Warning: fopen(/home/virtual/enm-kes/journal/upload/ip_log/ip_log_2024-03.txt): failed to open stream: Permission denied in /home/virtual/lib/view_data.php on line 88 Warning: fwrite() expects parameter 1 to be resource, boolean given in /home/virtual/lib/view_data.php on line 89 Endocrine Risk Factors for Cognitive Impairment
Skip Navigation
Skip to contents

Endocrinol Metab : Endocrinology and Metabolism

clarivate
OPEN ACCESS
SEARCH
Search

Articles

Page Path
HOME > Endocrinol Metab > Volume 31(2); 2016 > Article
Review Article
Endocrine Risk Factors for Cognitive Impairment
Jae Hoon Moonorcid
Endocrinology and Metabolism 2016;31(2):185-192.
DOI: https://doi.org/10.3803/EnM.2016.31.2.185
Published online: April 25, 2016

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Corresponding author: Jae Hoon Moon. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea. Tel: +82-31-787-7068, Fax: +82-31-787-4052, jaemoon76@gmail.com
• Received: January 20, 2016   • Revised: January 29, 2016   • Accepted: February 5, 2016

Copyright © 2016 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • 4,420 Views
  • 47 Download
  • 22 Web of Science
  • 22 Crossref
  • 22 Scopus
  • Cognitive impairment, including Alzheimer's disease and other kinds of dementia, is a major health problem in older adults worldwide. Although numerous investigators have attempted to develop effective treatment modalities or drugs, there is no reasonably efficacious strategy for preventing or recovering from cognitive impairment. Therefore, modifiable risk factors for cognitive impairment have received attention, and the growing literature of metabolic risk factors for cognitive impairment has expanded from epidemiology to molecular pathogenesis and therapeutic management. This review focuses on the epidemiological evidence for the association between cognitive impairment and several endocrine risk factors, including insulin resistance, dyslipidemia, thyroid dysfunction, vitamin D deficiency, and subclinical atherosclerosis. Researches suggesting possible mechanisms for this association are reviewed. The research investigating modifiable endocrine risk factors for cognitive impairment provides clues for understanding the pathogenesis of cognitive impairment and developing novel treatment modalities. However, so far, interventional studies investigating the beneficial effect of the "modification" of these "modifiable risk factors" on cognitive impairment have reported variable results. Therefore, well-designed, randomized prospective interventional studies are needed.
The prevalence and incidence of cognitive impairment, such as dementia, increases rapidly with advancing age, which results in a huge socioeconomic burden [1]. Dementia is a diagnosis including all kinds of cognitive dysfunction resulting in interference with everyday activities. Alzheimer's disease, Lewy body dementia, and vascular dementia are types of dementia with various causes and pathogenesis. Dementia is a growing socioeconomic burden that is paralleled by the epidemic increase in its prevalence and incidence. The prevalence of dementia is estimated to be as high as 24 million worldwide and is expected to double every 20 years until 2040 [2]. Medical expenses for people aged 65 years and older with dementia were more than $200 billion in 2013 in the United States [3]. In addition, mild cognitive impairment (MCI), which is a risk for progression to dementia but not sufficient for a diagnosis of dementia, is a common condition in old age: 15% to 42% of people aged ≥65 years are estimated to have MCI, and from about 5% to 15% of them progress to dementia annually [45]. Although numerous investigators have attempted to develop effective treatment modalities or drugs, there is no reasonably efficacious strategy for preventing or recovering from cognitive impairment. Only two classes of drugs, cholinesterase inhibitors and memantine, have been approved for the treatment of dementia, and they have shown only modest effects. Therefore, modifiable risk factors for cognitive impairment have received attention, and the growing literature on metabolic endocrine risk factors for cognitive impairment has expanded from epidemiology and molecular pathogenesis to therapeutic management. This review focuses on the epidemiological evidences of the association between cognitive impairment and several endocrine risk factors, including insulin resistance, dyslipidemia, thyroid dysfunction, vitamin D deficiency, and subclinical atherosclerosis.
