Metabolic Brain Disease

, Volume 31, Issue 2, pp 465–473 | Cite as

Elevated levels of serum cholesterol are associated with better performance on tasks of episodic memory

  • Elizabeth C. Leritz
  • Regina E. McGlinchey
  • David H. Salat
  • William P. Milberg
Original Article


We examined how serum cholesterol, an established risk factor for cerebrovascular disease (CVD), relates to cognitive function in healthy middle-older aged individuals with no neurologic or CVD history. A complete lipid panel was obtained from a cohort of one hundred twenty individuals, ages 43–85, who also underwent a comprehensive neuropsychological examination. In order to reduce the number of variables and empirically identify broad cognitive domains, scores from neuropsychological tests were submitted into a factor analysis. This analysis revealed three explainable factors: Memory, Executive Function and Memory/Language. Three separate hierarchical multiple regression analyses were conducted using individual cholesterol metrics (total cholesterol, low density lipoprotein; LDL, high density lipoprotein; HDL, and triglycerides), as well as age, education, medication status (lipid lowering agents), ApoE status, and additional risk factors for CVD to predict neuropsychological function. The Memory Factor was predicted by a combination of age, LDL, and triglyceride levels; both age and triglycerides were negatively associated with factor score, while LDL levels revealed a positive relationship. Both the Executive and Memory/Language factor were only explained by education, whereby more years were associated with better performance. These results provide evidence that individual cholesterol lipoproteins and triglycerides may differentially impact cognitive function, over and above other common CVD risk factors and ApoE status. Our findings demonstrate the importance of consideration of vascular risk factors, such as cholesterol, in studies of cognitive aging.


Cerebrovascular health Cerebrovascular risk Cholesterol Cognition 



This work was supported by the National Institute of Neurologic Disorders and Stroke (K23NS062148 & R01NS086882), the National Institute of Nursing Research (R01NR010827), the National Institute on Aging, and by Medical Research Service VA Merit Review Awards.


