso’) gene to reduced brain volume (particularly frontal and occipital lobes) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) is another example of a potential interaction between fat tissue and the brain [23]. FTO appears to be an obesity gene, and also related to type 2 diabetes. The mechanism of action or functionality of FTO is not clear. However, the resulting protein appears to be a member of the non-heme dioxygenase (Fe(II)- and 2-oxoglutarate-dependent dioxygenases) superfamily. FTO messenger RNA is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and levels in the arcuate nucleus are regulated by feeding and fasting, [57] thus a potential link to adipose hormones of the fat-brain axis.
4.2. Adiponectin 6. A case for a multiple metabolic markers Adiponectin (ACRP30) is an effective insulin sensitizer; and circulating levels are inversely correlated to insulin resistance, metabolic syndrome, obesity, type 2 diabetes, and cardiovascular
The fat-brain axis is a simplified way of referring to not completely understood, highly interactive metabolic regulatory processes.
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Fig. 2. Mechanisms whereby adipose tissue hormones affect the brain and the potential modifying effects of Alzheimer's disease pathology. Leptin and adiponectin, peripheral signals from adipose tissue, interact with hypothalamic nuclei such as the arcuate nucleus. These interactions trigger the release of orexigenic and anorectic peptides from PMC neurons. These peptides exert peripheral effects, modulating food intake, reproduction, water balance, body temperature and energy balance. In addition, leptin and adiponectin have been shown to enhance synaptic plasticity. In prodromal and clinical Alzheimer's disease, amyloid deposited in the areas of the hypothalamus such as the arcuate nucleus, potentially interfere with normal physiologic influences of leptin and adiponectin, downstream events and feedback loops. The vascular effects of adipose tissue may explain the mid-life associations between overweight and obesity and dementia. The influence of Alzheimer pathology on areas of the brain involved in homeostatic regulation may explain the weight loss observed in prodromal and overt dementia.
Understanding these complex interactions may facilitate amelioration of the obesity epidemic, as well as provide major insights in the prevention of obesity-related chronic diseases, such as dementia. While a positive energy balance and poor dietary quality are associated with overweight and obesity, the role of the brain in regulation of both food intake and obesity pathogenesis is fundamental. In addition, are the cognitive control aspects of food intake [58]. Centrally-derived endocrine factors, such as brain-derived neurotrophic factor (BDNF) and other neurotrophins, [59] regulate glucose and energy metabolism in concert with peripheral adipose tissue signals, such as leptin and adiponectin, that feedback and interact with brain nuclei [36]. Specific regions of the brain, such as prefrontal cortex, may be particularly important in food intake behaviour [58]. The interaction of an aging brain with peripheral signals may help explain dementia-related pathology and etiology. While it is known that peripheral signals, such as leptin and adiponectin, interact with critical brain regions associated with normal metabolic processes and dementia, it is not clear the extent to which aging and metabolic susceptibility play a role in altering the balance. Published data support the use of combinations of biomarkers important in population-based studies. Combinations of biomarkers should be considered in epidemiologic studies for a number of reasons. First, a combination of biomarkers for a tissue with wide metabolic implications such as adipose, allow more sensitive assessment of the metabolic impact of the tissue in relationship to brain health. While ‘what is good for the heart is also good for the brain’ appears to be consistently observed across populations, biological mechanisms behind that observation may vary depending on the disease manifestation or target tissue of interest as well as population characteristics. Second, identifying individuals at high risk or susceptible may be better accomplished using a combination of biomarkers versus a single marker. Third, exploring combinations of biomarkers allows identification of multiple potential drug targets and further development of drug treatments targeting specific pathologies, thus
saving money, maximizing treatment effects, and minimizing unnecessary treatments. Fourth, using clinical criteria alone may too often be insensitive for identifying those who will progress to more severe forms of disease. Better identification of susceptible adults would facilitate more targeted intervention strategies. 7. Potential future avenues of research To further tease out the role of hormonal factors in AD, new genetic information, as well as increasing understanding of the role of adipose tissue in health of the brain will help develop testable hypotheses in epidemiologic and clinical studies. A search on www.clinicaltrials.gov (April 28, 2010) using key words: leptin, adiponectin, dementia, cognition, or Alzheimer, resulted in no primary hypotheses being addressed that link these hormones to dementia or cognitive outcomes. Identification of genetic variation sets the stage for new and continued investigations on the roles of adipose tissue hormonal processes in AD. Molecular and clinical epidemiologic studies, focusing on novel biomarkers of pathogenic mechanisms, along with continued investigation of genetic susceptibility markers and their functional significance are needed. Taking a life course approach continues to be important, to understand the concept of critical periods related to hormonal effects preceding and occurring with AD, and what they mean in relationship to AD etiology. Accrual of evidence to advance the forum for scientific discourse relating both hormonal and AD pathology provides the basis for a more comprehensive and translational approach to disease etiology. For example, studies including measures of blood adipokines and APOE genotype in population and clinical samples of individuals with and without prodromal or overt AD, who are obese and not obese, and in combination with imaging modalities such as fMRI to better understand connectivity patterns based on oxygen utilization, and PET to identify amyloid and/or glucose metabolism correlates, are warranted.
