Abstract
A number of well-designed epidemiological studies have linked type 2 diabetes mellitus (T2DM) with an increased risk of Alzheimer's disease (AD). Several mechanisms could help to explain this proposed link, including insulin and insulin resistance, inflammatory cytokines, and oxidative stress. Obesity or physical inactivity might also influence AD through effects on hypertension, insulin sensitivity or inflammation. Typical AD pathology, such as amyloid-β deposits, might be exacerbated by insulin dysregulation, T2DM itself, or microvascular disease that is a consequence of T2DM. T2DM patients are not routinely evaluated for cognitive outcomes, and cognitive impairment in T2DM is rarely treated. Similarly, AD patients are not routinely evaluated for T2DM or hyperinsulinemia. Current treatments for AD have only modest benefits, and several drugs that target metabolic and inflammatory pathways are being evaluated, most notably the statins, which reduce LDL and inflammation but might not influence amyloid- deposition, an important precursor for AD. Although some evidence supports a potentially important role for peroxisome proliferative activated receptor agonists such as glitazones, at present there are no published randomized clinical trials in AD patients of any drugs that target insulin or insulin resistance. Clinical implications of the T2DM–AD link include cognitive evaluations of patients with T2DM, and potential benefits for such patients through treatment with statins or diabetes drugs that target insulin.
Key Points
-
Type 2 diabetes mellitus (T2DM) is no longer solely a disease of middle and old age; this condition is rapidly emerging as a serious health threat among younger adults and even adolescents
-
Numerous epidemiological studies have linked T2DM with an increased risk of Alzheimer's disease (AD)
-
Recent studies have explored the involvement of metabolic, inflammatory, vascular and oxidative pathways in AD etiology; these factors are also present in T2DM, and might provide an explanation for the link between T2DM and AD
-
No randomized trials of patients with T2DM have yet included patients with AD or dementia, although one study revealed that type 2 diabetics receiving therapy showed less deterioration on cognitive tests than untreated T2DM patients
-
Several lines of evidence support the idea that lifestyle interventions targeting obesity and exercise could reduce the development of cognitive impairment, and thereby reduce a proportion of AD cases
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Boyle JP et al. (2001) Projection of diabetes burden through 2050: impact of changing demography and disease prevalence in the US. Diabetes Care 24: 1936–1940
ADNI: Alzheimer's Disease Neuroimaging Initiative [http://www.clinicaltrials.gov/show/NCT00106899]
Haan MN and Wallace R (2004) Can dementia be prevented? Brain aging in a population-based context. Annu Rev Public Health 25: 1–24
Shumaker SA et al. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 289: 2651–2662
Ott A et al. (1999) Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53: 1937–1942
Peila R et al. (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu–Asia Aging Study. Diabetes 51: 1256–1262
Luchsinger JA et al. (2004) Hyperinsulinemia and risk of Alzheimer disease. Neurology 63: 1187–1192
Leibson CL et al. (1997) The risk of dementia among persons with diabetes mellitus: a population-based cohort study. Ann NY Acad Sci 826: 422–427
Arvanitakis Z et al. (2004) Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 61: 661–666
Curb JD et al. (1999) Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance. Neurology 52: 971–975
Luchsinger JA et al. (2001) Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol 154: 635–641
Xu WL et al. (2004) Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 63: 1181–1186
Launer LJ (2002) Demonstrating the case that AD is a vascular disease: epidemiologic evidence. Ageing Res Rev 1: 61–77
Kalaria R (2002) Similarities between Alzheimer's disease and vascular dementia. J Neurol Sci 203–204: 29–34
Chui H (2000) Vascular dementia, a new beginning: shifting focus from clinical phenotype to ischemic brain injury. Neurol Clin 18: 951–978
Janson J et al. (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53: 474–481
den Heijer T et al. (2003) Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46: 1604–1610
Kalaria RN (2002) Small vessel disease and Alzheimer's dementia: pathological considerations. Cerebrovasc Dis 13 (Suppl 2): S48–S52
Geroldi C et al. (2005) Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol 62: 1067–1072
Sommerfield AJ et al. (2004) Acute hyperglycemia alters mood state and impairs cognitive performance in people with type 2 diabetes. Diabetes Care 27: 2335–2340
Frolich L et al. (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm 105: 423–438
Craft S and Watson GS (2004) Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 3: 169–178
Hong M and Lee VM (1997) Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 272: 19547–19553
Craft S et al. (1999) Insulin metabolism in Alzheimer's disease differs according to apolipoprotein E genotype and gender. Neuroendocrinology 70: 146–152
Goodpaster BH et al. (2005) Obesity, regional body fat distribution, and the metabolic syndrome in older men and women. Arch Intern Med 165: 777–783
Campbell IW (2000) Antidiabetic drugs present and future: will improving insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus? Drugs 60: 1017–1028
Gustafson D et al. (2003) An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 163: 1524–1528
Kivipelto M et al. (2005) Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 62: 1556–1560
Whitmer RA et al. (2005) Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 330: 1360
Lane KA et al. (2003) Apolipoprotein E and mortality in African-Americans and Yoruba. J Alzheimers Dis 5: 383–390
Barrett-Connor E et al. (1996) Weight loss precedes dementia in community-dwelling older adults. J Am Geriatr Soc 44: 1147–1152
