[Skip to Content]
[Skip to Content Landing]

Association Between Age at Diabetes Onset and Subsequent Risk of Dementia

Educational Objective
To understand the association of dementia and type 2 diabetes.
1 Credit CME
Key Points

Question  What is the association between age at onset of type 2 diabetes and subsequent risk of dementia?

Findings  In this prospective cohort study of 10 095 participants, younger age at onset of type 2 diabetes was significantly associated with higher risk for incident dementia; at age 70, the hazard ratio for every 5-year earlier age at type 2 diabetes onset was 1.24.

Meaning  Younger age at diabetes onset was associated with higher risk of subsequent dementia.

Abstract

Importance  Trends in type 2 diabetes show an increase in prevalence along with younger age of onset. While vascular complications of early-onset type 2 diabetes are known, the associations with dementia remains unclear.

Objective  To determine whether younger age at diabetes onset is more strongly associated with incidence of dementia.

Design, Setting, and Participants  Population-based study in the UK, the Whitehall II prospective cohort study, established in 1985-1988, with clinical examinations in 1991-1993, 1997-1999, 2002-2004, 2007-2009, 2012-2013, and 2015-2016, and linkage to electronic health records until March 2019. The date of final follow-up was March 31, 2019.

Exposures  Type 2 diabetes, defined as a fasting blood glucose level greater than or equal to 126 mg/dL at clinical examination, physician-diagnosed type 2 diabetes, use of diabetes medication, or hospital record of diabetes between 1985 and 2019.

Main Outcomes and Measures  Incident dementia ascertained through linkage to electronic health records.

Results  Among 10 095 participants (67.3% men; aged 35-55 years in 1985-1988), a total of 1710 cases of diabetes and 639 cases of dementia were recorded over a median follow-up of 31.7 years. Dementia rates per 1000 person-years were 8.9 in participants without diabetes at age 70 years, and rates were 10.0 per 1000 person-years for participants with diabetes onset up to 5 years earlier, 13.0 for 6 to 10 years earlier, and 18.3 for more than 10 years earlier. In multivariable-adjusted analyses, compared with participants without diabetes at age 70, the hazard ratio (HR) of dementia in participants with diabetes onset more than 10 years earlier was 2.12 (95% CI, 1.50-3.00), 1.49 (95% CI, 0.95-2.32) for diabetes onset 6 to 10 years earlier, and 1.11 (95% CI, 0.70-1.76) for diabetes onset 5 years earlier or less; linear trend test (P < .001) indicated a graded association between age at onset of type 2 diabetes and dementia. At age 70, every 5-year younger age at onset of type 2 diabetes was significantly associated with an HR of dementia of 1.24 (95% CI, 1.06-1.46) in analyses adjusted for sociodemographic factors, health behaviors, and health-related measures.

Conclusions and Relevance  In this longitudinal cohort study with a median follow-up of 31.7 years, younger age at onset of diabetes was significantly associated with higher risk of subsequent dementia.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Archana Singh-Manoux, PhD, EpiAgeing, Université de Paris, Inserm U1153, 10 Avenue de Verdun, 75010 Paris, France (archana.singh-manoux@inserm.fr).

Accepted for Publication: March 2, 2021.

Author Contributions: Ms Fayosse and Dr Singh-Manoux had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Barbiellini Amidei and Ms Fayosse contributed equally to this article.

Concept and design: Barbiellini Amidei, Dugravot, Sabia, Singh-Manoux.

Acquisition, analysis, or interpretation of data: Barbiellini Amidei, Fayosse, Dumurgier, Machado-Fragua, Tabak, van Sloten, Kivimaki, Sabia, Singh-Manoux.

Drafting of the manuscript: Barbiellini Amidei, Singh-Manoux.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Barbiellini Amidei, Fayosse, Dumurgier, Dugravot, Sabia.

Obtained funding: Kivimaki, Singh-Manoux.

Administrative, technical, or material support: Singh-Manoux.

Supervision: Barbiellini Amidei, Fayosse, Singh-Manoux.