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Role of funding The research background leading to this review is the result of funding from the National Institutes of Health/National Institutes on Aging, USA, 5R03AG026098-02; the Swedish Research Council, No. 2005-8460; EU FP7 project LipiDiDiet, Grant Agreement No 211696; Swedish Brain Power Project; the Alzheimer's Association, USA; and the State University of New York Research Foundation. References [1] Gustafson D, Skoog I. Control of vascular risk factors. In: Wahlund TE L-O, Gauthier S, editors. Vascular dementia in clinical practice. London: Cambridge University Press; 2009. [2] Tyas SL, Snowdon DA, Desrosiers MF, Riley KP, Markesbery WR. Healthy ageing in the Nun Study: definition and neuropathologic correlates. Age Ageing 2007;36(6): 650–5. [3] Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci 2005;28(4):202–8. [4] Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008;57(2):178–201. [5] Gustafson DR, Karlsson C, Skoog I, Rosengren L, Lissner L, Blennow K. Mid-life adiposity factors relate to blood-brain barrier integrity in late life. J Intern Med 2007;262(6):643–50. [6] Dickstein DL, Walsh J, Brautigam H, Stockton SD, Gandy S, Hof PR. Roles of vascular risk factors and vascular dysfunction in Alzheimer's disease. Mt Sinai J Med 2010;77:82–102. [7] Bush AI, Beyreuther K, Masters CL. The beta A4 amyloid protein precursor in human circulation. Ann NY Acad Sci 1993;695:175–82. [8] Elmquist JK, Flier JS. Neuroscience. The fat-brain axis enters a new dimension. Science 2004;304(5667):63–4. [9] Gustafson D. Adiposity indices and dementia. Lancet Neurol 2006;5(8):713–20. [10] Gustafson D. A life course of adiposity and dementia. Eur J Pharmacol 2008;585(1): 163–75. [11] Whitmer RA, Gunderson EP, Quesenberry Jr CP, Zhou J, Yaffe K. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res 2007;4(2):103–9. [12] Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology 2008;71(14):1057–64. [13] Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O'Meara ES, Longstreth Jr WT, et al. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol 2009;66(3):336–42. [14] Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62(10):1556–60. [15] Gustafson DR, Bäckman K, Waern M, Östling S, Guo X, Zandi PP, et al. Adiposity indicators and dementia over 32 years in Sweden. Neurology 2009;73:1559–66. [16] Buchman AS, Wilson RS, Bienias JL, Shah RC, Evans DA, Bennett DA. Change in body mass index and risk of incident Alzheimer disease. Neurology 2005;65(6): 892–7. [17] Barrett-Connor E, Edelstein SL, Corey-Bloom J, Wiederholt WC. Weight loss precedes dementia in community-dwelling older adults. J Am Geriatr Soc 1996;44:1147–52. [18] Stewart R, Masaki K, Xue QL, Peila R, Petrovitch H, White LR, et al. A 32-year prospective study of change in body weight and incident dementia: the HonoluluAsia Aging Study. Arch Neurol 2005;62(1):55–60. [19] Gustafson DR, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow up of overweight and risk for Alzheimer's disease. Arch Intern Med 2003;163:1524–8. [20] Hayden KM, Zandi PP, Lyketsos CG, Khachaturian AS, Bastian LA, Charoonruk G, et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis Assoc Disord 2006;20(2):93–100. [21] Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-year longitudinal study of blood pressure and dementia. Lancet 1996;347:1141–5. [22] Gustafson D, Lissner L, Bengtsson C, Björkelund C, Skoog I. A 24-year follow-up of body mass index and cerebral atrophy. Neurology 2004;63:1876–81. [23] Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, et al. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci USA 2010. [24] Pannacciulli N, Del Parigi A, Chen K, Le DS, Reiman EM, Tataranni PA. Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage 2006;31(4):1419–25. [25] Gustafson D, Steen B, Skoog I. Body mass index and white matter lesions in elderly women. An 18-year longitudinal study. Intl J Psychogeriatrics 2004;16:327–36. [26] Lee YH, Tharp WG, Maple RL, Nair S, Permana PA, Pratley RE. Amyloid precursor protein expression is upregulated in adipocytes in obesity. Obesity (Silver Spring); 2008. [27] Shen W, Wang Z, Punyanita M, Lei J, Sinav A, Kral JG, et al. Adipose tissue quantification by imaging methods: a proposed classification. Obes Res 2003;11(1): 5–16.