The epidemiological association between insulin resistance or type 2 diabetes and cognitive impairment is well established. Several population-based prospective studies and meta-analyses have demonstrated an increased risk of dementia in diabetic patients [67]. A recent meta-analysis including 6,184 type 2 diabetes subjects and 38,350 subjects without diabetes pooled from 19 studies reported a combined overall relative risk (RR) of 1.51 (95% confidence interval [CI], 1.31 to 1.74) linking type 2 diabetes with dementia [7]. In particular, the risk of vascular dementia was increased in type 2 diabetes subjects with a RR of 1.46 (95% CI, 2.08 to 2.96) and the risk of Alzheimer's disease was also increased (RR, 1.46; 95% CI, 1.20 to 1.77) [7]. Diabetes increased not only the risk of MCI, an intermediate stage between normal cognitive function and dementia [8910], but also the conversion rate to dementia in the subjects with MCI [1112]. Despite this epidemiological evidence, the mechanisms underlying the association between insulin resistance and cognitive impairment have not been fully understood so far. In people without dementia, type 2 diabetes patients show slightly decreased cognitive function compared with subjects without diabetes in multiple cognitive domains [913]. This slight decline in cognitive function of diabetic patients starts from mid-life (about 40 years old) and slowly progresses throughout their lifetime, whereas the incidence of dementia increases sharply after the age of 65 to 70 years [914]. Therefore, cognitive decline in type 2 diabetes or insulin resistance and the pathologic process of dementia may be discrete processes, and insulin resistance seems to make the brain more vulnerable to the pathologic process of dementia. A recent review [9] suggested that type 2 diabetes or insulin resistance results in subtle brain atrophy [15], disrupted white matter integrity [16], and vascular abnormalities, including cortical and subcortical infarcts [1718]. These subtle changes accumulate from mid-life onwards, reducing the reserve capacity of the brain. Some experimental studies have demonstrated direct mechanisms explaining the association between insulin resistance and Alzheimer's disease. Insulin-degrading enzyme (IDE) breaks down excessive insulin in extracellular milieu and also degrades amyloid β—a key peptide of Alzheimer's disease pathogenesis, which is derived from the proteolytic cleavage of the amyloid precursor protein and forms the core of senile plaques. Excessive insulin resulting from insulin resistance can compete with amyloid β for the binding site on IDE, resulting in accumulating amyloid β in the central nervous system (CNS) [19]. Interventional studies investigating the effect of diabetes treatment on cognitive function have shown heterogeneous results. The Memory in Diabetes study as part of Action to Control Cardiovascular Risk in Diabetes study (ACCORD-MIND) [20], the largest published randomized controlled study, reported no difference in cognitive decline between type 2 diabetes patients who received intensive glycemic control and those who received conventional glycemic control. A small randomized double-blind trial including 145 subjects demonstrated significant cognitive improvement by add-on therapy of rosiglitazone or glyburide in type 2 diabetes patients receiving metformin monotherapy [21].
The association between hypercholesterolemia and cognitive impairment is still controversial. Several prospective studies demonstrated that hypercholesterolemia in mid-life increased the risk of Alzheimer's disease and vascular dementia [222324]. However, a study that followed 1,462 women over 32 years failed to demonstrate any association between midlife hypercholesterolemia and the risk of Alzheimer's disease, and some studies reported the protective effect of hypercholesterolemia in late life against Alzheimer's disease [252627]. Although vigorous treatment of hypercholesterolemia has been thought to decrease the risk of vascular dementia considering the benefits of statins in the primary and secondary prevention of stroke, the beneficial effect of statin therapy on cognitive impairment has not been firmly established. Based on isolated case reports without established causality, there has been concern that statins may actually worsen cognitive function and memory [2829]. A prospective study evaluating 1,674 participants without dementia showed that statin therapy decreased the risk of dementia during the 5-year follow-up period after adjustment for conventional risk factors for dementia [30]. Other cross-sectional and prospective studies also reported the beneficial effect of statin therapy on cognitive impairment [313233]. Experimental studies have suggested that the cholesterol distribution in neuronal cell membrane was associated with amyloid β synthesis and metabolism [27]. Proteins required for cholesterol recycling and trafficking, such as apolipoprotein E, low density lipoprotein (LDL) receptor, and low density lipoprotein receptor-related protein 1 (LRP1), also play a role in amyloid β homeostasis in the brain [343536]. In addition, LDL receptor and LRP1 have been reported to be regulated by statin drugs [37]. Altogether, lipid metabolism might be associated with the pathogenesis of Alzheimer's disease and vascular dementia, and some experimental and clinical studies have provided some evidence for this association. However, further studies, including well-designed interventional studies, are needed to confirm the association between dyslipidemia and cognitive impairment.
