Diabetes is a known risk factor for dementia, but when in a person's life is this connection most at play? In the April 27 JAMA, researchers led by Archana Singh-Manoux, INSERM, Paris, reported that the earlier diabetes sets in, the likelier—and the sooner—dementia may follow suit. Getting Type 2 diabetes before age 60 doubles dementia risk, and for every five years a person lives with diabetes, his or her dementia risk increases by 24 percent. People who had diabetes and vascular problems, such as heart failure or stroke, had even higher odds of dementia, while people with prediabetes did not appear to have significantly greater risk in this study.
- Five-year stepwise increases link diabetes duration to dementia risk.
- In people with diabetes, vascular problems compound dementia risk.
- Prediabetes did not robustly increase dementia risk in this study.
“This is one of the largest and well-done studies connecting diabetes to risk of dementia,” Kristine Yaffe, University of California, San Francisco, told Alzforum.
Type 2 diabetes is becoming more common in developed and developing nations, along with the rise of obesity, sedentary lifestyles, and ultra-processed food. Previous research has shown that diabetes comes with a 25 to 91 percent elevated risk of developing dementia (Xue et al., 2019; Zhang et al., 2017; AlzRisk). One recent study has shown that poor health, including obesity and diabetes, in early adulthood ups dementia risk (Yaffe et al., 2021; Aug 2020 conference news). Overall, however, research on the subject of diabetes and dementia has not yet addressed how this risk relates to age of diabetes onset.
To find out, first author Claudio Barbiellini Amidei, INSERM, and colleagues searched through national medical records on 10,095 people from Whitehall II. This ongoing, London-based study began recruiting participants ages 35 to 55 in 1985 and follows up with them every five years or so. Thus far, the participants have been followed for an average of 31.7 years. They are only now entering the age where dementia prevalence becomes high, so the study’s findings may strengthen. The cohort is two-thirds men and 90 percent white.
The researchers pulled data from the Whitehall database on fasting blood glucose and diagnoses of either Type 2 diabetes or dementia at 55, 60, 65, and 70 years old. They determined participants' dementia status based on diagnostic codes in their National Health Service and other medical database records. Diabetes was diagnosed by blood glucose level, diagnostic code, or use of diabetes medicines. The scientists corrected for age, sex, race, and years of education; health behaviors such as smoking, alcohol consumption, exercise, and diet; and high blood pressure, body mass index, and use of various common medications.
Overall, 639 participants had dementia and 1,710 had diabetes; 153 had both. Almost half of all diabetes diagnoses were given to participants 70 or older.
Compared to people without diabetes, those with this disease had a 3.5 times higher risk of dementia. Alas, the strength of this link changed with age. For example, by age 70, having developed diabetes in one’s 60s did not raise dementia risk much compared to not having diabetes, but having developed diabetes before 60 doubled one’s risk. This agrees with previous findings from the Swedish Twin Registry, which showed diabetes only in people younger than 65 bumped up their dementia risk (Xu et al., 2009).
The longer a person had diabetes, the earlier he or she tended to develop dementia. For example, people who were free of diabetes at their 65-year study visit were diagnosed with dementia, if they were, at a mean age of 77.5. This compares to age 76.7 at dementia diagnosis for people who’d developed diabetes in their early 60s, and 75.8 at dementia diagnosis in those who had diabetes since before age 60, respectively.
Yaffe noted that people who get diabetes during middle age versus in old age tend to have different contributing factors, such as weight, race, ethnicity, and genetic factors. “Is there another message here beyond duration of diabetes? Could people who get diabetes earlier have more severe disease?” she asked.
What about prediabetes? Similarly to dementia, diabetes develops slowly. If a participant’s fasting blood glucose was elevated but fell between normal and the diabetic cutoff, they were considered prediabetic. At all ages, prediabetic participants did not have a significantly higher risk of dementia. This surprised both Singh-Manoux and Yaffe. “I would have expected a small increase in dementia risk with prediabetes,” Yaffe told Alzforum.
The authors noted that the way the Whitehall study ascertains dementia—by way of participants’ electronic health records rather than in-person assessments by study doctors—means that mild cases of dementia are missed. The study made no distinction between Alzheimer’s and vascular dementia. Although the Whitehall study did not collect PET scans or AD blood biomarkers, Singh-Manoux’s group was recently funded to measure protein biomarkers, including markers of Alzheimer’s disease in the previously collected blood samples.
Singh-Manoux said diabetes may hurt the brain by way of damaging its small vessels. “If it was a primary mechanism, we would expect to see increased dementia risk with increasing blood sugar,” she said.
Vascular disease is known to worsen a person’s odds of dementia and, indeed, these problems compounded with diabetes in this study. Participants who had diabetes but no coronary heart disease, heart failure, or stroke had a fivefold lower risk of dementia than participants who suffered from diabetes plus all these conditions; dementia odds for people who had one of these vascular problems with their diabetes fell in between.
These new data imply that the 2020 Lancet Commission on Dementia may have underestimated the importance of Type 2 diabetes in all-cause dementia worldwide (Aug 2020 conference news). The commission's report did peg diabetes as a late-life risk factor, but attributed only 1.1 percent of the global dementia burden to it. Singh-Manoux noted that the commission used a lower diabetes prevalence—6.4 percent rather than the 15 to 20 percent for people over 55 estimated in recent research (Standl et al., 2019). “I expect diabetes to contribute to a much higher percentage of dementia cases,” she told Alzforum.—Chelsea Weidman Burke
- Heart Health Is Brain Health, and It Starts in Your 20s
- Lancet Commission’s Dementia Hit List Adds Alcohol, Pollution, TBI
- Xue M, Xu W, Ou YN, Cao XP, Tan MS, Tan L, Yu JT. Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies. Ageing Res Rev. 2019 Nov;55:100944. Epub 2019 Aug 17 PubMed.
- Zhang J, Chen C, Hua S, Liao H, Wang M, Xiong Y, Cao F. An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimer's disease. Diabetes Res Clin Pract. 2017 Feb;124:41-47. Epub 2016 Nov 9 PubMed.
- Yaffe K, Vittinghoff E, Hoang T, Matthews K, Golden SH, Zeki Al Hazzouri A. Cardiovascular Risk Factors Across the Life Course and Cognitive Decline: A Pooled Cohort Study. Neurology. 2021 Apr 27;96(17):e2212-e2219. Epub 2021 Mar 17 PubMed.
- 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 Jan 1;58(1):71-7. PubMed.
- 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 Dec;26(2_suppl):7-14. PubMed.
- Diabetic Monkeys Show Signs of Early Alzheimer’s
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- Research Brief: Diabetes—Risk Factor That Slows Cognitive Decline?
- Type 2 Diabetes and Neurodegeneration—The Plot Caramelizes
- Diabetes-Insulin Roundup: Dementia Connection Grows Stronger, Part 1
- Diabetes-Insulin Roundup: Dementia Connection Grows Stronger, Part 2
- Barbiellini Amidei C, Fayosse A, Dumurgier J, Machado-Fragua MD, Tabak AG, van Sloten T, Kivimäki M, Dugravot A, Sabia S, Singh-Manoux A. Association Between Age at Diabetes Onset and Subsequent Risk of Dementia. JAMA. 2021 Apr 27;325(16):1640-1649. PubMed.