Top

Diabetologia

Published in:

01-06-2009 | Article

Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study

Authors: W. L. Xu, E. von Strauss, C. X. Qiu, B. Winblad, L. Fratiglioni

Published in: Diabetologia | Issue 6/2009

Abstract

Aims/hypothesis

Diabetes has been related to Alzheimer’s disease with inconsistent findings. We aimed to clarify the association of diabetes with different dementing disorders taking into account glycaemic control, and to explore the link between glucose dysregulation and neurodegeneration.

Methods

A dementia-free cohort (n = 1,248) aged ≥75 years was longitudinally examined to detect dementia, Alzheimer’s disease and vascular dementia (VaD) cases (Diagnostic and Statistical Manual of Mental Disorders, revised third edition [DSM-III-R] criteria). The Alzheimer’s disease diagnoses were subdivided into Alzheimer’s disease with stroke and Alzheimer’s disease without hypertension, heart disease and stroke. Diabetes was ascertained based on medical history, or hypoglycaemic medication use, or a random blood glucose level ≥11.0 mmol/l, which included undiagnosed diabetes when neither a history of diabetes nor hypoglycaemic drugs use was present. Uncontrolled diabetes was classified as a random blood glucose level ≥11.0 mmol/l in diabetic patients. Borderline diabetes was defined as a random blood glucose level of 7.8–11.0 mmol/l in diabetes-free individuals. Cox models were used to estimate HRs.

Results

During the 9 year follow-up, 420 individuals developed dementia, including 47 with VaD and 320 with Alzheimer’s disease (of the 320 Alzheimer’s disease cases, 78 had previous, temporally unrelated stroke, and 137 had no major vascular comorbidities). Overall diabetes was only related to VaD (HR 3.21, 95% CI 1.20–8.63). Undiagnosed diabetes led to an HR of 3.29 (95% CI 1.20–9.01) for Alzheimer’s disease. Diabetic patients with random blood glucose levels <7.8 mmol/l showed no increased dementia risk. Uncontrolled and borderline diabetes were further associated with Alzheimer’s disease without vascular comorbidities.

Conclusions/interpretation

Uncontrolled diabetes increases the risk of Alzheimer’s disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.

Cole AR, Astell A, Green C, Sutherland C (2007) Molecular connexions between dementia and diabetes. Neurosci Biobehav Rev 31:1046–1063PubMedCrossRef

Alberti KG (2007) Screening and diagnosis of prediabetes: where are we headed? Diabetes Obes Metab 9(Suppl 1):12–16PubMedCrossRef

Ferri CP, Prince M, Brayne C et al (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–2117PubMedCrossRef

Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM (1999) Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53:1937–1942PubMed

Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R (2001) Diabetes mellitus and risk of Alzheimer’s disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol 154:635–641PubMedCrossRef

Hassing LB, Johansson B, Nilsson SE et al (2002) Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer’s disease: a population-based study of the oldest old. Int Psychogeriatr 14:239–248PubMedCrossRef

Peila R, Rodriguez BL, Launer LJ (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51:1256–1262PubMedCrossRef

MacKnight C, Rockwood K, Awalt E, McDowell I (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 14:77–83PubMedCrossRef

Luchsinger JA, Tang MX, Shea S, Mayeux R (2004) Hyperinsulinemia and risk of Alzheimer disease. Neurology 63:1187–1192PubMed

10.

Schnaider Beeri M, Goldbourt U, Silverman JM et al (2004) Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology 63:1902–1907PubMed

11.

Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 61:661–666PubMedCrossRef

12.

Borenstein AR, Wu Y, Mortimer JA et al (2005) Developmental and vascular risk factors for Alzheimer’s disease. Neurobiol Aging 26:325–334PubMedCrossRef

13.

Akomolafe A, Beiser A, Meigs JB et al (2006) Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Arch Neurol 63:1551–1555PubMedCrossRef

14.

Irie F, Fitzpatrick AL, Lopez OL et al (2008) Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. Arch Neurol 65:89–93PubMedCrossRef

15.

Xu WL, Qiu CX, Wahlin A, Winblad B, Fratiglioni L (2004) Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 63:1181–1186PubMed

16.

Hayden KM, Zandi PP, Lyketsos CG et al (2006) Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis Assoc Disord 20:93–100PubMedCrossRef

17.

van Harten B, de Leeuw FE, Weinstein HC, Scheltens P, Biessels GJ (2006) Brain imaging in patients with diabetes: a systematic review. Diabetes Care 29:2539–2548PubMedCrossRef

18.

Gao L, Matthews FE, Sargeant LA, Brayne C (2008) An investigation of the population impact of variation in HbA1c levels in older people in England and Wales: from a population based multi-centre longitudinal study. BMC Public Health 8:54PubMedCrossRef

19.

Shorr RI, de Rekeneire N, Resnick HE et al (2006) Glycemia and cognitive function in older adults using glucose-lowering drugs. J Nutr Health Aging 10:297–301PubMed

20.

van den Berg E, Kessels RP, Kappelle LJ, de Haan EH, Biessels GJ (2006) Type 2 diabetes, cognitive function and dementia: vascular and metabolic determinants. Drugs Today (Barc) 42:741–754CrossRef

21.