Thyroid hormone is an important neuroregulator in fetal development of the CNS and plays an important role in neurocognitive function after development. Overt hypothyroidism is a well-known reversible factor causing cognitive impairment including dementia [38]. Overt hyperthyroidism or thyrotoxicosis has also been known to be associated with altered concentration and perception [39]. Epidemiologically, thyroid dysfunction, depression, and cognitive impairment commonly increase in older adults and recent studies have reported that thyroid dysfunction is one of the risk factors for irreversible cognitive impairment, such as Alzheimer's disease [40]. On the basis of this association between thyroid dysfunction and psychiatric disorders, a number of investigators have sought to determine whether subclinical thyroid dysfunction is a risk factor for cognitive impairment, especially in older adults. Although the effect of subclinical hypothyroidism on cognitive impairment is still questionable [4041], the association between subclinical hyperthyroidism and cognitive impairment has been validated in several studies [39424344]. In the Rotterdam study [42] that followed up 1,843 non-demented participants for 2 years, subjects with thyroid stimulating hormone (TSH) levels below 0.4 mIU/L at baseline had a greater than 3-fold increased risk of dementia (RR, 3.5; 95% CI, 1.2 to 10.0) and Alzheimer's disease (RR, 3.5; 95% CI, 1.1 to 11.5) after adjusting for age and sex compared with those at the euthyroid level. In the Thyroid Epidemiology, Audit, and Research Study [44], a large observational study including 12,115 euthyroid and subclinical hyperthyroid subjects with a median follow-up period of 5.6 years, participants with serum TSH levels below 0.4 mIU/L at baseline had a 2-fold increased risk of dementia. Moreover, a few cross-sectional studies suggested that even a normal serum TSH level, when ranging in the lower reference level, might be associated with the risk of dementia [4546]. A recent community-based prospective cohort study demonstrated that lower serum TSH concentration within the reference range was associated with the development or progression of cognitive impairment including MCI and dementia in older adults [47]. MCI or dementia developed in 12.5% of 200 subjects with baseline TSH of more than 1.82 mIU/L, whereas MCI or dementia developed in 25.7% of 113 subjects with baseline TSH of less than 1.82 mIU/L [47]. However, there was no difference in the cognitive function between elderly patients with differentiated thyroid carcinoma who received long-term TSH suppressive therapy (iatrogenic subclinical thyrotoxicosis) and euthyroid control subjects; moreover, there were positive correlations between serum free thyroxine (T4) levels and some cognitive domains [48].
The mechanism underlying the association between low TSH and the risk of cognitive decline is still unclear. Of the two widely accepted explanations, the first and most conventional explanation is the toxic effect of excessive thyroid hormone on the CNS [39]. Brain oxidative stress caused by an excess of thyroid hormone or thromboembolism from the cardiac effects of mild hyperthyroidism have been suggested as underlying mechanisms [3949]. Second, neurodegenerative changes in the brain, which may cause a cognitive decline, can also result in a reduced secretion of thyrotropin releasing hormone (TRH) in the brain and, in turn, reduce the secretion of TSH [39]. TRH is secreted not only from the hypothalamus but also from other areas of the brain, and is known to play a role as a CNS neurotransmitter, suggesting that TRH secretion may decrease in the brain of subjects with cognitive impairment [3950]. As mentioned above, long-term iatrogenic subclinical thyrotoxicosis or a mild excess of thyroid hormone did not result in a cognitive decline in elderly subjects [48]. This finding suggests that reduced TRH in the degenerated brain is the most reliable explanation. Furthermore, the positive correlations between serum free T4 levels and some cognitive domains suggest the potential beneficial effect of exogenous levothyroxine on cognitive function.
Vitamin D status is determined by the serum level of 25-hydroxyvitamin D, or 25(OH)D, and a low vitamin D status is common and considered a major health problem in elderly populations [515253]. Several studies have reported that low vitamin D status is associated with poor bone health and other conditions including cardiovascular disease (CVD), insulin resistance, autoimmune diseases and certain malignancies [545556]. Low vitamin D status has also received attention as a potential metabolic risk factor for dementia. A number of studies have shown that a low serum 25(OH)D concentration is associated with an increased risk of dementia and Alzheimer's disease in older adults [5758]. A recent community-based prospective study of the elderly demonstrated that low vitamin D status increased the risk of MCI as well as dementia [59]. They reported that the RR of MCI development during a 5-year follow-up was 7.13 (95% CI, 1.54 to 32.92; P=0.012) in the elderly subjects whose serum 25(OH)D concentration was <25.0 nmol/L compared with those with a serum 25(OH)D concentration ≥50.0 nmol/L [59]. Several studies have suggested that long-term hypovitaminosis D status results in CNS inflammation and Aβ accumulation via oxidative stress, alteration in CNS cytokine levels, neurotransmitter dysregulation, and macrophage dysfunction [60]. However, it is still unclear whether vitamin D replacement therapy can prevent or aid recovery from cognitive impairment, and well-designed interventional studies are needed.
Recent large-scale prospective cohort studies have demonstrated that CVD risk factors, including 10-year CVD risk scores and individual CVD risk factors, are associated with cognitive decline [6162636465666768]. A longitudinal British cohort study (Whitehall-II) including 5,810 participants showed that elevated stroke risk as measured by the Framingham stroke risk (FSR) score in mid-life is associated with accelerated cognitive decline over 10 years [67]. The English Longitudinal Study of Aging including 8,780 subjects also reported the association between high FSR score and cognitive decline over 4 years [66]. FSR score was also associated with the 4-year cognitive decline in 1,907 stroke-free subjects [65]. The sex-specific 10-year CVD risk score was reported to be associated with the 10-year cognitive decline in 1,116 aged Mexican Americans [68]. Other individual CVD risk factors including hypertension, dyslipidemia, obesity, and diabetes in mid-life have been suggested as risk factors for cognitive decline and dementia in later life [61626364]. Surrogate markers for CVD risk, including carotid intimal-media thickness (CIMT) and pulse wave velocity (PWV) have been reported to be associated with cognitive impairment in a number of studies [6970717273747576]. A recent prospective cohort study investigated the association between CVD risk factors, including CIMT, PWV, ankle-brachial index and other biochemical and anthropometric markers, and the future risk of clinically diagnosed MCI or dementia [77]. They demonstrated that CIMT was the best predictor of the development of MCI and dementia over 5 years and the hazard ratio for the development of MCI and dementia per 0.1 mm increase in CIMT was about 1.25 [77].
