Home LiteratureArticle Details
PMID: 18384771 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease: an epidemiological perspective.

European journal of pharmacology ·Vol. 585 ·No. 1 ·2008-05-06 ·Pages 119-29

Luchsinger JA

Abstract

The objective of this manuscript is to provide a comprehensive review of the epidemiologic evidence linking the continuum of adiposity, hyperinsulinemia, and diabetes with Alzheimer's disease. The mechanisms for these associations remain to be elucidated, but may include direct actions from insulin, advanced products of glycosilation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of Alzheimer's disease. The evidence relating adiposity in old age to Alzheimer's disease is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of Alzheimer's disease. Hyperinsulinemia is a risk factor for diabetes, and numerous studies have shown a relation of diabetes with higher Alzheimer's disease risk. Most studies fail the take into account the continuum linking these risk factors which may result in underestimation of their importance in Alzheimer's disease. The implication of these associations is that a large proportion of the world population may be at increased risk of Alzheimer's disease given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and diabetes. However, if proven causal, these associations also present a unique opportunity for prevention and treatment of Alzheimer's disease.

MeSH Terms
Adiposity/physiology Alzheimer Disease/epidemiology,etiology,physiopathology Diabetes Mellitus, Type 2/complications,metabolism Humans Hyperinsulinism/complications,metabolism Insulin Resistance Obesity/complications,metabolism Risk Factors
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Luchsinger José Alejandro
Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. jal94@columbia.edu
References (108)
108 references, click to expand
  1. Midlife cardiovascular risk factors and risk of dementia in late life.
    Neurology. 2005 Jan 25;64(2):277-81 PMID: 15668425
  2. Use of waist circumference to predict insulin resistance: retrospective study.
    BMJ. 2005 Jun 11;330(7504):1363-4 PMID: 15833749
  3. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002.
    JAMA. 2004 Jun 16;291(23):2847-50 PMID: 15199035
  4. An 18-year follow-up of overweight and risk of Alzheimer disease.
    Arch Intern Med. 2003 Jul 14;163(13):1524-8 PMID: 12860573
  5. Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City.
    Am J Hum Genet. 1996 Mar;58(3):574-84 PMID: 8644717
  6. Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance.
    Neurology. 1999 Mar 23;52(5):971-5 PMID: 10102414
  7. Cachexia: pathophysiology and clinical relevance.
    Am J Clin Nutr. 2006 Apr;83(4):735-43 PMID: 16600922
  8. Relation of diabetes to mild cognitive impairment.
    Arch Neurol. 2007 Apr;64(4):570-5 PMID: 17420320
  9. Insulin resistance, type 2 diabetes mellitus, and cardiovascular disease: the end of the beginning.
    Circulation. 2005 Nov 15;112(20):3030-2 PMID: 16286599
  10. Vitamin E and donepezil for the treatment of mild cognitive impairment.
    N Engl J Med. 2005 Jun 9;352(23):2379-88 PMID: 15829527
  11. Weight change in Alzheimer's disease.
    J Am Geriatr Soc. 1996 Mar;44(3):265-72 PMID: 8600194
  12. The effect of age on the association between body-mass index and mortality.
    N Engl J Med. 1998 Jan 1;338(1):1-7 PMID: 9414324
  13. Alzheimer's disease.
    N Engl J Med. 2004 Jul 1;351(1):56-67 PMID: 15229308
  14. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease.
    Pharmacogenomics J. 2006 Jul-Aug;6(4):246-54 PMID: 16446752
  15. Human body composition and the epidemiology of chronic disease.
    Obes Res. 1995 Jan;3(1):73-95 PMID: 7712363
  16. Diabetes mellitus in midlife and the risk of dementia three decades later.
    Neurology. 2004 Nov 23;63(10):1902-7 PMID: 15557509
  17. Fasting insulin and incident dementia in an elderly population of Japanese-American men.
    Neurology. 2004 Jul 27;63(2):228-33 PMID: 15277613
  18. Trials that matter: rosiglitazone, ramipril, and the prevention of type 2 diabetes.
    Ann Intern Med. 2007 Mar 20;146(6):461-3 PMID: 17371892
  19. Noncholinergic treatment options for Alzheimer's disease.
    J Clin Psychiatry. 2003;64 Suppl 9:23-8 PMID: 12934971
  20. An evaluation of the metabolic syndrome in the HyperGEN study.
    Nutr Metab (Lond). 2005 Jan 18;2(1):2 PMID: 15656912
  21. Aggregation of vascular risk factors and risk of incident Alzheimer disease.
    Neurology. 2005 Aug 23;65(4):545-51 PMID: 16116114
  22. The dementias.
    Lancet. 2002 Nov 30;360(9347):1759-66 PMID: 12480441
  23. Prevalence and trends in obesity among US adults, 1999-2000.
    JAMA. 2002 Oct 9;288(14):1723-7 PMID: 12365955
  24. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease.