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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j n s
Adiposity hormones and dementia Deborah R. Gustafson ⁎ From the Section for Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit at the Sahlgrenska Academy, University of Gothenburg, Sweden Departments of Neurology and Medicine, Section for NeuroEpidemiology, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
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Article history: Received 30 April 2010 Received in revised form 19 August 2010 Accepted 22 August 2010 Available online 27 September 2010 Keywords: Adipose Leptin Adiponectin All cognitive disorders/dementia Alzheimer's disease Risk factors Epidemicology Endocrine
a b s t r a c t Adipose tissue is an endocrine and paracrine organ that contributes to both metabolic and vascular homeostasis. Overweight and obesity due to excess adipose tissue, are cornerstones of vascular risk and increase risk for late-onset dementia. Vascular risk does not exist in isolation, and is accompanied by alterations in hormonal metabolism and metabolic syndromes. Thus, while vascular risk is highlighted as a primary mechanism for elevated dementia occurrence due to obesity, hormonal risk states may also precede or result from underlying dementia-related neuropathologies and direct neuronal toxicity. This is exemplified during the prodromal phase of dementia, as vascular and metabolic parameters decline in relation to dementia development, and potentially in a way that is different from ‘normal’ aging. In this review will be presented a review of the epidemiology of adiposity and dementia; adipose tissue biology; and two major hormones produced by adipose tissue, leptin and adiponectin, that interact directly with the brain. In addition, a synthesis related to other lines of supporting evidence for the role of adipose hormones in dementia will be provided. Understanding the role of adipose tissue in health of the brain is pivotal to a deeper understanding of dementia processes. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Overweight and obesity are cornerstones of vascular risk, and increase risk for late-onset, sporadic dementia and Alzheimer's disease (AD), as well as corresponding risk factors such as hypertension, diabetes, and cardiovascular and cerebrovascular diseases. [1] While vascular pathologies are highlighted as a primary mechanism for increased dementia and AD occurrence due to overweight and obesity, [1] vascular pathologies are concurrent with neurodegenerative pathologies. Together, they may exacerbate each other; [2] vascular processes may augment neurodegeneration; or neurodegenerative processes may be vascular. [3,4] Irrespective of the direction and temporality of the associations, vascular and neurodegenerative pathologies in the brain against the background of peripheral overweight and obesity, may contribute to metabolic risk states characterized by alterations in adipose tissue hormone levels and subsequent feedback loops. These alterations may also lead to direct neuronal toxicity perhaps due to an altered blood brain barrier. [5] Vascular pathology includes white matter lesions, lacunar infarcts, hypoperfusion, blood vessel inflammation, and cerebrovascular disease. Hallmark neuropathology in dementia and AD include amyloid plaques and neurofibrillary tangles, and markers of neuro-
⁎ Institute for Neuroscience and Physiology, Section for Psychiatry and Neurochemistry, Wallinsgatan 6, 431 41 Mölndal, Sweden. Tel.: + 46 31 343 8646, + 1 718 270 1581; fax: + 46 31 776 04 03, + 1 718 270 3840. E-mail addresses: [email protected], [email protected]. 0022-510X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.08.036
degeneration such as cerebral atrophy and synaptic dysfunction. In addition, combined neurovascular mechanisms must be considered. [6] For example, nearly every neuron in the brain has its own capillary, there is a reduction and loss of integrity in the 20 m2 of capillary surface area in the AD brain, [3] amyloid precursor protein (APP) exists in platelets and plays a role in the clotting cascade, [7] and almost all persons with AD have cerebral amyloid angiopathy (CAA). [3] Thus adipose tissue may play multiple roles in the aging brain, and in the aging brain at risk for or possessing dementia-related pathologies (Fig. 1). Hormones are metabolic parameters of interest that are related to AD. New genetic findings enrich the evidence base for the vascular and metabolic etiology of AD, as well as provide a broader evidence base for potential involvement of peripheral metabolism in health of the brain. Major endocrine axes link brain with periphery. Data suggest that neuropathological changes in AD brains alter endocrine axis regulation. The hypothalamic-pituitary-adrenal, hypothalamicpituitary-thyroid, and hypothalamic-pituitary-gonadal axes have all shown peripheral and central affectation in dementia. A hypothalamic-pituitary-adipose axis or ‘Fat Brain’ axis has been suggested [8] given the range of central and peripheral metabolic implications associated with higher adiposity. 2. Epidemiology of adiposity and dementia Body fat measures, such as body mass index (BMI), over the life course are related to dementia. [9,10] Published reports can broadly