At present, it remains unclear whether a vascular pathology such as increased CIMT can cause cognitive decline in elderly subjects or whether it simply develops as an early vascular response associated with neuronal degeneration. Recent studies have shown that vascular dysfunction is involved in the pathogenesis of not only vascular dementia but also Alzheimer's disease [78]. Vascular dysfunction results in the restriction of oxygen and glucose supply to the brain, and Aβ accumulation in the brain affects vascular pathology and exacerbates blood flow restriction to the brain [787980]. In addition, vascular dysfunction can cause reduced Aβ clearance across the blood-brain barrier, and oxidative stress is also a common pathogenic mechanism between vascular dysfunction and Alzheimer's disease [78]. Therefore, vascular dysfunction and Aβ deposition might have synergistic effects on neuronal degeneration [78].
The effort to discover modifiable risk factors for cognitive impairment has identified important endocrine risk factors for cognitive impairment. Epidemiological studies have reported associations between metabolic risk factors and cognitive impairment, and experimental studies have suggested mechanisms that can explain these associations. This effort is important for providing a theoretical basis of novel treatment modalities for cognitive impairment. However, so far, interventional studies to investigate the beneficial effect of the "modification" of these "modifiable risk factors" on cognitive impairment have reported variable results. Therefore, future well-designed randomized controlled trials are needed.

CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

  • 1. Fratiglioni L, Launer LJ, Andersen K, Breteler MM, Copeland JR, Dartigues JF, et al. Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000;54(11 Suppl 5):S10–S15. PubMed
  • 2. Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol 2011;7:137–152. ArticlePubMedPMCPDF
  • 3. Alzheimer's Association. 2013 Alzheimer's disease facts and figures. Alzheimers Dement 2013;9:208–245. ArticlePubMed
  • 4. Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, et al. Mild cognitive impairment: beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004;256:240–246. ArticlePubMed
  • 5. Petersen RC, Caracciolo B, Brayne C, Gauthier S, Jelic V, Fratiglioni L. Mild cognitive impairment: a concept in evolution. J Intern Med 2014;275:214–228. ArticlePubMedPMC
  • 6. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006;5:64–74. ArticlePubMed
  • 7. 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;42:484–491. ArticlePubMed
  • 8. Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R. Relation of diabetes to mild cognitive impairment. Arch Neurol 2007;64:570–575. ArticlePubMed
  • 9. Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol 2014;2:246–255. ArticlePubMed
  • 10. Roberts RO, Knopman DS, Geda YE, Cha RH, Pankratz VS, Baertlein L, et al. Association of diabetes with amnestic and nonamnestic mild cognitive impairment. Alzheimers Dement 2014;10:18–26. ArticlePubMed
  • 11. Xu W, Caracciolo B, Wang HX, Winblad B, Backman L, Qiu C, et al. Accelerated progression from mild cognitive impairment to dementia in people with diabetes. Diabetes 2010;59:2928–2935. ArticlePubMedPMC
  • 12. Li J, Wang YJ, Zhang M, Xu ZQ, Gao CY, Fang CQ, et al. Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology 2011;76:1485–1491. ArticlePubMed
  • 13. Reijmer YD, van den Berg E, Ruis C, Kappelle LJ, Biessels GJ. Cognitive dysfunction in patients with type 2 diabetes. Diabetes Metab Res Rev 2010;26:507–519. ArticlePubMed
  • 14. Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, Amaducci LA, et al. Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology 1999;52:78–84. ArticlePubMed
  • 15. van Harten B, de Leeuw FE, Weinstein HC, Scheltens P, Biessels GJ. Brain imaging in patients with diabetes: a systematic review. Diabetes Care 2006;29:2539–2548. ArticlePubMed
  • 16. Reijmer YD, Leemans A, Brundel M, Kappelle LJ, Biessels GJ. Utrecht Vascular Cognitive Impairment Study Group. Disruption of the cerebral white matter network is related to slowing of information processing speed in patients with type 2 diabetes. Diabetes 2013;62:2112–2115. ArticlePubMedPMC
