Published Online:

In a multiethnic population-based sample, specific toxic and endogenous metabolic factors are correlated with smaller volume in brain segments linked with risk for neurodegenerative disease.


To determine in a large multiethnic cohort the cardiovascular and genetic risk factors associated with smaller volume in the hippocampus, precuneus, and posterior cingulate, and their association with preclinical deficits in cognitive performance in patients younger and older than 50 years.

Materials and Methods

The institutional review board approved the study and all participants provided written informed consent. Eligible for this study were 1629 participants (700 men and 929 women; mean age, 50.0 years ± 10.2 [standard deviation]) drawn from the population-based Dallas Heart Study who underwent laboratory and clinical analysis in an initial baseline visit and approximately 7 years later underwent brain magnetic resonance imaging with automated volumetry and cognitive assessment with the Montreal Cognitive Assessment (MoCA). Regression analysis showed associations between risk factors and segmental volumes, and associations between these volumes with cognitive performance in participants younger and older than 50 years.


Lower hippocampal volume was associated with previous alcohol consumption (standardized estimate, −0.04; P = .039) and smoking (standardized estimate, −0.04; P = .048). Several risk factors correlated with lower total brain, posterior cingulate, and precuneus volumes. Higher total (standardized estimate, 0.06; P = .050), high-density lipoprotein (standardized estimate, 0.07; P = .003), and low-density lipoprotein (standardized estimate, 0.04; P = .037) cholesterol levels were associated with larger posterior cingulate volume, and higher triglyceride levels (standardized estimate, 0.06; P = .004) were associated with larger precuneus volume. Total MoCA score was associated with posterior cingulate volume (standardized estimate, 0.13; P = .001) in younger individuals and with hippocampal (standardized estimate, 0.06; P < .05) and precuneus (standardized estimate, 0.08; P < .023) volumes in older adults.


Smaller volumes in specific brain regions considered to be early markers of dementia risk were associated with specific cardiovascular disease risk factors and cognitive deficits in a predominantly midlife multiethnic population-based sample. Additionally, the risk factors most associated with these brain volumes differed in participants younger and older than 50 years, as did the association between brain volume and MoCA score.

