Evidence-Based Reviews

Metabolic disturbance and dementia: A modifiable link

Current Psychiatry. 2013 March;12(3):17-23

References

1. Alzheimer’s Association; Thies W, Bleiler L. 2011 Alzheimer’s disease facts and figures. Alzheimers Dement. 2011;7(2):208-244.

2. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-241.

3. Wang Y, Beydoun MA, Liang L, et al. Will all Americans become overweight or obese? Estimating the progression and cost of the US obesity epidemic. Obesity (Silver Spring). 2008;16(10):2323-2330.

4. Craft S. Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effect on memory amyloid, and inflammation. Neurobiol Aging. 2005;26(suppl 1):S65-S69.

5. Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia – meta-analysis of 41 robust inception cohort studies. Acta Psychiat Scand. 2009;119(4):252-265.

6. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256(3):183-194.

7. Crook TH, Bartus RT, Ferris SH, et al. Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change—report of a National Institute of Mental Health work group. Dev Neuropsychol. 1986;2(4):261-276.

8. Neilsen H, Lolk A, Kragh-Sørensen P. Age-associated memory impairment–pathological memory decline or normal aging? Scand J Psychol. 1998;39(1):33-37.

9. Wilson RS, Leurgans SE, Boyle PA, et al. Neurodegenerative basis of age related cognitive decline. Neurology. 2010;75(12):1070-1078.

10. Saykin AJ, Wishart HA, Rabin LA, et al. Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI. Neurology. 2006;67(5):834-842.

11. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.

12. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359.

13. Baura GD, Foster DM, Kaiyala K, et al. Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs. Diabetes. 1996;45(1):86-90.

14. Wallum BJ, Taborsky GJ, Jr, Porte D Jr, et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocr Metab. 1987;64(1):190-194.

15. Woods SC, Seeley RJ, Baskin DG, et al. Insulin and the blood-brain barrier. Curr Pharm Des. 2003;9(10):795-800.

16. Facchini FS, Hua N, Abbasi F, et al. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab. 2001;86(8):3574-3578.

17. Kuusisto J, Koivisto K, Mykkänen L, et al. Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein E4 phenotype. BMJ. 1997;315(7115):1045-1049.

18. Luchsinger JA, Tang MX, Shea S, et al. Hyperinsulinemia and risk of Alzheimer’s disease. Neurology. 2004;63(7):1187-1192.

19. Hassing LB, Dahl AK, Thorvaldsson V, et al. Overweight in midlife and risk of dementia: a 40-year follow up study. Int J Obesity (Lond). 2009;33(8):893-898.

20. Young SE, Mainous AG 3rd, Carnemolla M. Hyperinsulinemia and cognitive decline in a middle-aged cohort. Diabetes Care. 2006;29(12):2688-2693.

21. Raji CA, Ho AJ, Parikshak NN, et al. Brain structure and obesity. Hum Brain Mapp. 2009;31(3):353-364.

22. Craft S, Peskind E, Schwartz MW, et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease. Neurology. 1998;50(1):164-168.

23. Craft S, Asthana S, Cook DG, et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology. 2003;28(6):809-822.

24. Zhao L, Teter B, Morihara T, et al. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer’s disease intervention. J Neurosci. 2004;24(49):11120-11126.

25. Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100(7):4162-4167.

26. Tabata S, Yoshimitsu S, Hamachi T, et al. Waist circumference and insulin resistance: a cross-sectional study of Japanese men. BMC Endocr Disord. 2009;9:1.-doi: 10.1186/1472-6823-9-1.

27. Wahrenberg H, Hertel K, Leijonhufvud B, et al. Use of waist circumference to predict insulin resistance: retrospective study. BMJ. 2005;330(7504):1363-1364.

28. Jang S, Lee CH, Choi KM, et al. Correlation of fatty liver and abdominal fat distribution using a simple fat computed tomography protocol. World J Gastroenterol. 2011;17(28):3335-3341.

29. Sutcliffe JG, Hedlund PB, Thomas EA, et al. Peripheral reduction of ß-amyloid is sufficient to reduce brain ß-amyloid: implications for Alzheimer’s disease. J Neurosci Res. 2011;89(6):808-814.

30. Marques MA, Kulstad JJ, Savard CE, et al. Peripheral amyloid-β levels regulate amyloid-β clearance from the central nervous system. J Alzheimers Dis. 2009;16(2):325-329.

31. Cotman CW. Homeostatic processes in brain aging: the role of apoptosis inflammation, and oxidative stress in regulating healthy neural circuitry in the aging brain. In: Stern P, Carstensen L, eds. The aging mind: opportunities in cognitive research. Washington, DC: National Academy Press; 2000:114–143.

32. Witte AV, Fobker M, Gellner R, et al. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. 2009;106(4):1255-1260.

33. Krikorian R, Shidler MD, Dangelo K, et al. Dietary ketosis enhances memory in mild cognitive impairment. Neurbiol Aging. 2012;33(2):425.e19-e27.

34. Letenneur L, Proust-Lima C, Le Gouge A, et al. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol. 2007;165(2):1364-1371.

35. Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive decline. J Neural Transm. 2003;110(3):95-110.

36. Williams CM, El Mohsen MA, Vauzour D, et al. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radical Bio Med. 2008;45(3):295-305.