  1. Babiker A, Dzeletovic S, Wiklund B, Pettersson N, Salonen J, Nyyssonen K, et al. (2005) Patients with atherosclerosis may have increased circulating levels of 27-hydroxycholesterol and cholestenoic acid. Scand J Clin Lab Invest 65(5):365–375CrossRefPubMedGoogle Scholar
  2. Badimon L, Vilahur G (2012) LDL-cholesterol versus HDL-cholesterol in the atherosclerotic plaque: inflammatory resolution versus thrombotic chaos. Ann N Y Acad Sci 1254:18–32CrossRefPubMedGoogle Scholar
  3. Bang OY, Saver JL, Liebeskind DS, Pineda S, Ovbiagele B (2008) Association of serum lipid indices with large artery atherosclerotic stroke. Neurology 70(11):841–847CrossRefPubMedGoogle Scholar
  4. Bender AR, Raz N (2012) Age-related differences in memory and executive functions in healthy APOE varepsilon4 carriers: the contribution of individual differences in prefrontal volumes and systolic blood pressure. Neuropsychologia 50(5):704–714CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bohnstedt M, Fox PJ, Kohatsu ND (1994) Correlates of mini-mental status examination scores among elderly demented patients: the influence of race-ethnicity. J Clin Epidemiol 47(12):1381–1387CrossRefPubMedGoogle Scholar
  6. Bryant FB, Yarnold PR (1995) Principle-components analysis and exploratory and confirmatory factor analysis. In: Grimm LG, Yarnold PR (eds) Reading and understanding multivariate statistics. American Psychological Association, Washington, D.C., pp. 99–136Google Scholar
  7. Dahle CL, Jacobs BS, Raz N (2009) Aging, vascular risk, and cognition: blood glucose, pulse pressure, and cognitive performance in healthy adults. Psychol Aging 24(1):154–162CrossRefPubMedPubMedCentralGoogle Scholar
  8. de Frias CM, Bunce D, Wahlin A, Adolfsson R, Sleegers K, Cruts M, et al. (2007) Cholesterol and triglycerides moderate the effect of apolipoprotein E on memory functioning in older adults. J Gerontol B Psychol Sci Soc Sci 62(2):112–118CrossRefGoogle Scholar
  9. Debette S, Seshadri S, Beiser A, Au R, Himali JJ, Palumbo C, et al. (2011) Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology 77(5):461–468CrossRefPubMedPubMedCentralGoogle Scholar
  10. Delano-Wood, L., Bondi, M. W., Jak, A. J., Horne, N. R., Schweinsburg, B. C., Frank, L. R., et al. (2008). Stroke risk modifies regional white matter differences in mild cognitive impairment. Neurobiol Aging 31(10), 1721–1731Google Scholar
  11. Delis DC, Kramer J, Kaplan E, Ober B (2000) California verbal learning test-second edition. The Psychological Corporation, San AntonioGoogle Scholar
  12. Elias PK, Elias MF, D'Agostino RB, Sullivan LM, Wolf PA (2005) Serum cholesterol and cognitive performance in the framingham heart study. Psychosom Med 67(1):24–30CrossRefPubMedGoogle Scholar
  13. Foley JM, Salat DH, Stricker NH, Zink TA, Grande LJ, McGlinchey RE, et al. (2014) Interactive effects of apolipoprotein E4 and diabetes risk on later myelinating white matter regions in neurologically healthy older aged adults. Am J Alzheimers Dis Other Demen 29(3):222–235CrossRefPubMedPubMedCentralGoogle Scholar
  14. Fortuny LA, Briggs M, Newcombe F, Ratcliff G, Thomas C (1980) Measuring the duration of post traumatic amnesia. J Neurol Neurosurg Psychiatry 43(5):377–379CrossRefPubMedPubMedCentralGoogle Scholar
  15. Gendle MH, Spaeth AM, Dollard SM, Novak CA (2008) Functional relationships between serum total cholesterol levels, executive control, and sustained attention. Nutr Neurosci 11(2):84–94CrossRefPubMedGoogle Scholar
  16. Gillum RF, Obisesan TO (2011) High-density lipoprotein cholesterol, cognitive function and mortality in a U.S. national cohort. Lipids Health Dis 10:26CrossRefPubMedPubMedCentralGoogle Scholar
  17. Henderson VW, Guthrie JR, Dennerstein L (2003) Serum lipids and memory in a population based cohort of middle age women. J Neurol Neurosurg Psychiatry 74(11):1530–1535CrossRefPubMedPubMedCentralGoogle Scholar
  18. Huang CQ, Dong BR, Wu HM, Zhang YL, Wu JH, Lu ZC, et al. (2009) Association of cognitive impairment with serum lipid/lipoprotein among Chinese nonagenarians and centenarians. Dement Geriatr Cogn Disord 27(2):111–116CrossRefPubMedGoogle Scholar