Stewart R et al. (2005) A 32-year prospective study of change in body weight and incident dementia: the Honolulu–Asia Aging Study. Arch Neurol 62: 55–60
Jagust W et al. (2005) Central obesity and the aging brain. Arch Neurol 62: 1545–1548
Rovio S et al. (2005) Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 4: 705–711
Lindsay J et al. (2002) Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 156: 445–453
Podewils LJ et al. (2005) Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am J Epidemiol 161: 639–651
Veurink G et al. (2003) Genetics, lifestyle and the roles of amyloid beta and oxidative stress in Alzheimer's disease. Ann Hum Biol 30: 639–667
Schmidt R et al. (2002) Early inflammation and dementia: a 25-year follow-up of the Honolulu–Asia Aging Study. Ann Neurol 52: 168–174
Engelhart MJ et al. (2004) Inflammatory proteins in plasma and the risk of dementia: the Rotterdam study. Arch Neurol 61: 668–672
van de Ree MA et al. (2003) Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus. Atherosclerosis 166: 129–135
Hotamisligil GS (2003) Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 27 (Suppl 3): S53–S55
Napoli C and Palinski W (2005) Neurodegenerative diseases: insights into pathogenic mechanisms from atherosclerosis. Neurobiol Aging 26: 293–302
Araki A et al. (2005) Association of plasma homocysteine with serum interleukin-6 and C-peptide levels in patients with type 2 diabetes. Metabolism 54: 809–814
Ozdemir G et al. (2005) Malondialdehyde, glutathione, glutathione peroxidase and homocysteine levels in type 2 diabetic patients with and without microalbuminuria. Ann Clin Biochem 42: 99–104
Helfenstein T et al. (2005) Prevalence of myocardial infarction is related to hyperhomocysteinemia but not influenced by C677T methylenetetrahydrofolate reductase and A2756G methionine synthase polymorphisms in diabetic and non-diabetic subjects. Clin Chim Acta 355: 165–172
Ceriello A and Motz E (2004) Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 24: 816–823
Quadri P et al. (2004) Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 80: 114–122
Seshadri S et al. (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346: 476–483
den Heijer T et al. (2003) Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126: 170–175
Williams JH et al. (2002) Minimal hippocampal width relates to plasma homocysteine in community-dwelling older people. Age Ageing 31: 440–444
Kuusisto J et al. (1997) Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ 315: 1045–1049
Nolan JJ et al. (2000) Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus. Diabet Med 17: 287–294
Brune S et al. (2003) Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease. J Neural Transm 110: 1041–1050
Watson GS et al. (2005) Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 13: 950–958
Wu JH et al. (2003) Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann Epidemiol 13: 369–376
UKPDS authors (1999) Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37). UK Prospective Diabetes Study Group. Diabetes Care 22: 1125–1136
DCCT authors (1996) Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. Ann Intern Med 124: 379–388
Aisen PS et al. (2003) Steroid-induced elevation of glucose in Alzheimer's disease: relationship to gender, apolipoprotein E genotype and cognition. Psychoneuroendocrinology 28: 113–120
Reines SA et al. (2004) Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 62: 66–71
Sidhu JS et al. (2003) The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. J Am Coll Cardiol 42: 1757–1763
Sommeijer DW et al. (2004) Anti-inflammatory and anticoagulant effects of pravastatin in patients with type 2 diabetes. Diabetes Care 27: 468–473
Charbonnel B et al. (2004) The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care 27: 1647–1653
Pfutzner A et al. (2005) Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. J Am Coll Cardiol 45: 1925–1931
Simons M et al. (2002) Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 52: 346–350
Sparks DL et al. (2005) Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 62: 753–757
Collins R et al. (2004) Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 363: 757–767
Hallsten K et al. (2004) Enhancement of insulin-stimulated myocardial glucose uptake in patients with Type 2 diabetes treated with rosiglitazone. Diabet Med 21: 1280–1287
Inestrosa NC et al. (2005) Peroxisome proliferator-activated receptor gamma is expressed in hippocampal neurons and its activation prevents beta-amyloid neurodegeneration: role of Wnt signaling. Exp Cell Res 304: 91–104
Solfrizzi V et al. (2004) Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 63: 1882–1891
Rasquin SM et al. (2005) Predictive accuracy of MCI subtypes for Alzheimer's disease and vascular dementia in subjects with mild cognitive impairment: a 2-year follow-up study. Dement Geriatr Cogn Disord 19: 113–119
MacKnight C et al. (2002) 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 14: 77–83
Acknowledgements
Acknowledgments to Nancy West, doctoral student at the University of Michigan, for her assistance with references and for her outstanding scientific thoughts.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
Haan, M. Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease. Nat Rev Neurol 2, 159–166 (2006). https://doi.org/10.1038/ncpneuro0124
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpneuro0124
This article is cited by
-
Adiponectin, the adiponectin paradox, and Alzheimer’s Disease: Is this association biologically plausible?
Metabolic Brain Disease (2023)
-
Crosstalk between Alzheimer’s disease and diabetes: a focus on anti-diabetic drugs
Metabolic Brain Disease (2023)
-
TFP5, a Peptide Derived from Cdk5 Activator p35, Protects Pancreatic β Cells from Glucose Toxicity
Bulletin of Experimental Biology and Medicine (2023)
-
Targeting Insulin-Like Growth Factor-I in Management of Neurological Disorders
Neurotoxicity Research (2022)
-
Identifying disease trajectories with predicate information from a knowledge graph
Journal of Biomedical Semantics (2020)