Asimakopoulou KG, Hampson SE, Morrish NJ (2002) Neuropsychological functioning in older people with type 2 diabetes: the effect of controlling for confounding factors. Diabet Med 19:311–316PubMedCrossRef

22.

Yamada M, Kasagi F, Sasaki H, Masunari N, Mimori Y, Suzuki G (2003) Association between dementia and midlife risk factors: the Radiation Effects Research Foundation Adult Health Study. J Am Geriatr Soc 51:410–414PubMedCrossRef

23.

Hassing LB, Hofer SM, Nilsson SE et al (2004) Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study. Age Ageing 33:355–361PubMedCrossRef

24.

Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K (2005) Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64:277–281PubMed

25.

Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R (2005) Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65:545–551PubMedCrossRef

26.

Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, Winblad B (1997) Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project, Stockholm. Neurology 48:132–138PubMed

27.

Fratiglioni L, Grut M, Forsell Y, Viitanen M, Winblad B (1992) Clinical diagnosis of Alzheimer’s disease and other dementias in a population survey. Agreement and causes of disagreement in applying Diagnostic and Statistical Manual of Mental Disorders, Revised 3rd edn, Criteria. Arch Neurol 49:927–932PubMed

28.

American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, revised 3rd edn (DSM-III-R). American Psychiatric Association, Washington, DC

29.

Qiu C, Backman L, Winblad B, Aguero-Torres H, Fratiglioni L (2001) The influence of education on clinically diagnosed dementia incidence and mortality data from the Kungsholmen Project. Arch Neurol 58:2034–2039PubMedCrossRef

30.

Qiu CX, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L (2006) Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med 166:1003–1008PubMedCrossRef

31.

Nordic Council on Medicines: Guidelines for ATC classification (1985). Nordic council on medicines (NLN Publication No. 16), Uppsala, Sweden

32.

Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ (2008) Translating the A1C assay into estimated average glucose values. Diabetes Care 31:1473–1478PubMedCrossRef

33.

Thomas MC, Walker MK, Emberson JR et al (2005) Prevalence of undiagnosed Type 2 diabetes and impaired fasting glucose in older British men and women. Diabet Med 22:789–793PubMedCrossRef

34.

Xu W, Qiu C, Winblad B, Fratiglioni L (2007) The effect of borderline diabetes on the risk of dementia and Alzheimer’s disease. Diabetes 56:211–216PubMedCrossRef

35.

Hachinski VC, Iliff LD, Zilhka E et al (1975) Cerebral blood flow in dementia. Arch Neurol 32:632–637PubMed

36.

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMed

37.

Roman GC, Tatemichi TK, Erkinjuntti T et al (1993) Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43:250–260PubMed

38.

Aguero-Torres H, Kivipelto M, von Strauss E (2006) Rethinking the dementia diagnoses in a population-based study: what is Alzheimer’s disease and what is vascular dementia? A study from the Kungsholmen Project. Dement Geriatr Cogn Disord 22:244–249PubMedCrossRef

39.

Andersson DK, Svardsudd K, Tibblin G (1991) Prevalence and incidence of diabetes in a Swedish community 1972–1987. Diabet Med 8:428–434PubMedCrossRef

40.

Xu W (2008) Diabetes mellitus and the risk of dementia: a population-based study. Karolinska Institutet. The outline of the thesis available from http://diss.kib.ki.se/2008/978-91-7357-516-4/, accessed 16 May 2008

41.

Wilson RS, Scherr PA, Schneider JA, Tang Y, Bennett DA (2007) Relation of cognitive activity to risk of developing Alzheimer disease. Neurology 69:1911–1920PubMedCrossRef

42.

Lopez OL, Kuller LH, Becker JT et al (2005) Classification of vascular dementia in the Cardiovascular Health Study Cognition Study. Neurology 64:1539–1547PubMedCrossRef

43.

Leibson CL, Rocca WA, Hanson VA et al (1997) Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 145:301–308PubMed

44.

Qiu WQ, Folstein MF (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging 27:190–198PubMedCrossRef

45.

Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P (2006) Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 5:64–74PubMedCrossRef

46.

Whitmer RA (2007) Type 2 diabetes and risk of cognitive impairment and dementia. Curr Neurol Neurosci Rep 7:373–380PubMedCrossRef

47.

Korf ES, White LR, Scheltens P, Launer LJ (2006) Brain aging in very old men with type 2 diabetes: the Honolulu-Asia aging study. Diabetes Care 29:2268–2274PubMedCrossRef

48.

Gasparini L, Xu H (2003) Potential roles of insulin and IGF-1 in Alzheimer’s disease. Trends Neurosci 26:404–406PubMedCrossRef

49.

McGeer PL, Rogers J, McGeer EG (2006) Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J Alzheimers Dis 9:271–276PubMed

50.

Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53:474–481PubMedCrossRef

Title: Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study
Authors: W. L. Xu
E. von Strauss
C. X. Qiu
B. Winblad
L. Fratiglioni
Publication date: 01-06-2009
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 6/2009
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-009-1323-x

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 6/2009

A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion

Bivariate genetic modelling of the response to an oral glucose tolerance challenge: A gene × environment interaction approach

Role of enteroviruses in the pathogenesis of type 1 diabetes

Thiamine in diabetic nephropathy: a novel treatment modality? Reply to Alkhalaf A, Kleefstra N, Groenier KH et al. [letter]

Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress

Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page