  19. Hughes TM, Kuller LH, Lopez OL, Becker JT, Evans RW, Sutton-Tyrrell K, et al. (2012) Markers of cholesterol metabolism in the brain show stronger associations with cerebrovascular disease than Alzheimer's disease. J Alzheimers Dis 30(1):53–61PubMedPubMedCentralGoogle Scholar
  20. Hughes TM, Rosano C, Evans RW, Kuller LH (2013) Brain cholesterol metabolism, oxysterols, and dementia. J Alzheimers Dis 33(4):891–911PubMedPubMedCentralGoogle Scholar
  21. Kaplan E, Goodglass H, Weintraub S (2001) Boston naming test. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  22. Khan U, Porteous L, Hassan A, Markus HS (2007) Risk factor profile of cerebral small vessel disease and its subtypes. J Neurol Neurosurg Psychiatry 78(7):702–706CrossRefPubMedPubMedCentralGoogle Scholar
  23. Lee PH, Lim TS, Shin HW, Yong SW, Nam HS, Sohn YH (2009) Serum cholesterol levels and the risk of multiple system atrophy: a case-control study. Mov Disord 24(5):752–758CrossRefPubMedGoogle Scholar
  24. Leoni V, Caccia C (2013) 24S-hydroxycholesterol in plasma: a marker of cholesterol turnover in neurodegenerative diseases. Biochimie 95(3):595–612CrossRefPubMedGoogle Scholar
  25. Leritz EC, Salat DH, Milberg WP, Williams VJ, Chapman CE, Grande LJ, et al. (2010) Variation in blood pressure is associated with white matter microstructure but not cognition in African Americans. Neuropsychology 24(2):199–208CrossRefPubMedPubMedCentralGoogle Scholar
  26. Leritz EC, Salat DH, Williams VJ, Schnyer DM, Rudolph JL, Lipsitz L, et al. (2011) Thickness of the human cerebral cortex is associated with metrics of cerebrovascular health in a normative sample of community dwelling older adults. NeuroImage 54(4):2659–2671CrossRefPubMedPubMedCentralGoogle Scholar
  27. Merched A, Xia Y, Visvikis S, Serot JM, Siest G (2000) Decreased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer's disease. Neurobiol Aging 21(1):27–30CrossRefPubMedGoogle Scholar
  28. Morley JE, Banks WA (2010) Lipids and cognition. J Alzheimers Dis 20(3):737–747PubMedGoogle Scholar
  29. Packard CJ, Westendorp RG, Stott DJ, Caslake MJ, Murray HM, Shepherd J, et al. (2007) Association between apolipoprotein E4 and cognitive decline in elderly adults. J Am Geriatr Soc 55(11):1777–1785CrossRefPubMedGoogle Scholar
  30. Perna L, Mons U, Rujescu D, Kliegel M, Brenner H (2015) Apolipoprotein E e4 and cognitive function: a modifiable association? Results from two independent cohort studies. Dement Geriatr Cogn Disord 41(1–2):35–45CrossRefPubMedGoogle Scholar
  31. Presecki P, Muck-Seler D, Mimica N, Pivac N, Mustapic M, Stipcevic T, et al. (2011) Serum lipid levels in patients with Alzheimer's disease. Coll Anthropol 35(Suppl 1):115–120Google Scholar
  32. Raz N, Rodrigue KM, Kennedy KM, Acker JD (2007) Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults. Neuropsychology 21(2):149–157CrossRefPubMedGoogle Scholar
  33. Reijmer YD, van den Berg E, Dekker JM, Nijpels G, Stehouwer CD, Kappelle LJ, et al. (2012) Development of vascular risk factors over 15 years in relation to cognition: the hoorn study. J Am Geriatr Soc 60(8):1426–1433CrossRefPubMedGoogle Scholar
  34. Reitz C, Tang MX, Luchsinger J, Mayeux R (2004) Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol 61(5):705–714CrossRefPubMedPubMedCentralGoogle Scholar
  35. Reitz C, Luchsinger J, Tang MX, Manly J, Mayeux R (2005) Impact of plasma lipids and time on memory performance in healthy elderly without dementia. Neurology 64(8):1378–1383CrossRefPubMedPubMedCentralGoogle Scholar
  36. Reitz C, Tang MX, Schupf N, Manly JJ, Mayeux R, Luchsinger JA (2010) Association of higher levels of high-density lipoprotein cholesterol in elderly individuals and lower risk of late-onset Alzheimer disease. Arch Neurol 67(12):1491–1497CrossRefPubMedPubMedCentralGoogle Scholar
  37. Salat DH, Williams VJ, Leritz EC, Schnyer DM, Rudolph JL, Lipsitz LA, et al. (2012) Inter-individual variation in blood pressure is associated with regional white matter integrity in generally healthy older adults. NeuroImage 59(1):181–192CrossRefPubMedPubMedCentralGoogle Scholar