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Fig. 1. Mechanisms whereby overweight and obesity may increase risk for cognitive impairment and dementia. Epidemiologic studies show that overweight and obesity are associated with cognitive impairment and dementia, as well as other brain outcomes. Overweight and obesity also increase risk for vascular diseases and blood vessel events that independently increase risk for dementia. While vascular processes have been touted as primary mechanisms of action, neurodegeneration and metabolic alterations are concomitant. Adipose tissue is also a source of hormones and other metabolic factors that have been related to dementia and dementia processes.
be divided into mid-life and late-life results. Mid-life overweight and obesity, measured as total adiposity (body mass index, BMI) or central adiposity (waist circumference or waist-to-hip ratio) measured decades before dementia onset has been linked to higher risk of dementia in late life. [11–15] In late-life, individuals with dementia, on average, have a lower body weight or BMI than those without dementia. [15,16] However, during the prodromal phase of dementia, the relationship is less clear, as greater body weight or BMI decline among those developing dementia has been shown, [16–18] as well as risky effects of high BMI as late as in the eighth decade of life. [19,20]. Observations of overweight and obesity increasing risk for AD follow consistent reports in the epidemiological literature over the past 20 years illustrating the importance of vascular factors in AD. Data from the Gothenburg Birth Cohort Studies in Sweden, are some of the first reported on vascular factors in AD [15,21] and global awareness increases. Despite the clustering of vascular and metabolic risk factors, epidemiological studies report independent associations of individual factors, such as BMI, with AD, indicating the contribution of multiple potential biological processes in dementia pathogenesis. BMI and central obesity are also related to underlying brain pathologies, such as temporal atrophy, [22–24] white matter changes, [24,25] and blood brain barrier disturbance, [5] which are more pronounced in late-life and AD. BMI and central obesity have also been related to brain structure and function in mid-life, pointing to earlier influences of higher adiposity on brain health [24]. Interestingly, there are also signs of classical AD pathology in peripheral adipose tissue, such as amyloid precursor protein (APP) production, APP upregulation in obesity, and a positive correlation between APP expression and insulin resistance and adipocyte cytokine expression levels [26] (Fig. 1). 3. Adipose tissue biology Adipose tissue is a metabolically active tissue and source of a variety of hormones, such as leptin and estrone, adiponectin and other
components of complement, pro-inflammatory cytokines, and components of the Renin Angiotensin System (RAS). [10] The metabolic implications of adipose are wide ranging, and knowledge related to this phenomenon is far from complete. In mammals, total body fat can be divided into various compartments. There is total fat; subcutaneous fat, which is both superficial and deep; and internal fat, which is comprised of visceral (within chest, abdomen, pelvis), nonvisceral (intramuscular, perimuscular), and other fat (e.g., lipoma). [27] Adipocytes originate from mesenchymal (multipotetent) stem cells in bone marrow. [28] These cells migrate to adipose tissue itself where they form the underlying stroma or supportive connective tissue, and are functional. The stroma is highly vascularized and contains the progenitor cells that give rise to the adipose cell. Preadipocytes are immature fat cells that have not yet accumulated lipid. Fully differentiated fat cells contain lipid. While BMI is a marker of total body fat stores, most of which are subcutaneous, there is also fat surrounding internal organs, such as the heart or pancreas. Visceral fat depots within close proximity to target organs, may have more to do with and be a more sensitive indicator of the potential physiological impact of adipose on human health [29]. Locally produced hormones, inflammatory cytokines, and oxidative end products released from adipose tissue directly surrounding these organs play, as yet, not fully characterized roles. 