13 March 2009. Several studies published this week in a theme issue of the Archives of Neurology add some ifs, ands, and buts to the general notion that obesity, diabetes, and their comorbidities increase risk for dementia.
Previous work in middle-aged people suggests that bulging waistlines are associated with a greater chance of future cognitive decline (Whitmer et al., 2005; Kivipelto et al., 2005). A host of other modifiable midlife risk factors, including high blood pressure and cholesterol, also seem to predict cognitive impairment decades later (Kivipelto et al., 2006 and ARF related news story). In older people, though, the connection between body fat and dementia risk has been harder to untangle. Certain studies indicate that seniors with higher body mass index (BMI) are more likely to develop dementia (Gustafson et al., 2003), whereas some find no such association (Stewart et al., 2005) and others suggest the inverse correlation (Nourhashémi et al., 2003). More recent reports also document the “obesity paradox.” In those studies of heart failure (Curtis et al., 2005) and dialysis (Beddhu et al., 2005) patients, extra pounds, in fact, correlated with survival.
In the theme issue, a prospective study led by José Luchsinger at Columbia University Medical Center, New York, lends further support to this conundrum. Whereas most analyses of body fat and cognition have made measurements either at midlife or late life, the new study uses assessments at both time points taken from the same individuals. First author Annette Fitzpatrick of the University of Washington, Seattle, and colleagues analyzed 2,798 dementia-free adults (mean age 74.7 years) who had reported their weight at age 50 (midlife) and had their BMI measured at age 65 or older (late life). Over an average follow-up of 5.4 years, 480 people developed dementia, including 245 with Alzheimer disease (AD) and 213 with vascular dementia.
Consistent with past studies of midlife BMI, those who were obese (BMI >30) at age 50 were more likely to develop dementia than were participants who had a normal weight. However, the trend was reversed for BMI assessments done in late life (age 65 and above). Underweight (BMI <20) seniors had increased risk of dementia, whereas being overweight had no influence on cognitive decline. Those who were obese in old age were actually less likely to develop dementia compared to the normal BMI group.
Luchsinger offered several explanations for these findings. “Maybe your obesity status at midlife is more important than in older age,” he told ARF. “If you’re obese at midlife, you're going to be obese for a longer time. The longer you're obese, the higher your risk.” At the same time, the apparent protection from dementia in the obese group could reflect selection bias. Since people who are obese tend to die earlier, he suggested, one could imagine that those who survived long enough to enroll in the study had other safeguarding elements at work—factors that might influence their ability to resist dementia conditions. Another interpretation of the new data “is that measures of obesity in middle age are not the same as in older age,” Luchsinger said. “In older age, they lose their validity. They don't capture the same thing as the measures in middle age do.”
BMI is, after all, just a surrogate marker, and most in the field agree that it does not measure adiposity as well for folks in their golden years. “As they get old, they lose muscle mass, and that makes their BMI go down,” said Alka Kanaya of the University of California, San Francisco, who was lead author of another study of adiposity and cognition in the same issue of Archives of Neurology. With senior investigator Kristine Yaffe, also at UCSF, and colleagues, Kanaya looked at the association between body fat and cognitive decline in older people using more precise measures of fat mass. Beyond routine weight, height, and waist measurements, the researchers sent their 3,054 participants (ages 70-79) through dual energy X-ray absorptiometry and abdominal computed tomography scanners to more directly assess total fat and “belly fat,” respectively.
Their findings present yet another enigma—not related to age, but gender. “For women, at least, being overweight or fat with any measure of adiposity didn't seem to portend any worsening of cognitive function. But it did in men.” Kanaya told ARF. “For whatever reason, women seem to be more protected in old age.” Similar gender-specific conclusions have emerged in previous studies—one that assessed obesity using BMI in 1,423 individuals (Elias et al., 2003), and another that measured fat mass by whole-body dual X-ray absorptiometry in 5,607 postmenopausal women (Bagger et al., 2004).
In the new study, Kanaya and colleagues analyzed a number of factors that could potentially connect the dots between adiposity and cognitive impairment, hoping something in the mix would explain the puzzling difference between men and women. They considered diabetes, kidney function, and their comorbidities, as well as levels of adipocytokines and sex hormones. But none of these accounted for the gender disparity. “We still really don't have a good handle why, but it is pretty intriguing,” Kanaya said.