Conflict of Interest Disclosures: Dr Tabak reported salary supported by grants from the UK Medical Research Council (MRC) (S011676) and NordForsk (the Nordic Research Programme on Health and Welfare, 75021) during the conduct of the study. Dr van Sloten reported grants from the Netherlands Organization for Scientific Research and the Netherlands Organization for Health Research and Development (VENI research grant 916.19.074) and the Dutch Heart Foundation (2018T025) outside the submitted work. Dr Kivimaki reported grants from the UK MRC (R024227; S011676), the National Institute on Aging (NIA), National Institutes of Health (NIH) (R01AG056477; RF1AG062553), NordForsk (70521), and the Academy of Finland (311492) during the conduct of the study. Dr Sabia reported a grant from the French National Research Agency (ANR-19-CE36-0004-01). Dr Singh-Manoux reported grants from NIH (R01AG056477; RF1AG062553), the UK MRC (R024227; S011676), and the British Heart Foundation (BHF) (RG/16/11/32334) during the conduct of the study. No other disclosures were reported.

Funding/Support: The Whitehall II study is supported by grants from NIA, NIH (R01AG056477; RF1AG062553); UK MRC (R024227; S011676); the BHF (RG/16/11/32334); and the Wellcome Trust (221854/Z/20/Z). Dr Tabak is supported by the UK MRC (S011676) and NordForsk (75021). Dr Kivimaki is supported by NordForsk (70521) and the Academy of Finland (311492). Dr Van Sloten is supported by the Netherlands Organization for Scientific Research (VENI research grant 916.19.074) and the Dutch Heart Foundation (research grant 2018T025).

Role of the Funder/Sponsor: The NIH, MRC, and BHF had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank all of the participating civil service departments and their welfare, personnel, and establishment officers; the British Occupational Health and Safety Agency; the British Council of Civil Service Unions; all participating civil servants in the Whitehall II study; and all members of the Whitehall II study team. The Whitehall II Study team comprises research scientists, statisticians, study coordinators, nurses, data managers, administrative assistants, and data entry staff, who make the study possible.