37. Martineau LC, Couture A, Spoor D, et al. Anti-diabetic properties of the Canadian lowbush blueberry Vaccinium angustifolium Ait. Phytomedicine. 2006;13(9-10):612-623.

38. Tsuda T. Regulation of adipocyte function by anthocyanins; possibility of preventing the metabolic syndrome. J Agr Food Chem. 2008;56(3):642-646.

39. Krikorian R, Shidler MD, Nash TA, et al. Blueberry supplementation improves memory in older adults. J Agric Food Chem. 2010;58(7):3996-4000.

Hyperinsulinemia typically is evident in increasing waist circumference and body weight.²⁶ Waist circumference of ≥100 cm (39 inches) is a sensitive, specific, and independent predictor of hyperinsulinemia for men and women and a stronger predictor than BMI, waist-to-hip ratio, and other measures of body fat.²⁷ Unpublished data derived from our clinical research with MCI subjects supports the association of metabolic disturbance with age-related cognitive decline. Our subjects are recruited from the community on the basis of mild memory decline and—other than excluding those with diabetes—weight and metabolic status are not considered in evaluating individuals for enrollment. The Table contains data on waist circumference and metabolic function in 122 older adults (age ≥68) with MCI. On average, these individuals exhibited fasting insulin values in the hyperinsulinemia range and elevated fasting glucose levels that indicated borderline diabetes. Waist circumference also was high, indicating excessive visceral fat deposition. We also observed a relationship between waist circumference and insulin, a consistent observation in older adults with memory decline. These data would not be surprising in any sample of older adults because of the population base rates for these conditions. However, we also found that waist circumference was a significant predictor of memory performance in patients with MCI. Abdominal adiposity is highly correlated with intrahepatic fat.²⁸ Given this and recent indications that Alzheimer’s-type neuropathologic factors are generated in the liver,^29,30 the predictive value of waist circumference to memory performance may reflect the fact that it is a proxy for downstream actions of liver fat.

Table

Waist circumference and metabolic factors in 122 older adults with MCI^a

Metabolic indicator	Value
Mean (SD) fasting glucose, mg/dL	99.5 (11.2)
Mean (SD) fasting insulin, μIU/mL	15.2 (8.1)
Mean (SD) waist, cm	96.4 (13.3)
Waist-insulin correlation	r=0.51, P < .001
^aOlder adult patients (age ≥68) with subjective memory complaints were recruited from the community and screened with instruments assessing everyday functioning and objective memory performance to establish the presence of MCI MCI: mild cognitive impairment; SD: standard deviation

Dietary interventions

There is no cure for dementia, and it is not clear when effective therapy might be developed. Prevention and risk mitigation represent the best means of reducing the impact of this public health problem. Researchers have proposed that interventions initiated when individuals have predementia conditions such as AAMI and MCI might stall progression of cognitive decline, and MCI may be the last point when interventions might be effective because of the self-reinforcing neuropathologic cascades of AD.³¹ Because central hypoinsulinemia may promote central inflammation, Aβ generation, and reduced neuroplasticity, approaches aimed at improving metabolic function (and in particular correcting hyperinsulinemia) could influence fundamental neurodegenerative processes. Dietary approaches to preventing dementia are effective, low-risk, yet underutilized interventions. Reducing insulin by restricting calories³² or maintaining a ketogenic diet³³ has been associated with improved memory function in middle-aged and older adults.

Clinical Point

Reducing insulin by restricting calories or maintaining a ketogenic diet has been associated with improved memory function

Carbohydrate consumption is the principal determinant of insulin secretion. Eliminating high-glycemic foods, including processed carbohydrates and sweets, would sensitize insulin receptors and correct hyperinsulinemia. In addition, replacing high glycemic foods with fruits and vegetables would increase polyphenol intake. Epidemiologic evidence supports the idea that greater consumption of polyphenol-containing vegetables and fruits mitigates risk for neurocognitive decline and dementia.^34,35 Preclinical evidence suggests that such protection may be related to neuronal signaling effects and anti- inflammatory and antioxidant actions.³⁶ In addition, certain polyphenol compounds, such as those found in berries, enhance metabolic function.^37,38 In a 12-week pilot trial, older adults with early memory changes (N=9, mean age 76) who drank supplemental blueberry juice showed enhanced memory and improved metabolic parameters.³⁹

Clinical Point

Greater consumption of polyphenol-containing vegetables and fruits might mitigate risk for neurocognitive decline and dementia

Dietary changes that preserve insulin receptor sensitivity can help ensure general health with aging and substantially mitigate risk for neurodegeneration. The Western diet is particularly insulinogenic and dietary habits are difficult to change. However, the substantial benefits, absence of adverse effects, and low cost make dietary intervention the optimal means of protecting against neurodegeneration and other age-related diseases. Embarking on such a program early in life would be best, although late-life intervention can be effective.

Related Resources

Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3(3):169-178.
Luchsinger JA, Tang MX, Shea S, et al. Hyperinsulinemia and risk of Alzheimer’s disease. Neurology. 2004; 63(7):1187-1192.
Krikorian R, Shidler MD, Dangelo K, et al. Dietary ketosis enhances memory in mild cognitive impairment. Neurbiol Aging. 2012;33(2):425.e19-e27.

Disclosure

Dr. Krikorian receives grant support from the National Institutes of Health, 1R01AG034617-01.