Though weight appeared to have little influence on cognition in older women in this study, other cardiovascular risk factors did have a measurable impact on this population in a separate analysis. That investigation of 4,895 older women found that those with metabolic syndrome (defined as having three or more of the following: abdominal obesity, high blood pressure, high triglycerides, high fasting glucose, or low HDL cholesterol) were more likely to develop cognitive problems in the future. Yaffe was lead author on that research, which appears in the same issue of the Archives of Neurology and validates her previous smaller study linking metabolic syndrome to cognitive decline (Yaffe et al., 2004 and ARF related news story).
Earlier this year, researchers led by Suzanne Craft at the University of Washington, Seattle, reported that individuals with diabetes mellitus and dementia die with lower levels of Aβ pathology compared to diabetes-free dementia patients (Sonnen et al., 2009 and ARF related news story). Those findings, which were published online 12 January in the Archives of Neurology and now appear in print in the theme issue, suggest that diabetics may succumb more easily to dementia. Even in patients who already have dementia, diabetes—but not heart disease, stroke, or high blood pressure—was associated with faster cognitive deterioration, according to an analysis of 156 seniors with incipient AD. In that study, published in the theme Archives of Neurology issue, Yaakov Stern of Columbia University Medical Center, New York, and colleagues report that concentrations of total and low-density lipoprotein (LDL) cholesterol were also linked to accelerated cognitive decline.
Also in this themed issue, Craft reviews recent efforts to identify common mechanisms underlying metabolic disorders and dementia risk. Another commentary discusses possible strategies for reducing obesity and its comorbidities by targeting neural circuits activated by amylin, a peptide hormone secreted with insulin by pancreatic β cells. That review comes from Jonathan Roth and colleagues at Amylin Pharmaceuticals, Inc. in San Diego, California. The special issue also features a study by Giulio Pasinetti, Mount Sinai School of Medicine, New York, and colleagues, who describe a potential clinical strategy more relevant to AD. The scientists report that expression of peroxisome proliferator-activated receptor γ (PPAR-γ) co-activator (PGC-1α), a key regulator of glucose homeostasis, drops as dementia progresses in the AD brain. They show, furthermore, that boosting PGC-1α levels in neurons of the Tg2576 AD mouse model prevents generation of toxic Aβ peptides by shunting the processing of amyloid precursor protein (APP) toward the non-amyloidogenic pathway.—Esther Landhuis.
Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O’Meara ES, Longstreth WT, Luchsinger JA. Midlife and late-life obesity and the risk of dementia. Mar 2009. Arch Neurol. 66(3):336-42. Abstract
Kanaya AM, Lindquist K, Harris TB, Launer L, Rosano C, Satterfield S, Yaffe K. Total and regional adiposity and cognitive change in older adults: The Health, Aging and Body Composition (ABC) study. Mar 2009. Arch Neurol. 66(3):329-35. Abstract
Yaffe K, Weston AL, Blackwell T, Krueger KA. The metabolic syndrome and development of cognitive impairment among older women. Mar 2009. Arch Neurol. 66(3):324-8. Abstract
Sonnen JA, Larson EB, Brickell K, Crane PK, Woltjer R, Montine TJ, Craft S. Different patterns of cerebral injury in dementia with or without diabetes. Mar 2009. Arch Neurol.66(3):315-22. Abstract
Helzner EP, Luchsinger JA, Scarmeas N, Cosentino S, Brickman AM, Glymour M, Stern Y. Contribution of vascular risk factors to the progression in Alzheimer disease. Mar 2009. Arch Neurol. 66(3):343-8. Abstract
Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia. Mar 2009. Arch Neurol. 66(3):300-305. Abstract
Roth JD, Maier H, Chen S, Roland BL. Implications of amylin receptor agonism: integrated neurohormonal mechanisms and therapeutic applications. Mar 2009. Arch Neurol. 66(3):306-310. Abstract
Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD, Pasinetti GM. PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Mar 2009. Arch Neurol. 66(3):352-61. Abstract