References
1.
Chatterjee  S , Khunti  K , Davies  MJ .  Type 2 diabetes.   Lancet. 2017;389(10085):2239-2251. doi:10.1016/S0140-6736(17)30058-2PubMedGoogle ScholarCrossref
2.
Sarwar  N , Gao  P , Seshasai  SR ,  et al; Emerging Risk Factors Collaboration.  Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.   Lancet. 2010;375(9733):2215-2222. doi:10.1016/S0140-6736(10)60484-9PubMedGoogle ScholarCrossref
3.
Rao Kondapally Seshasai  S , Kaptoge  S , Thompson  A ,  et al; Emerging Risk Factors Collaboration.  Diabetes mellitus, fasting glucose, and risk of cause-specific death.   N Engl J Med. 2011;364(9):829-841. doi:10.1056/NEJMoa1008862PubMedGoogle ScholarCrossref
4.
Cheng  G , Huang  C , Deng  H , Wang  H .  Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies.   Intern Med J. 2012;42(5):484-491. doi:10.1111/j.1445-5994.2012.02758.xPubMedGoogle ScholarCrossref
5.
Chatterjee  S , Peters  SA , Woodward  M ,  et al.  Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100 000 cases of dementia.   Diabetes Care. 2016;39(2):300-307. doi:10.2337/dc15-1588PubMedGoogle Scholar
6.
Zhang  J , Chen  C , Hua  S ,  et al.  An updated meta-analysis of cohort studies: diabetes and risk of alzheimer’s disease.   Diabetes Res Clin Pract. 2017;124:41-47. doi:10.1016/j.diabres.2016.10.024PubMedGoogle ScholarCrossref
7.
Kivimäki  M , Singh-Manoux  A , Pentti  J ,  et al; IPD-Work consortium.  Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis.   BMJ. 2019;365:l1495. doi:10.1136/bmj.l1495PubMedGoogle ScholarCrossref
8.
Xue  M , Xu  W , Ou  YN ,  et al.  Diabetes mellitus and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 144 prospective studies.   Ageing Res Rev. 2019;55:100944. doi:10.1016/j.arr.2019.100944PubMedGoogle Scholar
9.
Sattar  N , Rawshani  A , Franzén  S ,  et al.  Age at diagnosis of type 2 diabetes mellitus and associations with cardiovascular and mortality risks.   Circulation. 2019;139(19):2228-2237. doi:10.1161/CIRCULATIONAHA.118.037885PubMedGoogle ScholarCrossref
10.
Huo  X , Gao  L , Guo  L ,  et al.  Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study.   Lancet Diabetes Endocrinol. 2016;4(2):115-124. doi:10.1016/S2213-8587(15)00508-2PubMedGoogle ScholarCrossref
11.
Tancredi  M , Rosengren  A , Svensson  AM ,  et al.  Excess mortality among persons with type 2 diabetes.   N Engl J Med. 2015;373(18):1720-1732. doi:10.1056/NEJMoa1504347PubMedGoogle ScholarCrossref
12.
Livingston  G , Huntley  J , Sommerlad  A ,  et al.  Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.   Lancet. 2020;396(10248):413-446. doi:10.1016/S0140-6736(20)30367-6PubMedGoogle ScholarCrossref
13.
Koopman  RJ , Mainous  AG  III , Diaz  VA , Geesey  ME .  Changes in age at diagnosis of type 2 diabetes mellitus in the United States, 1988 to 2000.   Ann Fam Med. 2005;3(1):60-63. doi:10.1370/afm.214PubMedGoogle ScholarCrossref
14.
Marmot  MG , Smith  GD , Stansfeld  S ,  et al.  Health inequalities among British civil servants: the Whitehall II study.   Lancet. 1991;337(8754):1387-1393. doi:10.1016/0140-6736(91)93068-KPubMedGoogle ScholarCrossref
15.
Tabák  AG , Jokela  M , Akbaraly  TN , Brunner  EJ , Kivimäki  M , Witte  DR .  Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study.   Lancet. 2009;373(9682):2215-2221. doi:10.1016/S0140-6736(09)60619-XPubMedGoogle ScholarCrossref
16.
Lindström  J , Tuomilehto  J .  The diabetes risk score: a practical tool to predict type 2 diabetes risk.   Diabetes Care. 2003;26(3):725-731. doi:10.2337/diacare.26.3.725PubMedGoogle ScholarCrossref
17.
Sommerlad  A , Perera  G , Singh-Manoux  A , Lewis  G , Stewart  R , Livingston  G .  Accuracy of general hospital dementia diagnoses in England: sensitivity, specificity, and predictors of diagnostic accuracy 2008-2016.   Alzheimers Dement. 2018;14(7):933-943. doi:10.1016/j.jalz.2018.02.012PubMedGoogle ScholarCrossref
18.
Wilkinson  T , Ly  A , Schnier  C ,  et al; UK Biobank Neurodegenerative Outcomes Group and Dementias Platform UK.  Identifying dementia cases with routinely collected health data: a systematic review.   Alzheimers Dement. 2018;14(8):1038-1051. doi:10.1016/j.jalz.2018.02.016PubMedGoogle ScholarCrossref
19.
Austin  PC , Lee  DS , Fine  JP .  Introduction to the analysis of survival data in the presence of competing risks.   Circulation. 2016;133(6):601-609. doi:10.1161/CIRCULATIONAHA.115.017719PubMedGoogle ScholarCrossref
20.