4. Adipose hormones 4.1. Leptin Leptin is a 16 kDa protein hormone discovered in 1994. While deemed to be the putative obesity hormone in the mid-1990s, [30,31] with effects possibly mediated by an impaired BBB, [32] it did not become the answer to the current obesity epidemic as originally hoped. Amount of adipose tissue is positively related to blood leptin levels, as adipose is the major source of this hormone. [33,34] The Prospective Study of Women in Gothenburg, Sweden show mid-life
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correlations of r = 0.67, and late-life correlations of r = 0.61 between BMI and blood leptin levels (unpublished). Classical functions of leptin include signalling inadequate energy stores through the regulation of food intake, regulation of energy expenditure, improving insulin sensitivity, facilitating lipolysis, inhibiting lipogenesis, and reducing intracellular lipids [35,36]. In addition, leptin plays a permissive role in neuroendocrine immune function [35]. Leptin has numerous effects on brain development [37] and potentially on brain health in cognition and aging. Leptin affects hypothalamic function, and learning and memory processes controlled by the hippocampus [38]. Experimental data show that leptin, and other adipose tissue compounds, interact directly with hypothalamic nuclei, such as the arcuate nucleus, and regulate energy expenditure and food intake through production of orexigenic (NPY, agrp) and anorectic (aMSH) peptides [39,40]. In addition, leptin appears to facilitate pre- and postsynaptic transmitter release and sensitivity, respectively, in hippocampal CA1 neurons [41]. This translates to improved performance related to spatial learning and memory function. Leptin may even shape the hypothalamus in the earliest stages of development and enhance cognition [37]. Leptin reduces beta-secretase, increases APOE-dependent Abeta uptake in vitro, and via lipolytic mechanisms, affects Abeta turnover [42]. Understanding interactions between leptin and insulin in the brain may weave together the interrelationship of adiposity and diabetes in AD. Not only leptin, as aforementioned, but insulin, interacts directly with hypothalamic nuclei, and it appears that both are necessary characters in the insulin resistance story. The pro-opiomelanocortin (POMC) neurons in the hypothalamus express both leptin and insulin receptors and regulate energy balance and glucose homeostasis. Experimental mouse models lacking both leptin and insulin receptors in POMC neurons, display systemic insulin resistance, which is distinct from what occurs with the single deletion of either receptor. These mice also show alterations in sex hormone levels that reduce fertility. Thus, direct action of both insulin and leptin on POMC neurons appears required to maintain normal glucose homeostasis and reproductive function [43]. It has also been proposed that cross talk between leptin and insulin occurs within a network of cells rather than within individual POMC neurons [44]. Limited data in human populations suggest different temporal relationships of leptin on the brain. A report from Gothenburg, Sweden, shows overweight and obesity, but not leptin, to be related to blood-brain barrier integrity after 24 years, from mid- to late-life in women [45]. However, within a median time of 8 years to dementia onset among a subsample of the Framingham cohort (mean age 79 years), higher leptin levels were associated with a lower dementia risk [46]. Leptin was also related to higher brain volume among those not developing dementia. Thus, it appears that change in leptin levels follow changes in BMI with dementia and aging, and may also reflect the influence of underlying dementia neuropathology on the fat-brain axis related to leptin. Effects of overweight and obesity are chronic due to the sustainability of resulting vascular damage, alterations in the metabolic milieu, and adaptive, yet irreversible resetting of regulatory axes. [47] In the case of leptin, a more acute relationship is suggested since the relationship between BMI and brain health appears to change direction over the life course. Markers such as those produced by adipose, may be acute rather than long-term prognostic indicators. This is exemplified by cross-sectional imaging data in younger adults, showing inverse correlations between leptin levels and grey matter volumes [48].