  • 17. Nelson PT, Smith CD, Abner EA, Schmitt FA, Scheff SW, Davis GJ, et al. Human cerebral neuropathology of type 2 diabetes mellitus. Biochim Biophys Acta 2009;1792:454–469. ArticlePubMed
  • 18. Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010;75:1195–1202. ArticlePubMed
  • 19. Craft S, Cholerton B, Baker LD. Insulin and Alzheimer's disease: untangling the web. J Alzheimers Dis 2013;33(Suppl 1):S263–S275. ArticlePubMed
  • 20. Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol 2011;10:969–977. ArticlePubMedPMC
  • 21. Ryan CM, Freed MI, Rood JA, Cobitz AR, Waterhouse BR, Strachan MW. Improving metabolic control leads to better working memory in adults with type 2 diabetes. Diabetes Care 2006;29:345–351. ArticlePubMed
  • 22. Evans RM, Emsley CL, Gao S, Sahota A, Hall KS, Farlow MR, et al. Serum cholesterol, APOE genotype, and the risk of Alzheimer's disease: a population-based study of African Americans. Neurology 2000;54:240–242. ArticlePubMed
  • 23. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ 2001;322:1447–1451. ArticlePubMedPMC
  • 24. 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. ArticlePubMedPMC
  • 25. Mielke MM, Zandi PP, Shao H, Waern M, Ostling S, Guo X, et al. The 32-year relationship between cholesterol and dementia from midlife to late life. Neurology 2010;75:1888–1895. ArticlePubMedPMC
  • 26. Cedazo-Minguez A, Ismail MA, Mateos L. Plasma cholesterol and risk for late-onset Alzheimer's disease. Expert Rev Neurother 2011;11:495–498. ArticlePubMed
  • 27. Chakrabarti S, Khemka VK, Banerjee A, Chatterjee G, Ganguly A, Biswas A. Metabolic risk factors of sporadic Alzheimer's disease: implications in the pathology, pathogenesis and treatment. Aging Dis 2015;6:282–299. ArticlePubMedPMC
  • 28. Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 2003;23:871–880. ArticlePubMed
  • 29. Menezes AR, Lavie CJ, Milani RV, O'Keefe J. The effects of statins on prevention of stroke and dementia: a review. J Cardiopulm Rehabil Prev 2012;32:240–249. ArticlePubMed
  • 30. Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 2008;71:344–350. ArticlePubMedPMC
  • 31. Santanello NC, Barber BL, Applegate WB, Elam J, Curtis C, Hunninghake DB, et al. Effect of pharmacologic lipid lowering on health-related quality of life in older persons: results from the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study. J Am Geriatr Soc 1997;45:8–14. ArticlePubMed
  • 32. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439–1443. ArticlePubMed
  • 33. Muangpaisan W, Brayne C. Alzheimer's Society Vascular Dementia Systematic Review Group. Systematic review of statins for the prevention of vascular dementia or dementia. Geriatr Gerontol Int 2010;10:199–208. ArticlePubMed
  • 34. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, et al. Clearance of Alzheimer's amyloidss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000;106:1489–1499. ArticlePubMedPMC
  • 35. Goto JJ, Tanzi RE. The role of the low-density lipoprotein receptor-related protein (LRP1) in Alzheimer's A beta generation: development of a cell-based model system. J Mol Neurosci 2002;19:37–41. ArticlePubMedPDF
  • 36. Zlokovic BV, Deane R, Sagare AP, Bell RD, Winkler EA. Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer's amyloid beta-peptide elimination from the brain. J Neurochem 2010;115:1077–1089. ArticlePubMedPMC
  • 37. Moon JH, Kang SB, Park JS, Lee BW, Kang ES, Ahn CW, et al. Up-regulation of hepatic low-density lipoprotein receptor-related protein 1: a possible novel mechanism of antiatherogenic activity of hydroxymethylglutaryl-coenzyme A reductase inhibitor Atorvastatin and hepatic LRP1 expression. Metabolism 2011;60:930–940. ArticlePubMed
  • 38. Davis JD, Tremont G. Neuropsychiatric aspects of hypothyroidism and treatment reversibility. Minerva Endocrinol 2007;32:49–65. PubMed
  • 39. Gan EH, Pearce SH. Clinical review: the thyroid in mind: cognitive function and low thyrotropin in older people. J Clin Endocrinol Metab 2012;97:3438–3449. ArticlePubMedPMC
  • 40. Tan ZS, Vasan RS. Thyroid function and Alzheimer's disease. J Alzheimers Dis 2009;16:503–507. ArticlePubMed
  • 41. Samuels MH. Cognitive function in subclinical hypothyroidism. J Clin Endocrinol Metab 2010;95:3611–3613. ArticlePubMedPDF
  • 42. Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM. Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. Clin Endocrinol (Oxf) 2000;53:733–737. ArticlePubMed
