Endocrinol Metab.  2021 Apr;36(2):424-435. 10.3803/EnM.2020.935.

Cumulative Exposure to Metabolic Syndrome Components and the Risk of Dementia: A Nationwide Population-Based Study

• Cho Y
• Han K
• Kim DH
• Park YM
• Yoon KH
• Kim MK
• Lee SH

• KMID: 2515468
• DOI: http://doi.org/10.3803/EnM.2020.935

Abstract

Background
Metabolic disturbances are modifiable risk factors for dementia. Because the status of metabolic syndrome (MetS) and its components changes over time, we aimed to investigate the association of the cumulative exposure to MetS and its components with the risk of dementia.
Methods
Adults (n=1,492,776; ≥45-years-old) who received health examinations for 4 consecutive years were identified from a nationwide population-based cohort in Korea. Two exposure-weighted scores were calculated: cumulative number of MetS diagnoses (MetS exposure score, range of 0 to 4) and the composite of its five components (MetS component exposure score, range of 0 to 20). Hazard ratio (HR) and 95% confidence interval (CI) values for dementia were analyzed using the multivariable Cox proportional-hazards model.
Results
Overall, 47.1% of subjects were diagnosed with MetS at least once, and 11.5% had persistent MetS. During the mean 5.2 years of follow-up, there were 7,341 cases (0.5%) of incident dementia. There was a stepwise increase in the risk of all-cause dementia, Alzheimer’s disease, and vascular dementia with increasing MetS exposure score and MetS component exposure score (each P for trend <0.0001). The HR of all-cause dementia was 2.62 (95% CI, 1.87 to 3.68) in subjects with a MetS component exposure score of 20 compared with those with a score of 0. People fulfilling only one MetS component out of 20 already had an approximately 40% increased risk of all-cause dementia and Alzheimer’s disease.
Conclusion
More cumulative exposure to metabolic disturbances was associated with a higher risk of dementia. Of note, even minimal exposure to MetS components had a significant effect on the risk of dementia.

Keyword

Alzheimer disease; Dementia; Metabolic syndrome

Figure

• 

  Fig. 1 Hazard ratios (HR) (95% confidence intervals [CIs]) and incidence rate of (A) all-cause dementia, (B) Alzheimer’s disease, and (C) vascular dementia according to the metabolic syndrome component exposure score. The data were adjusted for age, sex, alcohol drinking, smoking, regular exercise, income status, systolic blood pressure, waist circumference, fasting glucose, triglyceride, and high-density lipoprotein cholesterol levels.

Reference

1. Prince M, Wimo A, Guerchet M, Ali G, Wu Y, Prina M. World Alzheimer Report 2015 the global impact of dementia. London: Alzheimer’s Disease International;2015.

2. Kim YJ, Han JW, So YS, Seo JY, Kim KY, Kim KW. Prevalence and trends of dementia in Korea: a systematic review and meta-analysis. J Korean Med Sci. 2014; 29:903–12.

3. Park JH, Eum JH, Bold B, Cheong HK. Burden of disease due to dementia in the elderly population of Korea: present and future. BMC Public Health. 2013; 13:293.

4. Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004; 292:2237–42.

5. Dik MG, Jonker C, Comijs HC, Deeg DJ, Kok A, Yaffe K, et al. Contribution of metabolic syndrome components to cognition in older individuals. Diabetes Care. 2007; 30:2655–60.

6. Kuusisto J, Koivisto K, Mykkanen L, Helkala EL, Vanhanen M, Hanninen T, et al. Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ. 1997; 315:1045–9.

7. Curb JD, Rodriguez BL, Abbott RD, Petrovitch H, Ross GW, Masaki KH, et al. Longitudinal association of vascular and Alzheimer’s dementias, diabetes, and glucose tolerance. Neurology. 1999; 52:971–5.

8. Ninomiya T, Ohara T, Hirakawa Y, Yoshida D, Doi Y, Hata J, et al. Midlife and late-life blood pressure and dementia in Japanese elderly: the Hisayama study. Hypertension. 2011; 58:22–8.

9. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-Year longitudinal study of blood pressure and dementia. Lancet. 1996; 347:1141–5.

10. Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000; 21:49–55.

11. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002; 137:149–55.

12. Mielke MM, Zandi PP, Sjogren M, Gustafson D, Ostling S, Steen B, et al. High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology. 2005; 64:1689–95.

13. Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA. Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement Geriatr Cogn Disord. 2009; 28:75–80.

14. Tan ZS, Seshadri S, Beiser A, Wilson PW, Kiel DP, Tocco M, et al. Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Arch Intern Med. 2003; 163:1053–7.