    Arch Neurol. 2005 Oct;62(10):1556-60 PMID: 16216938
  25. Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study.
    Neurology. 1995 Jun;45(6):1161-8 PMID: 7783883
  26. Fasting serum insulin concentration and early insulin response as risk determinants for developing diabetes.
    Diabet Med. 1990 Jun;7(5):407-13 PMID: 2142037
  27. Dietary factors and Alzheimer's disease.
    Lancet Neurol. 2004 Oct;3(10):579-87 PMID: 15380154
  28. Anorexia, sarcopenia, and aging.
    Nutrition. 2001 Jul-Aug;17(7-8):660-3 PMID: 11448592
  29. Mild cognitive impairment: clinical characterization and outcome.
    Arch Neurol. 1999 Mar;56(3):303-8 PMID: 10190820
  30. The metabolic syndrome, inflammation, and risk of cognitive decline.
    JAMA. 2004 Nov 10;292(18):2237-42 PMID: 15536110
  31. A work in progress: the metabolic syndrome.
    Sci Aging Knowledge Environ. 2006 Jun 28;2006(10):pe19 PMID: 16807483
  32. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu-Asia aging study.
    Arterioscler Thromb Vasc Biol. 2000 Oct;20(10):2255-60 PMID: 11031212
  33. Plasma C peptide level and cognitive function among older women without diabetes mellitus.
    Arch Intern Med. 2005 Jul 25;165(14):1651-6 PMID: 16043685
  34. Insulin: in search of a syndrome.
    Diabet Med. 2002 Sep;19(9):724-9 PMID: 12207807
  35. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older.
    Ann Intern Med. 2006 Jan 17;144(2):73-81 PMID: 16418406
  36. Modeling the prevalence and incidence of Alzheimer's disease and mild cognitive impairment.
    J Psychiatr Res. 2002 Sep-Oct;36(5):281-6 PMID: 12127595
  37. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.
    Neurobiol Aging. 2006 Mar;27(3):451-8 PMID: 15964100
  38. Vascular risk factors, incidence of MCI, and rates of progression to dementia.
    Neurology. 2004 Nov 23;63(10):1882-91 PMID: 15557506
  39. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7 PMID: 12634421
  40. Adiponectin--journey from an adipocyte secretory protein to biomarker of the metabolic syndrome.
    J Intern Med. 2005 Feb;257(2):167-75 PMID: 15656875
  41. The homeostasis model in the San Antonio Heart Study.
    Diabetes Care. 1997 Jul;20(7):1087-92 PMID: 9203442
  42. Cardiovascular risk factors and Alzheimer's disease.
    Curr Atheroscler Rep. 2004 Jul;6(4):261-6 PMID: 15191699
  43. How good a marker is insulin level for insulin resistance?
    Am J Epidemiol. 1993 May 1;137(9):959-65 PMID: 8317453
  44. American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke. Risk factors.
    Stroke. 1997 Jul;28(7):1507-17 PMID: 9227708
  45. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported.
    JAMA. 1989 Nov 10;262(18):2551-6 PMID: 2810583
  46. Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease.
    Eur J Pharmacol. 2004 Apr 19;490(1-3):97-113 PMID: 15094077
  47. Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study.
    BMJ. 1997 Oct 25;315(7115):1045-9 PMID: 9366728
  48. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial.
    Ann Intern Med. 2005 Apr 19;142(8):611-9 PMID: 15838067
  49. Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort.
    Am J Epidemiol. 2001 Oct 1;154(7):635-41 PMID: 11581097
  50. Caloric intake and the risk of Alzheimer disease.
    Arch Neurol. 2002 Aug;59(8):1258-63 PMID: 12164721
  51. Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution.
    Diabetes. 1990 Mar;39(3):283-8 PMID: 2407581
  52. Waist circumference and not body mass index explains obesity-related health risk.
    Am J Clin Nutr. 2004 Mar;79(3):379-84 PMID: 14985210
  53. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin.