  • 43. Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, et al. Thyroid function and the risk of Alzheimer disease: the Framingham Study. Arch Intern Med 2008;168:1514–1520. ArticlePubMedPMC
  • 44. Vadiveloo T, Donnan PT, Cochrane L, Leese GP. The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab 2011;96:1344–1351. ArticlePubMed
  • 45. Dobert N, Hamscho N, Menzel C, Peters J, Frolich L, Tsolakis A, et al. Subclinical hyperthyroidism in dementia and correlation of the metabolic index in FDG-PET. Acta Med Austriaca 2003;30:130–133. PubMed
  • 46. van Osch LA, Hogervorst E, Combrinck M, Smith AD. Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease. Neurology 2004;62:1967–1971. ArticlePubMed
  • 47. Moon JH, Park YJ, Kim TH, Han JW, Choi SH, Lim S, et al. Lower-but-normal serum TSH level is associated with the development or progression of cognitive impairment in elderly: Korean Longitudinal Study on Health and Aging (KLoSHA). J Clin Endocrinol Metab 2014;99:424–432. ArticlePubMedPDF
  • 48. Moon JH, Ahn S, Seo J, Han JW, Kim KM, Choi SH, et al. The effect of long-term thyroid-stimulating hormone suppressive therapy on the cognitive function of elderly patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 2014;99:3782–3789. ArticlePubMed
  • 49. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008;29:76–131. ArticlePubMedPDF
  • 50. Brownstein MJ, Palkovits M, Saavedra JM, Bassiri RM, Utiger RD. Thyrotropin-releasing hormone in specific nuclei of rat brain. Science 1974;185:267–269. ArticlePubMed
  • 51. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–281. ArticlePubMed
  • 52. Pearce SH, Cheetham TD. Diagnosis and management of vitamin D deficiency. BMJ 2010;340:b5664ArticlePubMed
  • 53. Formiga F, Ferrer A, Almeda J, San Jose A, Gil A, Pujol R. Utility of geriatric assessment tools to identify 85-years old subjects with vitamin D deficiency. J Nutr Health Aging 2011;15:110–114. ArticlePubMedPDF
  • 54. Perez-Lopez FR, Chedraui P, Fernandez-Alonso AM. Vitamin D and aging: beyond calcium and bone metabolism. Maturitas 2011;69:27–36. ArticlePubMed
  • 55. Holick MF. Vitamin D: a D-lightful vitamin for health. Endocrinol Metab 2012;27:255–267.Article
  • 56. Lim S, Shin H, Kim MJ, Ahn HY, Kang SM, Yoon JW, et al. Vitamin D inadequacy is associated with significant coronary artery stenosis in a community-based elderly cohort: the Korean Longitudinal Study on Health and Aging. J Clin Endocrinol Metab 2012;97:169–178. ArticlePubMed
  • 57. Balion C, Griffith LE, Strifler L, Henderson M, Patterson C, Heckman G, et al. Vitamin D, cognition, and dementia: a systematic review and meta-analysis. Neurology 2012;79:1397–1405. ArticlePubMedPMC
  • 58. Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PH, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology 2014;83:920–928. ArticlePubMedPMC
  • 59. Moon JH, Lim S, Han JW, Kim KM, Choi SH, Kim KW, et al. Serum 25-hydroxyvitamin D level and the risk of mild cognitive impairment and dementia: the Korean Longitudinal Study on Health and Aging (KLoSHA). Clin Endocrinol (Oxf) 2015;83:36–42. ArticlePubMed
  • 60. Gezen-Ak D, Yılmazer S, Dursun E. Why vitamin D in Alzheimer's disease? The hypothesis. J Alzheimers Dis 2014;40:257–269. ArticlePubMed
  • 61. 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;347:1141–1145. ArticlePubMed
  • 62. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 2003;163:1524–1528. ArticlePubMed
  • 63. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004;61:661–666. ArticlePubMed
  • 64. Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol 2006;5:735–741. ArticlePubMed
  • 65. Unverzagt FW, McClure LA, Wadley VG, Jenny NS, Go RC, Cushman M, et al. Vascular risk factors and cognitive impairment in a stroke-free cohort. Neurology 2011;77:1729–1736. ArticlePubMedPMC
  • 66. Dregan A, Stewart R, Gulliford MC. Cardiovascular risk factors and cognitive decline in adults aged 50 and over: a population-based cohort study. Age Ageing 2013;42:338–345. ArticlePubMedPDF
  • 67. Kaffashian S, Dugravot A, Brunner EJ, Sabia S, Ankri J, Kivimaki M, et al. Midlife stroke risk and cognitive decline: a 10-year follow-up of the Whitehall II cohort study. Alzheimers Dement 2013;9:572–579. ArticlePubMed
