(PSYCHIATRIC TIMES) - Obesity has long been recognized as increasing the risk of associated conditions, including hypertension, diabetes, and cardiovascular disease. Now another disorder has been added to this chilling list: Alzheimer disease (AD). Increasingly, research indicates that obesity and its relatives-the metabolic syndrome and associated inflammatory processes-may play a significant role in cognitive decline and dementia, including AD. A 27-year longitudinal study published in the January 2006 issue of the British Medical Journal describes the risk related to obesity.1 Beginning in the 1960s, for example, researchers monitored 10,276 members of an HMO who, at the study's outset, were aged 40 to 45 years. By 2003, dementia had been diagnosed in 713 (6.9%) of them. Compared with those of normal body weight, obese subjects had a 74% increased risk of dementia; those who were overweight had a 35% greater risk. The effect was particularly noticeable in women; dementia was twice as likely to develop in obese women (55% more likely in overweight women) than in women of normal weight. In all patients studied, adjustment for diabetes and cardiovascular disease at midlife and later did not lessen the association. One of the study's authors, Kristine Yaffe, MD, is an associate professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco, as well as chief of geriatric psychiatry at the San Francisco VA Medical Center. Yaffe confirmed that the thinking in the field has undergone significant changes in recent years. Researchers had long supposed that increased risks of dementia were mediated by cardiovascular disease-specifically, that atherosclerosis, hypertension, and stroke were bound to affect cognition. "That's probably true," said Yaffe, "but it now looks like there are other pathways that affect neurons, amyloid metabolism, and the like. There is a lot of interest now in how these syndromes might interplay in the brain and lead to increased dementia risk." THE METABOLIC SYNDROME AND INFLAMMATION In a 5-year prospective study published in the Journal of the American Medical Association, Yaffe and colleagues looked at the association of the metabolic syndrome and inflammation with cognitive decline in 2632 subjects with a mean age of 74 years.2 Cognitive impairment was more likely to develop in subjects who had the metabolic syndrome (n = 1016) than it was in those who did not (26% vs 21%), but those with concurrent high levels of inflammation were at significantly higher risk (adjusted relative risk, 1.66) for cognitive impairment. The study tracked all-cause cognitive impairment, which included both vascular dementia and AD. "The metabolic syndrome could be causing the inflammation, or inflammation could lead to metabolic dysregulation," Yaffe said. "It's probably bidirectional, but I think that inflammation as measured in serum reflects something in the brain that may be independent of the metabolic syndrome. There is an interesting interaction with cardiovascular disease, metabolic syndrome, and inflammation; if you have both [of the latter], you do worse." Yaffe is preparing a manuscript that describes the results of another study showing that the metabolic syndrome is a risk factor for mild cognitive impairment and all-cause dementia in a separate patient population. "One take-home message is that these things-obesity, insulin resistance, diabetes, metabolic disturbances, and dysregulation-are clearly bad for the brain as well as the body," Yaffe explained. "Your average physician is not thinking that if someone is fat it may affect [his] brain, and that's an important paradigm shift. What's exciting is that this gives us an opportunity to intervene, to try to get people to lose weight, take better care of their diabetes and hypertension to help prevent Alzheimer's." Other researchers have reached similar conclusions about the risks of obesity and associated conditions. In a Swedish study of overweight patients, 392 older patients were monitored for 18 years, during which dementia was diagnosed in 93 of them.3 Compared with age-matched nondemented women, women aged 79 to 88 years in whom dementia developed were overweight and had a higher average body mass index (BMI) at ages 70, 75, and 79 years. Moreover, every 1.0 increase in BMI at age 70 years was associated with an increased AD risk of 36% in these women. The associations were not found in men. Another Swedish study, in which patients were observed for 21 years, concluded that midlife obesity, high total cholesterol level, and high systolic blood pressure were all significant risk factors for dementia later in life and that together, such factors increased AD risk.4 CHEMISTRY 101 Because the ways in which obesity, the metabolic syndrome, and inflammation may affect cognition are physiologically complex, researchers have begun to piece the puzzle together at the chemical level. A key peptide in AD pathogenesis, amyloid-beta (Abeta) is one focus of attention because it changes its shape and accumulates in the brain, forming the sticky plaques characteristic of AD. A recent study in the Journal of Alzheimer's Disease linked BMI and fat mass (FM) to plasma levels of Abeta42, which is the longer, more pathogenic form of Abeta.5 The study found that proteins associated with inflammation, cardiovascular disease, and type 2 diabetes may contribute to the associations between BMI/FM and plasma levels of Abeta42. Samuel Gandy, MD, PhD, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and one of the paper's coauthors, explained the importance of the research: "We linked obesity, in the absence of any other confounding factors, to the elevation of the amyloid peptide. This may mean that this is a common final pathway for dementia. We are seeing all these diverse factors-hypercholesterolemia, obesity, diabetes-converging, in that they all seem to increase the risk for dementia, and biochemically, they all elevate levels of Abeta42 to initiate the process." Gandy and colleagues point out in their paper that hyperinsulinemia frequently develops in overweight and obese individuals-it's also associated with increased AD risk-and that those who progress to type 2 diabetes increase that risk still further if they carry the apolipoprotein E epsilon4 allele. Other investigators have reached compelling conclusions about the role of hyperinsulinemia and insulin resistance syndrome in AD pathophysiology. A study in the October 2005 Archives of Neurology found that hyperinsulinemia provoked increases in both central inflammation and Abeta in healthy adults aged 55 to 81 years, potentially increasing AD risk.6 The authors noted that AD patients have elevated cerebrospinal fluid (CSF) concentrations of the inflammatory cytokine interleukin 6 and that inflammation interacts with the processing and deposition of Abeta. Moreover, hyperinsulinemia exacerbates inflammation-including that of the CNS-partially through effects on Abeta. The researchers also found that insulin's effect on plasma Abeta42 levels was enhanced in subjects with greater BMIs; this suggests that the interactive effect between hyperinsulinemia and BMI on Abeta42 may contribute to AD risk. Another study by several of the same researchers demonstrated that insulin increased CSF levels of Abeta42 in normal older adults.7 Still another study found that peripheral hyperinsulinemia and insulin resistance had deleterious effects on the CNS that could interfere with brain function, including effects on Abeta regulation and inflammation.8 One author of all 3 papers is Suzanne Craft, PhD, professor of psychiatry at the VA Puget Sound Health Care System and the University of Washington. "Our work for the past 10 years has focused on the role of insulin in normal brain function, and how perturbation of that may increase the risk of neurodegenerative diseases and Alzheimer's disease in particular," Craft said. "Our knowledge has increased exponentially in the past few years; it's clear that insulin plays a role in getting glucose to the brain, in regulating levels of neurotransmitters, and in cognitive functions like memory. It may also have an impact on inflammation in the brain." Craft said that insulin resistance syndrome is associated with 2 related but independent phenomena: (1) the failure of insulin to carry out its normal activities because of resistance to it in tissue and (2) hyperinsulinemia. "Most tissues become more and more resistant to insulin, but other tissues-and we think the brain is one-don't become resistant,"
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