    Diabetes. 2005 Aug;54(8):2404-14 PMID: 16046308
  54. Higher fasting insulin but lower fasting C-peptide levels in African Americans in the US population.
    Diabetes Metab Res Rev. 2002 Mar-Apr;18(2):149-55 PMID: 11994907
  55. Hypothesis concerning the U-shaped relation between body mass index and mortality.
    Am J Epidemiol. 1997 Aug 15;146(4):339-49 PMID: 9270413
  56. Association of metabolic syndrome with Alzheimer disease: a population-based study.
    Neurology. 2006 Sep 12;67(5):843-7 PMID: 16966548
  57. The obesity epidemic: pathophysiology and consequences of obesity.
    Obes Res. 2002 Dec;10 Suppl 2:97S-104S PMID: 12490658
  58. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
    JAMA. 2003 May 21;289(19):2560-72 PMID: 12748199
  59. Hyperinsulinaemia and Alzheimer's disease.
    Age Ageing. 1994 Sep;23(5):396-9 PMID: 7825486
  60. Diabetes guidelines: a summary and comparison of the recommendations of the American Diabetes Association, Veterans Health Administration, and American Association of Clinical Endocrinologists.
    Clin Ther. 2000 Aug;22(8):899-910; discussion 898 PMID: 10972628
  61. Diabetes mellitus and the risk of dementia: The Rotterdam Study.
    Neurology. 1999 Dec 10;53(9):1937-42 PMID: 10599761
  62. Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study of Health and Aging.
    Dement Geriatr Cogn Disord. 2002;14(2):77-83 PMID: 12145454
  63. Atherosclerosis and AD: analysis of data from the US National Alzheimer's Coordinating Center.
    Neurology. 2005 Feb 8;64(3):494-500 PMID: 15699381
  64. Hyperinsulinemia and risk of Alzheimer disease.
    Neurology. 2004 Oct 12;63(7):1187-92 PMID: 15477536
  65. Silent brain infarcts and the risk of dementia and cognitive decline.
    N Engl J Med. 2003 Mar 27;348(13):1215-22 PMID: 12660385
  66. Insulin resistance precedes weight loss in adults without diabetes : the Rancho Bernardo Study.
    Am J Epidemiol. 2001 Jun 15;153(12):1199-205 PMID: 11415955
  67. The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study.
    Diabetes. 2006 Apr;55(4):1114-20 PMID: 16567536
  68. Metabolic syndrome and dementia risk in a multiethnic elderly cohort.
    Dement Geriatr Cogn Disord. 2007;24(3):185-92 PMID: 17641531
  69. Impact of age on associations between weight and mortality.
    Nutr Rev. 2000 May;58(5):129-37 PMID: 10860392
  70. Serum or cerebrospinal fluid levels of glyceraldehyde-derived advanced glycation end products (AGEs) may be a promising biomarker for early detection of Alzheimer's disease.
    Med Hypotheses. 2005;64(6):1205-7 PMID: 15823718
  71. The origins of Alzheimer disease: a is for amyloid.
    JAMA. 2000 Mar 22-29;283(12):1615-7 PMID: 10735401
  72. Association of life activities with cerebral blood flow in Alzheimer disease: implications for the cognitive reserve hypothesis.
    Arch Neurol. 2003 Mar;60(3):359-65 PMID: 12633147
  73. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians.
    N Engl J Med. 1993 Dec 30;329(27):1988-92 PMID: 8247074
  74. Insulin and cognitive function in an elderly population. The Rotterdam Study.
    Diabetes Care. 1997 May;20(5):792-5 PMID: 9135944
  75. Lilly lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic.
    Diabetes. 2004 Jul;53(7):1633-42 PMID: 15220184
  76. Insulin effects on CSF norepinephrine and cognition in Alzheimer's disease.
    Neurobiol Aging. 2006 Jan;27(1):38-41 PMID: 16298239
  77. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function.
    Arch Neurol. 2004 May;61(5):661-6 PMID: 15148141
  78. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women.
    Neurology. 2004 Aug 24;63(4):658-63 PMID: 15326238
  79. Risk of dementia among persons with diabetes mellitus: a population-based cohort study.
    Am J Epidemiol. 1997 Feb 15;145(4):301-8 PMID: 9054233
  80. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study.
    Diabetes. 2002 Apr;51(4):1256-62 PMID: 11916953
  81. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
    N Engl J Med. 2002 Feb 7;346(6):393-403 PMID: 11832527
  82. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study.