diseases. It is also predictive of type 2 diabetes, and observations appear consistent cross-culturally. Adiponectin exists as complex multimeric isoforms comprised of High Molecular Weight (HMW), hexamers and trimers [49]. HMW adiponectin or HMW adiponectin/ total adiponectin may be better indicators of insulin sensitivity than total adiponectin in obesity, diabetes, and cardiovascular disease [49]. Adiponectin is not only produced by adipose tissue, but by numerous other tissues including the brain. BMI is inversely related to circulating adiponectin. The Prospective Study of Women in Gothenburg, Sweden show late-life correlations of r = −0.29, between BMI and blood adiponectin levels (unpublished). There are no published reports of adiponectin in relationship to dementia or AD (PubMed, August 18, 2010). Total adiponectin was not related to mild cognitive impairment (MCI) in a case-control study in Olmsted County, Minnesota USA, [50]; nor to vascular dementia in a small case-control study in Japan [51] . Given adiponectin's inverse relationship with BMI, one may expect higher adiponectin levels to be related to prevalent dementia and AD, since individuals with dementia tend to have lost weight prior to a clinical diagnosis, and subsequently weigh less than those without dementia [16]. However, this has not been reported. In addition, perhaps total adiponectin levels are not as sensitive as HMW adiponectin or the HMW adiponectin to total adiponectin ratio in relationship to brain health; and while moderately correlated to BMI, adiponectin may be a more sensitive indicator of visceral fat, which is more difficult to quantify and not as strongly correlated to BMI as leptin [52]. Fig. 2 illustrates mechanisms of interaction of leptin and adiponectin with the human brain. 5. Supporting cross-disciplinary evidence The role of adipose tissue, and the metabolic syndromes or milieu it represents, is underscored by Genome Wide Association Study (GWAS) results based on over 16,000 individuals with and without AD [53–55]. These reports [53,54] showed not only a relationship between the major susceptibility gene for AD, APOE, but three other DNA variants (SNPs) within loci encoding for proteins associated with vascular and metabolic health. These include SNPs: 1) in the clustering (CLU, also known as APOJ) gene, located within an intron on chromosome 8; 2) located downstream from PICALM on chromosome 11; and 3) in CR, the gene encoding for complement component receptor 1 on chromosome 1. These genes complement the list of vascular and metabolic susceptibility genes that is maintained at www.alzgene.org. [56] and which includes additional genes such as sortilin-related receptor (SORL1, which is related to the low density lipoprotein receptor, LDLR), angiotensin converting enzyme (ACE), interleukin 8 (IL8), LDLR, and cystatin 3 (CST3). The functional significance of these vascular and metabolic genes is linked to adipose tissue and its downstream effects. A recent report linking the FTO (‘fatso’) gene to reduced brain volume (particularly frontal and occipital lobes) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) is another example of a potential interaction between fat tissue and the brain [23]. FTO appears to be an obesity gene, and also related to type 2 diabetes. The mechanism of action or functionality of FTO is not clear. However, the resulting protein appears to be a member of the non-heme dioxygenase (Fe(II)- and 2-oxoglutarate-dependent dioxygenases) superfamily. FTO messenger RNA is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and levels in the arcuate nucleus are regulated by feeding and fasting, [57] thus a potential link to adipose hormones of the fat-brain axis.
4.2. Adiponectin 6. A case for a multiple metabolic markers Adiponectin (ACRP30) is an effective insulin sensitizer; and circulating levels are inversely correlated to insulin resistance, metabolic syndrome, obesity, type 2 diabetes, and cardiovascular
The fat-brain axis is a simplified way of referring to not completely understood, highly interactive metabolic regulatory processes.