  38. Sato N, Morishita R (2015) The roles of lipid and glucose metabolism in modulation of beta-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease. Front Aging Neurosci 7:199CrossRefPubMedPubMedCentralGoogle Scholar
  39. Sparks DL, Kryscio RJ, Connor DJ, Sabbagh MN, Sparks LM, Lin Y, et al. (2010) Cholesterol and cognitive performance in normal controls and the influence of elective statin use after conversion to mild cognitive impairment: results in a clinical trial cohort. Neurodegener Dis 7(1–3):183–186CrossRefPubMedPubMedCentralGoogle Scholar
  40. Spreen O, Strauss E (1998) A compendium of neuropsychological tests. Oxford University Press, New YorkGoogle Scholar
  41. Staekenborg SS, van Straaten EC, van der Flier WM, Lane R, Barkhof F, Scheltens P (2008) Small vessel versus large vessel vascular dementia: risk factors and MRI findings. J Neurol 255(11):1644–1651 discussion 1813-1644CrossRefPubMedGoogle Scholar
  42. Talayero BG, Sacks FM (2011) The role of triglycerides in atherosclerosis. Curr Cardiol Rep 13(6):544–552CrossRefPubMedPubMedCentralGoogle Scholar
  43. van den Kommer TN, Dik MG, Comijs HC, Fassbender K, Lutjohann D, Jonker C (2009) Total cholesterol and oxysterols: early markers for cognitive decline in elderly? Neurobiol Aging 30(4):534–545CrossRefPubMedGoogle Scholar
  44. van den Kommer TN, Dik MG, Comijs HC, Jonker C, Deeg DJ (2010) The role of lipoproteins and inflammation in cognitive decline: do they interact? Neurobiol Aging 33(1):196.e1–196.e12CrossRefGoogle Scholar
  45. van Es AC, van der Grond J, de Craen AJ, Admiraal-Behloul F, Blauw GJ, van Buchem MA (2008) Risk factors for cerebral microbleeds in the elderly. Cerebrovasc Dis 26(4):397–403CrossRefPubMedGoogle Scholar
  46. van Exel E, de Craen AJ, Gussekloo J, Houx P, Bootsma-van der Wiel A, Macfarlane PW, et al. (2002) Association between high-density lipoprotein and cognitive impairment in the oldest old. Ann Neurol 51(6):716–721CrossRefPubMedGoogle Scholar
  47. Weber C, Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17(11):1410–1422CrossRefPubMedGoogle Scholar
  48. Wechsler D (1997) Wechsler memory scale - third edition. The Psychological Corporation, San AntonioGoogle Scholar
  49. West R, Beeri MS, Schmeidler J, Hannigan CM, Angelo G, Grossman HT, et al. (2008) Better memory functioning associated with higher total and low-density lipoprotein cholesterol levels in very elderly subjects without the apolipoprotein e4 allele. Am J Geriatr Psychiatr 16(9):781–785CrossRefGoogle Scholar
  50. Williams VJ, Leritz EC, Shepel J, McGlinchey RE, Milberg WP, Rudolph JL, et al. (2013) Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults. Hum Brain Mapp 34(8):1826–1841CrossRefPubMedPubMedCentralGoogle Scholar
  51. Wolf H, Hensel A, Arendt T, Kivipelto M, Winblad B, Gertz HJ (2004) Serum lipids and hippocampal volume: the link to Alzheimer's disease? Ann Neurol 56(5):745–748CrossRefPubMedGoogle Scholar
  52. Yaffe K, Barrett-Connor E, Lin F, Grady D (2002) Serum lipoprotein levels, statin use, and cognitive function in older women. Arch Neurol 59(3):378–384CrossRefPubMedGoogle Scholar
  53. Yuan J, Wen G, Li Y, Liu C (2013) The occurrence of cerebrovascular atherosclerosis in Alzheimer's disease patients. Clin Interv Aging 8:581–584PubMedPubMedCentralGoogle Scholar
  54. Zheng L, Mack WJ, Chui HC, Heflin L, Mungas D, Reed B, et al. (2012) Coronary artery disease is associated with cognitive decline independent of changes on magnetic resonance imaging in cognitively normal elderly adults. J Am Geriatr Soc 60(3):499–504CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2016

Authors and Affiliations

  • Elizabeth C. Leritz
    • 1
    • 2
    • 3
  • Regina E. McGlinchey
    • 1
    • 2
    • 3
  • David H. Salat
    • 1
    • 2
    • 3
    • 4
  • William P. Milberg
    • 1
    • 2
    • 3
  1. 1.Geriatric Research, Education and Clinical Center (GRECC), VA Boston Healthcare SystemBostonUSA
  2. 2.Neuroimaging Research for Veterans Center (NERVE), VA Boston Healthcare SystemBostonUSA
  3. 3.Harvard Medical SchoolBostonUSA
  4. 4.Athinoula A. Martinos Center for Biomedical ImagingCharlestownUSA

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