    BMJ. 2005 Jun 11;330(7504):1360 PMID: 15863436
  83. Which measure of body fat distribution is best for epidemiologic research?
    Am J Epidemiol. 1991 May 1;133(9):858-69 PMID: 2028976
  84. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--The Evidence Report. National Institutes of Health.
    Obes Res. 1998 Sep;6 Suppl 2:51S-209S PMID: 9813653
  85. Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan.
    Neurology. 2001 Jan 9;56(1):49-56 PMID: 11148235
  86. Risk factors for NIDDM in white population. Paris prospective study.
    Diabetes. 1991 Jul;40(7):796-9 PMID: 2060716
  87. Mild cognitive impairment: directions for future research.
    Neurology. 2003 Aug 26;61(4):438-44 PMID: 12939414
  88. Pharmacologic therapy for type 2 diabetes mellitus.
    Ann Intern Med. 2000 Jul 4;133(1):73-4 PMID: 10877745
  89. Insulin and cognitive function.
    Lancet. 2003 Oct 18;362(9392):1253 PMID: 14575966
  90. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.
    Circulation. 2005 Oct 25;112(17):2735-52 PMID: 16157765
  91. Alzheimer's disease: genotypes, phenotypes, and treatments.
    Science. 1997 Jan 31;275(5300):630-1 PMID: 9019820
  92. Vascular risks and incident dementia: results from a cohort study of the very old.
    Dement Geriatr Cogn Disord. 1998 May-Jun;9(3):175-80 PMID: 9622006
  93. Mild cognitive impairment: prevalence and incidence according to different diagnostic criteria. Results of the Leipzig Longitudinal Study of the Aged (LEILA75+).
    Br J Psychiatry. 2003 May;182:449-54 PMID: 12724250
  94. Trends in waist circumference among U.S. adults.
    Obes Res. 2003 Oct;11(10):1223-31 PMID: 14569048
  95. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons.
    JAMA. 1999 Jul 7;282(1):40-6 PMID: 10404910
  96. Body mass index and incidence of dementia: the PAQUID study.
    Neurology. 2003 Jan 14;60(1):117-9 PMID: 12525731
  97. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue.
    Circ Res. 2005 May 27;96(10):1042-52 PMID: 15920027
  98. Stroke and the risk of Alzheimer disease.
    Arch Neurol. 2003 Dec;60(12):1707-12 PMID: 14676044
  99. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism.
    Circulation. 2006 Feb 14;113(6):898-918 PMID: 16380542
  100. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset.
    Am J Public Health. 1998 Sep;88(9):1337-42 PMID: 9736873
  101. Rosiglitazone and cardiotoxicity--weighing the evidence.
    N Engl J Med. 2007 Jul 5;357(1):64-6 PMID: 17551161
  102. Hypercholesterolemia. The NCEP Adult Treatment Panel III Guidelines.
    Geriatrics. 2003 Aug;58(8):33-8; quiz 41 PMID: 12938250
  103. Cognitive reserve and lifestyle.
    J Clin Exp Neuropsychol. 2003 Aug;25(5):625-33 PMID: 12815500
  104. Measures of adiposity and dementia risk in elderly persons.
    Arch Neurol. 2007 Mar;64(3):392-8 PMID: 17353383
  105. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study.
    Am J Geriatr Psychiatry. 2005 Nov;13(11):950-8 PMID: 16286438
  106. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study.
    Neurology. 2004 Oct 12;63(7):1181-6 PMID: 15477535
  107. A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study.
    Arch Neurol. 2005 Jan;62(1):55-60 PMID: 15642850
  108. What to do about the metabolic syndrome?
    Arch Intern Med. 2003 Feb 24;163(4):395-7 PMID: 12588197
Article Info
Journal
European journal of pharmacology
Abbr.
Eur J Pharmacol
ISSN
0014-2999
DOI
10.1016/j.ejphar.2008.02.048
Email
jal94@columbia.edu
Published
2008-05-06
Epub
2008-00-04
Pages
119-29
Language
English
Region
Netherlands
NLM ID
1254354
PMCID
PMC2474785
Subset
IM
Grants
NIA NIH HHS · P01 AG007232 · United States
NIA NIH HHS · P01 AG007232-190009 · United States
NIA NIH HHS · AG07232 · United States
External Links
PubMed source DOI: 10.1016/j.ejphar.2008.02.048 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2