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 INFLAMMATIONIn 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.4CHEMISTRY 101Because 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.8One 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," she explained. "They continue to be driven by these increasingly high levels of insulin. Insulin has a role in normal brain function and memory processing, and insulin resistance interferes with that, so that patients are more likely to have memory impairment. And patients who have severe and prolonged insulin resistance are much more likely to develop Alzheimer's disease."CNS EFFECTS ELUCIDATEDIn the Archives study,6 Craft and her colleagues developed a cross-over protocol that was elegant in its design and demanding of its subjects. On separate mornings, the 16 participants received infusions of either saline or insulin, with variable dextrose levels to maintain euglycemia, so that they reached plasma insulin levels typical of those found in insulin resistance. After about 105 minutes, researchers took plasma samples and, via lumbar puncture, CSF samples from the subjects."This let us compare changes in the proteins in spinal fluid, which is our closest index of brain chemistry," Craft said. "We had previously published that, with this challenge, we were able to raise Abeta42 levels in spinal fluid. In the latest paper, we took the spinal fluid from those subjects and looked at changes in cytokines-inflammatory markers-and saw huge changes. Levels had doubled or tripled."Diabetes researchers have focused on hyperinsulinemia and insulin resistance as inflammatory conditions in the body's periphery for a long time, Craft explained. The new findings suggest that hyperinsulinemia leads to CNS inflammation as well. "The rise in these inflammatory markers was strongly correlated with the change in Abeta42 levels," Craft said. "There has been a debate for a while as to whether brain inflammation in Alzheimer's and increase in Abeta42 are linked. We still don't know, but we can say that there is a synchronous increase in b-amyloid and inflammation in a condition that mimics insulin resistance."Craft and her colleagues noted that their results could be integrated into a model describing the role of peripheral insulin resistance and hyperinsulinemia in AD pathogenesis. In the early stages, high plasma insulin levels raise plasma Abeta42 levels by promoting Abeta release and inhibiting its clearance, resulting in more Abeta transport to or retention in the brain. Concomitantly, peripheral hyperinsulinemia increases CNS levels of agents that promote Abeta synthesis and reduce its clearance; the resulting Abeta increases provoke even more inflammation, which continues the cycle and may independently contribute to AD pathogenesis by, for example, noradrenergic dysfunction."I do think this is a unifying construct," Craft said. "It suggests that lowering peripheral insulin levels and enhancing insulin sensitivity may improve cognitive function in aging. We don't know, however, whether this phenomenon is actually related to age or to duration. As people begin developing insulin resistance at much younger ages, it's possible that problems may start to become apparent in middle age."GENDER DIFFERENCES MAY GIVE CLUESThe increased cognitive decline observed in obese women may provide a clue to potential therapeutic approaches, according to Gandy. "Postmenopausal women have had estrogen at postpubertal levels for decades, then precipitously had it withdrawn," he said. "Estrogen has anti-inflammatory properties, so that rapid withdrawal and re-equilibration may create a period of vulnerability."Gandy said that some epidemiologic studies suggest that hormone replacement therapy (HRT) cuts the risk of AD development in half. Nevertheless, other studies investigating the institution of HRT in patients older than 65 years found that such an approach did nothing to prevent or delay dementia. One new and ongoing study-the Kronos Early Estrogen Prevention Study-begins HRT perimenopausally in women aged 40 to 55 years to determine whether such an approach decreases the rate of accumulation of atherosclerotic plaque. The implications would be clear for cognitive decline in older women (although not specifically for AD). Researchers also will assess whether the therapy's benefits outweigh established cardiac risks associated with HRT. (For clinical trials information, visit www.clinicaltrials.gov/ ct/show/ NCT00154180.)Gandy sees the most therapeutic promise in understanding the link between processes that increase levels of Abeta42, however. "If this is the final common pathway by which all these diseases cause dementia, then developing an effective antiamyloid medicine would be widely useful."Pharmaceutical and biotech researchers have already put about 35 such medications into various stages of clinical trials, Gandy said. Such pharmacotherapeutics fall into 3 categories: antiaggregants, designed to keep the amyloid dispersed; immunotherapy designed as an amyloid vaccine so that antibodies destroy excessive amounts of the peptide; and enzyme modulators targeting cellular enzymes that generate amyloid.The implications of such research go beyond therapeutics for AD, Gandy added. "This mechanism of clumping relates not only to Alzheimer's but to Parkinson's and Huntington's," he said. "Each of these diseases involves a different protein, but they have in common the buildup of a gooey substance. The proteins have at least 2 ways to fold, and the bad way exposes hydrophobic regions that stick together, which is what initiates the clumping." The implication is that finding effective therapies for one such disease could help develop treatments for the others."There's been a lot of progress in experimental therapies that should give people hope," Gandy pointed out. "Lots of new medicines are being evaluated, and I would encourage people to find out what's available in their communities in terms of experimental treatment to delay or prevent Alzheimer's."Fortunately, people concerned about AD needn't wait for such medicines to become available. A study published in the January 2006 issue of the Annals of Internal Medicine supported earlier research suggesting that exercise is associated with a reduced risk of dementia in older people.9 Although researchers are not yet certain of exercise's protective mechanism, its beneficial effects on obesity and overweight, the metabolic syndrome, and other factors now associated with dementia are well established. As such, it isn't a huge stretch to suggest that this most accessible of remedies may fit very well into the new understanding of these diseases and the emerging treatment paradigms that accompany it.REFERENCES1. Whitmer RA, Gunderson EP, Barrett-Connor E, et al. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ. 2005;330:1360.2. Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292:2237-2242.3. Gustafson D, Rothenberg E, Bennow K, et al. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med. 2003;163:1524-1528.4. Kivipelto M, Ngandu T, Fratiglioni L, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005;62:1556-1560.5. Balakrishnan K, Verdile G, Mehta PD, et al. Plasma Abeta42 correlates positively with increased body fat in healthy individuals. J Alzheimers Dis. 2005;8:269-282.6. Fishel MA, Watson GS, Montine TJ, et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. 2005;62:1539-1544.7. Watson GS, Peskind ER, Asthana S, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology. 2003;60:1899-1903.8. Craft S. Insulin resistance syndrome and Alzheimer's disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging. 2005;26(suppl 1):65-69.9. Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006;144:73-81.Cary Groner is a freelance writer in northern California.