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Fig. 2. Mechanisms whereby adipose tissue hormones affect the brain and the potential modifying effects of Alzheimer's disease pathology. Leptin and adiponectin, peripheral signals from adipose tissue, interact with hypothalamic nuclei such as the arcuate nucleus. These interactions trigger the release of orexigenic and anorectic peptides from PMC neurons. These peptides exert peripheral effects, modulating food intake, reproduction, water balance, body temperature and energy balance. In addition, leptin and adiponectin have been shown to enhance synaptic plasticity. In prodromal and clinical Alzheimer's disease, amyloid deposited in the areas of the hypothalamus such as the arcuate nucleus, potentially interfere with normal physiologic influences of leptin and adiponectin, downstream events and feedback loops. The vascular effects of adipose tissue may explain the mid-life associations between overweight and obesity and dementia. The influence of Alzheimer pathology on areas of the brain involved in homeostatic regulation may explain the weight loss observed in prodromal and overt dementia.
Understanding these complex interactions may facilitate amelioration of the obesity epidemic, as well as provide major insights in the prevention of obesity-related chronic diseases, such as dementia. While a positive energy balance and poor dietary quality are associated with overweight and obesity, the role of the brain in regulation of both food intake and obesity pathogenesis is fundamental. In addition, are the cognitive control aspects of food intake [58]. Centrally-derived endocrine factors, such as brain-derived neurotrophic factor (BDNF) and other neurotrophins, [59] regulate glucose and energy metabolism in concert with peripheral adipose tissue signals, such as leptin and adiponectin, that feedback and interact with brain nuclei [36]. Specific regions of the brain, such as prefrontal cortex, may be particularly important in food intake behaviour [58]. The interaction of an aging brain with peripheral signals may help explain dementia-related pathology and etiology. While it is known that peripheral signals, such as leptin and adiponectin, interact with critical brain regions associated with normal metabolic processes and dementia, it is not clear the extent to which aging and metabolic susceptibility play a role in altering the balance. Published data support the use of combinations of biomarkers important in population-based studies. Combinations of biomarkers should be considered in epidemiologic studies for a number of reasons. First, a combination of biomarkers for a tissue with wide metabolic implications such as adipose, allow more sensitive assessment of the metabolic impact of the tissue in relationship to brain health. While ‘what is good for the heart is also good for the brain’ appears to be consistently observed across populations, biological mechanisms behind that observation may vary depending on the disease manifestation or target tissue of interest as well as population characteristics. Second, identifying individuals at high risk or susceptible may be better accomplished using a combination of biomarkers versus a single marker. Third, exploring combinations of biomarkers allows identification of multiple potential drug targets and further development of drug treatments targeting specific pathologies, thus
saving money, maximizing treatment effects, and minimizing unnecessary treatments. Fourth, using clinical criteria alone may too often be insensitive for identifying those who will progress to more severe forms of disease. Better identification of susceptible adults would facilitate more targeted intervention strategies. 7. Potential future avenues of research To further tease out the role of hormonal factors in AD, new genetic information, as well as increasing understanding of the role of adipose tissue in health of the brain will help develop testable hypotheses in epidemiologic and clinical studies. A search on www.clinicaltrials.gov (April 28, 2010) using key words: leptin, adiponectin, dementia, cognition, or Alzheimer, resulted in no primary hypotheses being addressed that link these hormones to dementia or cognitive outcomes. Identification of genetic variation sets the stage for new and continued investigations on the roles of adipose tissue hormonal processes in AD. Molecular and clinical epidemiologic studies, focusing on novel biomarkers of pathogenic mechanisms, along with continued investigation of genetic susceptibility markers and their functional significance are needed. Taking a life course approach continues to be important, to understand the concept of critical periods related to hormonal effects preceding and occurring with AD, and what they mean in relationship to AD etiology. Accrual of evidence to advance the forum for scientific discourse relating both hormonal and AD pathology provides the basis for a more comprehensive and translational approach to disease etiology. For example, studies including measures of blood adipokines and APOE genotype in population and clinical samples of individuals with and without prodromal or overt AD, who are obese and not obese, and in combination with imaging modalities such as fMRI to better understand connectivity patterns based on oxygen utilization, and PET to identify amyloid and/or glucose metabolism correlates, are warranted.