  • 68. Zeki Al Hazzouri A, Haan MN, Neuhaus JM, Pletcher M, Peralta CA, Lopez L, et al. Cardiovascular risk score, cognitive decline, and dementia in older Mexican Americans: the role of sex and education. J Am Heart Assoc 2013;2:e004978PubMedPMC
  • 69. Komulainen P, Kivipelto M, Lakka TA, Hassinen M, Helkala EL, Patja K, et al. Carotid intima-media thickness and cognitive function in elderly women: a population-based study. Neuroepidemiology 2007;28:207–213. ArticlePubMed
  • 70. Wendell CR, Zonderman AB, Metter EJ, Najjar SS, Waldstein SR. Carotid intimal medial thickness predicts cognitive decline among adults without clinical vascular disease. Stroke 2009;40:3180–3185. ArticlePubMedPMC
  • 71. Sander K, Bickel H, Forstl H, Etgen T, Briesenick C, Poppert H, et al. Carotid-intima media thickness is independently associated with cognitive decline. The INVADE study. Int J Geriatr Psychiatry 2010;25:389–394. ArticlePubMed
  • 72. Silvestrini M, Viticchi G, Falsetti L, Balucani C, Vernieri F, Cerqua R, et al. The role of carotid atherosclerosis in Alzheimer's disease progression. J Alzheimers Dis 2011;25:719–726. ArticlePubMed
  • 73. Arntzen KA, Schirmer H, Johnsen SH, Wilsgaard T, Mathiesen EB. Carotid artery plaque progression and cognitive decline: the Tromso Study 1994-2008. Eur J Neurol 2012;19:1318–1324. ArticlePubMed
  • 74. Zhong W, Cruickshanks KJ, Schubert CR, Acher CW, Carlsson CM, Klein BE, et al. Carotid atherosclerosis and 10-year changes in cognitive function. Atherosclerosis 2012;224:506–510. ArticlePubMedPMC
  • 75. Zeki Al Hazzouri A, Newman AB, Simonsick E, Sink KM, Sutton Tyrrell K, Watson N, et al. Pulse wave velocity and cognitive decline in elders: the Health, Aging, and Body Composition study. Stroke 2013;44:388–393. ArticlePubMedPMC
  • 76. Masley SC, Masley LV, Gualtieri CT. Cardiovascular biomarkers and carotid IMT scores as predictors of cognitive function. J Am Coll Nutr 2014;33:63–69. ArticlePubMed
  • 77. Moon JH, Lim S, Han JW, Kim KM, Choi SH, Park KS, et al. Carotid intima-media thickness is associated with the progression of cognitive impairment in older adults. Stroke 2015;46:1024–1030. ArticlePubMed
  • 78. Murray IV, Proza JF, Sohrabji F, Lawler JM. Vascular and metabolic dysfunction in Alzheimer's disease: a review. Exp Biol Med (Maywood) 2011;236:772–782. ArticlePubMed
  • 79. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 2004;3:169–178. ArticlePubMed
  • 80. Girouard H, Iadecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol (1985) 2006;100:328–335. ArticlePubMed

Figure & Data

References

    Citations

    Citations to this article as recorded by  
    • Association between the neutrophil to lymphocyte ratio and mild cognitive impairment in patients with type 2 diabetes
      Zi-Wei Yu, Ying Wang, Xin Li, Xue-Wei Tong, Yi-Tong Zhang, Xin-Yuan Gao
      Aging Clinical and Experimental Research.2023; 35(6): 1339.     CrossRef
    • Cognitive status and its risk factors in patients with hypertension and diabetes in a low‐income rural area of China: A cross‐sectional study
      Yuyan Guo, Ruifeng Liang, Jingjuan Ren, Liting Cheng, Mengqin Wang, Huilin Chai, Xiaoyu Cheng, Yaowen Yang, Yajuan Sun, Jiantao Li, Shuhong Zhao, Wenjing Hou, Jianhua Zhang, Feng Liu, Rong Wang, Qiao Niu, Hongmei Yu, Shoulin Yang, Jianying Bai, Hongmei Zh
      International Journal of Geriatric Psychiatry.2023;[Epub]     CrossRef
    • Insulin Resistance and Glucose Metabolism during Infection
      Borros Arneth
      Endocrines.2023; 4(4): 685.     CrossRef
    • Corresponding risk factors between cognitive impairment and type 1 diabetes mellitus: A narrative review
      Chen-Yang Jin, Shi-Wen Yu, Jun-Ting Yin, Xiao-Ying Yuan, Xu-Gang Wang
      Heliyon.2022; 8(8): e10073.     CrossRef
    • Cerebrospinal fluid heart fatty acid‐binding protein as a predictive biomarker of neurodegeneration in Alzheimer’s disease
      Lu Pan, Ya-Nan Ou, Lin Tan, Lan Tan, Jin-Tai Yu
      Brain Science Advances.2021; 7(1): 44.     CrossRef
    • Endocrine dysfunction and cognitive impairment
      Valeria CALSOLARO, Marina BOTTARI, Giulia COPPINI, Bianca LEMMI, Fabio MONZANI
      Minerva Endocrinology.2021;[Epub]     CrossRef
    • Effect of hypothyroidism on cognitive status: Evidence from stroop task
      Shilpi Goyal, Abhinav Dixit, Neelam Vaney, SV Madhu