Lau  B , Cole  SR , Gange  SJ .  Competing risk regression models for epidemiologic data.   Am J Epidemiol. 2009;170(2):244-256. doi:10.1093/aje/kwp107PubMedGoogle ScholarCrossref
21.
Harrell  FE  Jr .  Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. Springer; 2001. doi:10.1007/978-1-4757-3462-1
22.
Standl  E , Khunti  K , Hansen  TB , Schnell  O .  The global epidemics of diabetes in the 21st century: current situation and perspectives.   Eur J Prev Cardiol. 2019;26(2_suppl):7-14. doi:10.1177/2047487319881021PubMedGoogle ScholarCrossref
24.
Xu  W , Qiu  C , Gatz  M , Pedersen  NL , Johansson  B , Fratiglioni  L .  Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study.   Diabetes. 2009;58(1):71-77. doi:10.2337/db08-0586PubMedGoogle ScholarCrossref
25.
Rawlings  AM , Sharrett  AR , Albert  MS ,  et al.  The association of late-life diabetes status and hyperglycemia with incident mild cognitive impairment and dementia: the ARIC study.   Diabetes Care. 2019;42(7):1248-1254. doi:10.2337/dc19-0120PubMedGoogle ScholarCrossref
26.
Rawlings  AM , Sharrett  AR , Schneider  AL ,  et al.  Diabetes in midlife and cognitive change over 20 years: a cohort study.   Ann Intern Med. 2014;161(11):785-793. doi:10.7326/M14-0737PubMedGoogle ScholarCrossref
27.
Tuligenga  RH , Dugravot  A , Tabák  AG ,  et al.  Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study.   Lancet Diabetes Endocrinol. 2014;2(3):228-235. doi:10.1016/S2213-8587(13)70192-XPubMedGoogle ScholarCrossref
28.
Crane  PK , Walker  R , Hubbard  RA ,  et al.  Glucose levels and risk of dementia.   N Engl J Med. 2013;369(6):540-548. doi:10.1056/NEJMoa1215740PubMedGoogle ScholarCrossref
29.
Hamed  SA .  Brain injury with diabetes mellitus: evidence, mechanisms and treatment implications.   Expert Rev Clin Pharmacol. 2017;10(4):409-428. doi:10.1080/17512433.2017.1293521PubMedGoogle ScholarCrossref
30.
Wang  Z , Marseglia  A , Shang  Y , Dintica  C , Patrone  C , Xu  W .  Leisure activity and social integration mitigate the risk of dementia related to cardiometabolic diseases: a population-based longitudinal study.   Alzheimers Dement. 2020;16(2):316-325. doi:10.1016/j.jalz.2019.09.003PubMedGoogle ScholarCrossref
31.
Beeri  MS , Bendlin  BB .  The link between type 2 diabetes and dementia: from biomarkers to treatment.   Lancet Diabetes Endocrinol. 2020;8(9):736-738. doi:10.1016/S2213-8587(20)30267-9PubMedGoogle ScholarCrossref
32.
Cunnane  SC , Trushina  E , Morland  C ,  et al.  Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.   Nat Rev Drug Discov. 2020;19(9):609-633. doi:10.1038/s41573-020-0072-xPubMedGoogle ScholarCrossref
33.
Kellar  D , Craft  S .  Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches.   Lancet Neurol. 2020;19(9):758-766. doi:10.1016/S1474-4422(20)30231-3PubMedGoogle ScholarCrossref
34.
Arnold  SE , Arvanitakis  Z , Macauley-Rambach  SL ,  et al.  Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums.   Nat Rev Neurol. 2018;14(3):168-181. doi:10.1038/nrneurol.2017.185PubMedGoogle ScholarCrossref
35.
Willette  AA , Bendlin  BB , Starks  EJ ,  et al.  Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease.   JAMA Neurol. 2015;72(9):1013-1020. doi:10.1001/jamaneurol.2015.0613PubMedGoogle ScholarCrossref
36.
van Sloten  TT , Sedaghat  S , Carnethon  MR , Launer  LJ , Stehouwer  CDA .  Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression.   Lancet Diabetes Endocrinol. 2020;8(4):325-336. doi:10.1016/S2213-8587(19)30405-XPubMedGoogle ScholarCrossref
37.
Yaffe  K , Falvey  CM , Hamilton  N ,  et al; Health ABC Study.  Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus.   JAMA Intern Med. 2013;173(14):1300-1306. doi:10.1001/jamainternmed.2013.6176PubMedGoogle ScholarCrossref
38.
McMillan  JM , Mele  BS , Hogan  DB , Leung  AA .  Impact of pharmacological treatment of diabetes mellitus on dementia risk: systematic review and meta-analysis.   BMJ Open Diabetes Res Care. 2018;6(1):e000563. doi:10.1136/bmjdrc-2018-000563PubMedGoogle Scholar
39.
Rothman  KJ , Gallacher  JE , Hatch  EE .  Why representativeness should be avoided.   Int J Epidemiol. 2013;42(4):1012-1014. doi:10.1093/ije/dys223PubMedGoogle ScholarCrossref
40.
Batty  GD , Shipley  M , Tabák  A ,  et al.  Generalizability of occupational cohort study findings.   Epidemiology. 2014;25(6):932-933. doi:10.1097/EDE.0000000000000184PubMedGoogle ScholarCrossref
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close