15. Reitz C, Tang MX, Luchsinger J, Mayeux R. Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol. 2004; 61:705–14.

16. Tynkkynen J, Hernesniemi JA, Laatikainen T, Havulinna AS, Sundvall J, Leiviska J, et al. Apolipoproteins and HDL cholesterol do not associate with the risk of future dementia and Alzheimer’s disease: the National Finnish population study (FINRISK). Age (Dordr). 2016; 38:465–73.

17. Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev. 2011; 12:e426–37.

18. Loef M, Walach H. Midlife obesity and dementia: meta-analysis and adjusted forecast of dementia prevalence in the United States and China. Obesity (Silver Spring). 2013; 21:E51–5.

19. Bowman K, Thambisetty M, Kuchel GA, Ferrucci L, Melzer D. Obesity and longer term risks of dementia in 65–74 year olds. Age Ageing. 2019; 48:367–73.

20. Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP Jr, Yaffe K. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ. 2005; 330:1360.

21. Singh-Manoux A, Dugravot A, Shipley M, Brunner EJ, Elbaz A, Sabia S, et al. Obesity trajectories and risk of dementia: 28 years of follow-up in the Whitehall II Study. Alzheimers Dement. 2018; 14:178–86.

22. Kim JA, Kim DH, Kim SM, Park YG, Kim NH, Baik SH, et al. Impact of the dynamic change of metabolic health status on the incident type 2 diabetes: a nationwide population-based cohort study. Endocrinol Metab (Seoul). 2019; 34:406–14.

23. Akbaraly TN, Kivimaki M, Shipley MJ, Tabak AG, Jokela M, Virtanen M, et al. Metabolic syndrome over 10 years and cognitive functioning in late midlife: the Whitehall II study. Diabetes Care. 2010; 33:84–9.

24. Fan YC, Chou CC, You SL, Sun CA, Chen CJ, Bai CH. Impact of worsened metabolic syndrome on the risk of dementia: a nationwide cohort study. J Am Heart Assoc. 2017; 6:e004749.

25. Lee JE, Shin DW, Han K, Kim D, Yoo JE, Lee J, et al. Changes in metabolic syndrome status and risk of dementia. J Clin Med. 2020; 9:122.

26. Lee YH, Han K, Ko SH, Ko KS, Lee KU. Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Data analytic process of a nationwide population-based study using national health information database established by National Health Insurance Service. Diabetes Metab J. 2016; 40:79–82.

27. Lee J, Lee JS, Park SH, Shin SA, Kim K. Cohort profile: the National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J Epidemiol. 2017; 46:e15.

28. Seo MH, Lee WY, Kim SS, Kang JH, Kang JH, Kim KK, et al. 2018 Korean Society for the Study of Obesity guideline for the management of obesity in Korea. J Obes Metab Syndr. 2019; 28:40–5.

29. Lee SH, Han K, Cho H, Park YM, Kwon HS, Kang G, et al. Variability in metabolic parameters and risk of dementia: a nationwide population-based study. Alzheimers Res Ther. 2018; 10:110.

30. Yu JH, Han K, Park S, Cho H, Lee DY, Kim JW, et al. Incidence and risk factors for dementia in type 2 diabetes mellitus: a nationwide population-based study in Korea. Diabetes Metab J. 2020; 44:113–24.

31. Kalmijn S, Foley D, White L, Burchfiel CM, Curb JD, Petrovitch H, et al. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu-Asia aging study. Arterioscler Thromb Vasc Biol. 2000; 20:2255–60.

32. Liu M, He Y, Jiang B, Wu L, Wang J, Yang S, et al. Association between metabolic syndrome and mild cognitive impairment and its age difference in a Chinese community elderly population. Clin Endocrinol (Oxf). 2015; 82:844–53.

33. Ng TP, Feng L, Nyunt MS, Feng L, Gao Q, Lim ML, et al. Metabolic syndrome and the risk of mild cognitive impairment and progression to dementia: follow-up of the Singapore longitudinal ageing study cohort. JAMA Neurol. 2016; 73:456–63.

34. Pal K, Mukadam N, Petersen I, Cooper C. Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis. Soc Psychiatry Psychiatr Epidemiol. 2018; 53:1149–60.

35. Assuncao N, Sudo FK, Drummond C, de Felice FG, Mattos P. Metabolic syndrome and cognitive decline in the elderly: a systematic review. PLoS One. 2018; 13:e0194990.

36. Borshchev YY, Uspensky YP, Galagudza MM. Pathogenetic pathways of cognitive dysfunction and dementia in metabolic syndrome. Life Sci. 2019; 237:116932.

37. Van Dyken P, Lacoste B. Impact of metabolic syndrome on neuroinflammation and the blood-brain barrier. Front Neurosci. 2018; 12:930.