© RSNA, 2015


  • 1. Lehmann M, Koedam EL, Barnes J, et al. Posterior cerebral atrophy in the absence of medial temporal lobe atrophy in pathologically-confirmed Alzheimer’s disease. Neurobiol Aging 2012;33(3):627.e1–627.e12. Crossref, MedlineGoogle Scholar
  • 2. Pengas G, Hodges JR, Watson P, Nestor PJ. Focal posterior cingulate atrophy in incipient Alzheimer’s disease. Neurobiol Aging 2010;31(1):25–33. Crossref, MedlineGoogle Scholar
  • 3. Choo IH, Lee DY, Oh JS, et al. Posterior cingulate cortex atrophy and regional cingulum disruption in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 2010;31(5):772–779. Crossref, MedlineGoogle Scholar
  • 4. Kivipelto M, Helkala EL, Laakso MP, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ 2001;322(7300):1447–1451. Crossref, MedlineGoogle Scholar
  • 5. Debette S, Seshadri S, Beiser A, et al. Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology 2011;77(5):461–468. Crossref, MedlineGoogle Scholar
  • 6. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 2005;64(2):277–281. Crossref, MedlineGoogle Scholar
  • 7. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42(9):2672–2713. Crossref, MedlineGoogle Scholar
  • 8. Schuff N, Woerner N, Boreta L, et al. MRI of hippocampal volume loss in early Alzheimer’s disease in relation to ApoE genotype and biomarkers. Brain 2009;132(Pt 4):1067–1077. MedlineGoogle Scholar
  • 9. Gupta M, King KS, Srinivasa R, et al. Association of 3.0-T brain magnetic resonance imaging biomarkers with cognitive function in the Dallas Heart Study. JAMA Neurol 2015;72(2):170–175. Crossref, MedlineGoogle Scholar
  • 10. Victor RG, Haley RW, Willett DL, et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am J Cardiol 2004;93(12):1473–1480. Crossref, MedlineGoogle Scholar
  • 11. Lucarelli RT, Peshock RM, McColl R, et al. MR imaging of hippocampal asymmetry at 3T in a multiethnic, population-based sample: results from the Dallas Heart Study. AJNR Am J Neuroradiol 2013;34(4):752–757. Crossref, MedlineGoogle Scholar
  • 12. Tamashiro-Duran JH, Squarzoni P, de Souza Duran FL, et al. Cardiovascular risk in cognitively preserved elderlies is associated with glucose hypometabolism in the posterior cingulate cortex and precuneus regardless of brain atrophy and apolipoprotein gene variations. Age (Dordr) 2013;35(3):777–792. Crossref, MedlineGoogle Scholar
  • 13. de Toledo Ferraz Alves TC, Scazufca M, Squarzoni P, et al. Subtle gray matter changes in temporo-parietal cortex associated with cardiovascular risk factors. J Alzheimers Dis 2011;27(3):575–589. Crossref, MedlineGoogle Scholar
  • 14. Seshadri S, Wolf PA, Beiser A, et al. Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring Study. Neurology 2004;63(9):1591–1599. Crossref, MedlineGoogle Scholar
  • 15. Cardenas VA, Reed B, Chao LL, et al. Associations among vascular risk factors, carotid atherosclerosis, and cortical volume and thickness in older adults. Stroke 2012;43(11):2865–2870. Crossref, MedlineGoogle Scholar
  • 16. de la Torre JC. Vascular risk factors: a ticking time bomb to Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2013;28(6):551–559. Crossref, MedlineGoogle Scholar
  • 17. den Heijer T, van der Lijn F, Ikram A, et al. Vascular risk factors, apolipoprotein E, and hippocampal decline on magnetic resonance imaging over a 10-year follow-up. Alzheimers Dement 2012;8(5):417–425. Crossref, MedlineGoogle Scholar
  • 18. Fotuhi M, Do D, Jack C. Modifiable factors that alter the size of the hippocampus with ageing. Nat Rev Neurol 2012;8(4):189–202. Crossref, MedlineGoogle Scholar
  • 19. Middleton LE, Yaffe K. Promising strategies for the prevention of dementia. Arch Neurol 2009;66(10):1210–1215. Crossref, MedlineGoogle Scholar
  • 20. Morris JK, Vidoni ED, Perea RD, et al. Insulin resistance and gray matter volume in neurodegenerative disease. Neuroscience 2014;270:139–147. Crossref, MedlineGoogle Scholar
  • 21. Alzheimer’s Association. 2010 Alzheimer’s disease facts and figures. Alzheimers Dement 2010;6(2):158–194. Crossref, MedlineGoogle Scholar
  • 22. Nordström P, Nordström A, Eriksson M, Wahlund LO, Gustafson Y. Risk factors in late adolescence for young-onset dementia in men: a nationwide cohort study. JAMA Intern Med 2013;173(17):1612–1618. Crossref, MedlineGoogle Scholar
  • 23. Singh-Manoux A, Gimeno D, Kivimaki M, Brunner E, Marmot MG. Low HDL cholesterol is a risk factor for deficit and decline in memory in midlife: the Whitehall II study. Arterioscler Thromb Vasc Biol 2008;28(8):1556–1562. Crossref, MedlineGoogle Scholar
  • 24. Hughes TM, Rosano C, Evans RW, Kuller LH. Brain cholesterol metabolism, oxysterols, and dementia. J Alzheimers Dis 2013;33(4):891–911. Crossref, MedlineGoogle Scholar
  • 25. Prospective Studies Collaboration, Lewington S, Whitlock G, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370(9602):1829–1839. Crossref, MedlineGoogle Scholar
  • 26. van den Kommer TN, Dik MG, Comijs HC, et al. The role of extracerebral cholesterol homeostasis and ApoE e4 in cognitive decline. Neurobiol Aging 2012;33(3):622.e17–622.e28. Crossref, MedlineGoogle Scholar
  • 27. Solomon A, Leoni V, Kivipelto M, et al. Plasma levels of 24S-hydroxycholesterol reflect brain volumes in patients without objective cognitive impairment but not in those with Alzheimer’s disease. Neurosci Lett 2009;462(1):89–93. Crossref, MedlineGoogle Scholar
  • 28. Stiles AR, Kozlitina J, Thompson BM, McDonald JG, King KS, Russell DW. Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels. Proc Natl Acad Sci U S A 2014;111(38):E4006–E4014. Crossref, MedlineGoogle Scholar
  • 29. van de Pol LA, van der Flier WM, Korf ES, Fox NC, Barkhof F, Scheltens P. Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment. Neurology 2007;69(15):1491–1497. Crossref, MedlineGoogle Scholar
  • 30. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261(5123):921–923. Crossref, MedlineGoogle Scholar
  • 31. Rebeck GW, Kindy M, LaDu MJ. Apolipoprotein E and Alzheimer’s disease: the protective effects of ApoE2 and E3. J Alzheimers Dis 2002;4(3):145–154. Crossref, MedlineGoogle Scholar
  • 32. Hedman AM, van Haren NE, Schnack HG, Kahn RS, Hulshoff Pol HE. Human brain changes across the life span: a review of 56 longitudinal magnetic resonance imaging studies. Hum Brain Mapp 2012;33(8):1987–2002. Crossref, MedlineGoogle Scholar
  • 33. Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging 2000;21(1):49–55. Crossref, MedlineGoogle Scholar

Article History

Received November 4, 2014; revision requested December 17; revision received February 4, 2015; accepted February 20; final version accepted May 8.
Published online: July 28 2015
Published in print: Jan 2016