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Role of funding The research background leading to this review is the result of funding from the National Institutes of Health/National Institutes on Aging, USA, 5R03AG026098-02; the Swedish Research Council, No. 2005-8460; EU FP7 project LipiDiDiet, Grant Agreement No 211696; Swedish Brain Power Project; the Alzheimer's Association, USA; and the State University of New York Research Foundation. References [1] Gustafson D, Skoog I. Control of vascular risk factors. In: Wahlund TE L-O, Gauthier S, editors. Vascular dementia in clinical practice. London: Cambridge University Press; 2009. [2] Tyas SL, Snowdon DA, Desrosiers MF, Riley KP, Markesbery WR. Healthy ageing in the Nun Study: definition and neuropathologic correlates. Age Ageing 2007;36(6): 650–5. [3] Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci 2005;28(4):202–8. [4] Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008;57(2):178–201. [5] Gustafson DR, Karlsson C, Skoog I, Rosengren L, Lissner L, Blennow K. Mid-life adiposity factors relate to blood-brain barrier integrity in late life. J Intern Med 2007;262(6):643–50. [6] Dickstein DL, Walsh J, Brautigam H, Stockton SD, Gandy S, Hof PR. Roles of vascular risk factors and vascular dysfunction in Alzheimer's disease. Mt Sinai J Med 2010;77:82–102. [7] Bush AI, Beyreuther K, Masters CL. The beta A4 amyloid protein precursor in human circulation. Ann NY Acad Sci 1993;695:175–82. [8] Elmquist JK, Flier JS. Neuroscience. The fat-brain axis enters a new dimension. Science 2004;304(5667):63–4. [9] Gustafson D. Adiposity indices and dementia. Lancet Neurol 2006;5(8):713–20. [10] Gustafson D. A life course of adiposity and dementia. Eur J Pharmacol 2008;585(1): 163–75. [11] Whitmer RA, Gunderson EP, Quesenberry Jr CP, Zhou J, Yaffe K. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res 2007;4(2):103–9. [12] Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology 2008;71(14):1057–64. [13] Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O'Meara ES, Longstreth Jr WT, et al. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol 2009;66(3):336–42. [14] Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62(10):1556–60. [15] Gustafson DR, Bäckman K, Waern M, Östling S, Guo X, Zandi PP, et al. Adiposity indicators and dementia over 32 years in Sweden. Neurology 2009;73:1559–66. [16] Buchman AS, Wilson RS, Bienias JL, Shah RC, Evans DA, Bennett DA. Change in body mass index and risk of incident Alzheimer disease. Neurology 2005;65(6): 892–7. [17] Barrett-Connor E, Edelstein SL, Corey-Bloom J, Wiederholt WC. Weight loss precedes dementia in community-dwelling older adults. J Am Geriatr Soc 1996;44:1147–52. [18] Stewart R, Masaki K, Xue QL, Peila R, Petrovitch H, White LR, et al. A 32-year prospective study of change in body weight and incident dementia: the HonoluluAsia Aging Study. Arch Neurol 2005;62(1):55–60. [19] Gustafson DR, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow up of overweight and risk for Alzheimer's disease. Arch Intern Med 2003;163:1524–8. [20] Hayden KM, Zandi PP, Lyketsos CG, Khachaturian AS, Bastian LA, Charoonruk G, et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis Assoc Disord 2006;20(2):93–100. [21] Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-year longitudinal study of blood pressure and dementia. Lancet 1996;347:1141–5. [22] Gustafson D, Lissner L, Bengtsson C, Björkelund C, Skoog I. A 24-year follow-up of body mass index and cerebral atrophy. Neurology 2004;63:1876–81. [23] Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, et al. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci USA 2010. [24] Pannacciulli N, Del Parigi A, Chen K, Le DS, Reiman EM, Tataranni PA. Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage 2006;31(4):1419–25. [25] Gustafson D, Steen B, Skoog I. Body mass index and white matter lesions in elderly women. An 18-year longitudinal study. Intl J Psychogeriatrics 2004;16:327–36. [26] Lee YH, Tharp WG, Maple RL, Nair S, Permana PA, Pratley RE. Amyloid precursor protein expression is upregulated in adipocytes in obesity. Obesity (Silver Spring); 2008. [27] Shen W, Wang Z, Punyanita M, Lei J, Sinav A, Kral JG, et al. Adipose tissue quantification by imaging methods: a proposed classification. Obes Res 2003;11(1): 5–16.
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