      Indian Journal of Medical Specialities.2020; 11(1): 34.     CrossRef
    • Statin use and safety concerns: an overview of the past, present, and the future
      Rubina Mulchandani, Tanica Lyngdoh, Ashish Kumar Kakkar
      Expert Opinion on Drug Safety.2020; 19(8): 1011.     CrossRef
    • Neurocognitive impairment in type 2 diabetes mellitus
      Marianna Karvani, P. Simos, S. Stavrakaki, D. Kapoukranidou
      Hormones.2019; 18(4): 523.     CrossRef
    • TDP-43 proteinopathy in aging: Associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels
      Peter T. Nelson, Zsombor Gal, Wang-Xia Wang, Dana M. Niedowicz, Sergey C. Artiushin, Samuel Wycoff, Angela Wei, Gregory A. Jicha, David W. Fardo
      Neurobiology of Disease.2019; 125: 67.     CrossRef
    • Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults
      Willa D. Brenowitz, Fang Han, Walter A. Kukull, Peter T. Nelson
      Neurobiology of Aging.2018; 62: 64.     CrossRef
    • Translating molecular advances in Down syndrome and Fragile X syndrome into therapies
      Victor Faundez, Ilario De Toma, Barbara Bardoni, Renata Bartesaghi, Dean Nizetic, Rafael de la Torre, Roi Cohen Kadosh, Yann Herault, Mara Dierssen, Marie-Claude Potier, Stylianos Antonarakis, Renata Bartesaghi, Andrea Contestabile, Tonnie Coppus, Peter D
      European Neuropsychopharmacology.2018; 28(6): 675.     CrossRef
    • Associations between waist circumference, metabolic risk and executive function in adolescents: A cross-sectional mediation analysis
      Anna Bugge, Sören Möller, Daniel R. Westfall, Jakob Tarp, Anne K. Gejl, Niels Wedderkopp, Charles H. Hillman, Ying-Mei Feng
      PLOS ONE.2018; 13(6): e0199281.     CrossRef
    • BsmI polymorphism in the vitamin D receptor gene is associated with 25-hydroxy vitamin D levels in individuals with cognitive decline
      Ana Carolina R. de Oliveira, Carolina A. Magalhães, Cristina M. G. Loures, Vanessa G. Fraga, Leonardo C. de Souza, Henrique C. Guimarães, Marco T. G. Cintra, Maria A. Bicalho, Maira C. R. Sousa, Josianne N. Silveira, Ieda F. O. Silva, Paulo Caramelli, Mar
      Arquivos de Neuro-Psiquiatria.2018; 76(11): 760.     CrossRef
    • Traumatic brain injury: sex, gender and intersecting vulnerabilities
      Tatyana Mollayeva, Shirin Mollayeva, Angela Colantonio
      Nature Reviews Neurology.2018; 14(12): 711.     CrossRef
    • Determinants of poor cognitive function using A-IQCODE among Lebanese older adults: a cross-sectional study
      Ibrahim R. Bou-Orm, Assem M. Khamis, Monique Chaaya
      Aging & Mental Health.2018; 22(6): 844.     CrossRef
    • Articles inEndocrinology and Metabolismin 2016
      Won-Young Lee
      Endocrinology and Metabolism.2017; 32(1): 62.     CrossRef
    • Alcohol consumption and gastric cancer risk: a meta-analysis of prospective cohort studies
      Xue Han, Li Xiao, Yao Yu, Yu Chen, Hai-Hua Shu
      Oncotarget.2017; 8(47): 83237.     CrossRef
    • Functional capacity and obesity reflect the cognitive performance of older adults living in long‐term care facilities
      Karine Gonçalves Damascena, Cristiane Batisti Ferreira, Pâmela dos Santos Teixeira, Bibiano Madrid, Alexandre Gonçalves, Cláudio Córdova, Otávio de Toledo Nóbrega, Aparecido Pimentel Ferreira
      Psychogeriatrics.2017; 17(6): 439.     CrossRef
    • Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease
      Therese S Salameh, Elizabeth M Rhea, William A Banks, Angela J Hanson
      Experimental Biology and Medicine.2016; 241(15): 1676.     CrossRef
    • Role of the Orexin System on the Hypothalamus-Pituitary-Thyroid Axis
      Antonietta Messina, Carolina De Fusco, Vincenzo Monda, Maria Esposito, Fiorenzo Moscatelli, Anna Valenzano, Marco Carotenuto, Emanuela Viggiano, Sergio Chieffi, Vincenzo De Luca, Giuseppe Cibelli, Marcellino Monda, Giovanni Messina
      Frontiers in Neural Circuits.2016;[Epub]     CrossRef
    • Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging
      Peter T. Nelson, Yuriko Katsumata, Kwangsik Nho, Sergey C. Artiushin, Gregory A. Jicha, Wang-Xia Wang, Erin L. Abner, Andrew J. Saykin, Walter A. Kukull, David W. Fardo
      Acta Neuropathologica.2016; 132(6): 841.     CrossRef

    • PubReader PubReader
    • Cite
      CITE
      export Copy
      Close
    • XML DownloadXML Download

    Endocrinol Metab : Endocrinology and Metabolism