Sex differences in Alzheimer’s disease and common neuropathologies of aging

Abstract

Alzheimer’s dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer’s disease (AD) and other brain pathologies. We leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two-thirds of subjects were women (n = 971; 67%), with a mean age at death of 89.8 (SD = 6.6) years in women and 87.3 (SD = 6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate = 0.102, SE = 0.022, p < 0.001), and tau tangle density in particular (estimate = 0.334, SE = 0.074, p < 0.001), and there was a borderline difference between women and men in amyloid-β load (estimate = 0.124, SE = 0.065, p = 0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR = 1.28, 95% CI:1.04–1.58, p = 0.018), and less likely to have gross infarcts (OR = 0.78, 95% CI:0.61–0.98, p = 0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of aging.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Alvarez-de-la-Rosa M, Silva I, Nilsen J, Perez MM, Garcia-Segura LM, Avila J et al (2005) Estradiol prevents neural tau hyperphosphorylation characteristic of Alzheimer’s disease. Ann N Y Acad Sci 1052:210–224

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Association Alzheimer’s (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509

    Article  Google Scholar 

  3. 3.

    Arvanitakis Z, Capuano AW, Lamar M, Shah RC, Barnes LL, Bennett DA et al (2018) Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology. Neurology. https://doi.org/10.1212/wnl.0000000000005951

    Article  PubMed  Google Scholar 

  4. 4.

    Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA (2016) Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 15:934–943

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Arvanitakis Z, Capuano AW, Leurgans SE, Buchman AS, Bennett DA, Schneider JA (2017) The relationship of cerebral vessel pathology to brain microinfarcts. Brain Pathol 27:77–85

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA (2011) Microinfarct pathology, dementia, and cognitive systems. Stroke 42:722–727

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Arvanitakis Z, Schneider JA, Wilson RS, Li Y, Arnold SE, Wang Z et al (2006) Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 67:1960–1965

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA (2005) Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 62:685–691

    Article  PubMed  Google Scholar 

  9. 9.

    Barnes LL, Wilson RS, Schneider JA, Bienias JL, Evans DA, Bennett DA (2003) Gender, cognitive decline, and risk of AD in older persons. Neurology 60:1777–1781

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Bennett DA, Buchman AS, Boyle PA, Barnes LL, Wilson RS, Schneider JA (2018) Religious orders study and rush memory and aging project. J Alzheimers Dis 64:S161–S189

    Article  PubMed  Google Scholar 

  11. 11.

    Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE (2004) Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol 61:378–384

    Article  PubMed  Google Scholar 

  12. 12.

    Bennett DA, Wilson RS, Boyle PA, Buchman AS, Schneider JA (2012) Relation of neuropathology to cognition in persons without cognitive impairment. Ann Neurol 72:599–609

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE et al (2003) Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology 60:246–252

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA et al (2014) Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 82:222–229

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Boyle PA, Yu L, Nag S, Leurgans S, Wilson RS, Bennett DA et al (2015) Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology 85:1930–1936

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Congdon EE (2018) Sex differences in autophagy contribute to female vulnerability in Alzheimer’s disease. Front Neurosci 12:372

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Corder EH, Ghebremedhin E, Taylor MG, Thal DR, Ohm TG, Braak H (2004) The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann N Y Acad Sci 1019:24–28

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Deming Y, Dumitrescu L, Barnes LL, Thambisetty M, Kunkle B, Gifford KA et al (2018) Sex-specific genetic predictors of Alzheimer’s disease biomarkers. Acta Neuropathol. https://doi.org/10.1007/s00401-018-1881-4

    Article  PubMed  Google Scholar 

  19. 19.

    Devi L, Alldred MJ, Ginsberg SD, Ohno M (2010) Sex- and brain region-specific acceleration of beta-amyloidogenesis following behavioral stress in a mouse model of Alzheimer’s disease. Mol Brain 3:34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Edland SD, Rocca WA, Petersen RC, Cha RH, Kokmen E (2002) Dementia and Alzheimer disease incidence rates do not vary by sex in Rochester, Minn. Arch Neurology 59:1589–1593

    Article  Google Scholar 

  21. 21.

    Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta analysis consortium. JAMA 278:1349–1356

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Filon JR, Intorcia AJ, Sue LI, Vazquez Arreola E, Wilson J, Davis KJ et al (2016) Gender differences in Alzheimer disease: brain atrophy, histopathology burden, and cognition. J Neuropathol Exp Neurol. https://doi.org/10.1093/jnen/nlw047

    Article  PubMed  Google Scholar 

  23. 23.

    Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, Winblad B (1997) Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project, Stockholm. Neurology 48:132–138

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Ghebremedhin E, Schultz C, Thal DR, Rub U, Ohm TG, Braak E et al (2001) Gender and age modify the association between APOE and AD-related neuropathology. Neurology 56:1696–1701

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B et al (2018) Sex-specific association of apolipoprotein E With cerebrospinal fluid levels of Tau. JAMA Neurol 75(8):989–998

    Article  PubMed  Google Scholar 

  26. 26.

    Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Iacobas DA, Iacobas S, Thomas N, Spray DC (2010) Sex-dependent gene regulatory networks of the heart rhythm. Funct Itegr Genomics 10:73–86

    CAS  Article  Google Scholar 

  28. 28.

    Ighodaro ET, Abner EL, Fardo DW, Lin AL, Katsumata Y, Schmitt FA et al (2017) Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals. J Cereb Blood Flow Metab 37:201–216

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    James BD, Bennett DA, Boyle PA, Leurgans S, Schneider JA (2012) Dementia from Alzheimer disease and mixed pathologies in the oldest old. JAMA 307:1798–1800

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA (2016) TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia. Brain 139:2983–2993

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Jellinger KA, Attems J (2015) Challenges of multimorbidity of the aging brain: a critical update. J Neural Transm (Vienna) 122:505–521

    Article  Google Scholar 

  32. 32.

    Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman A (2000) Age-specific incidence rates of Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 54:2072–2077

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Koglsberger S, Cordero-Maldonado ML, Antony P, Forster JI, Garcia P, Buttini M et al (2017) Gender-specific expression of ubiquitin-specific peptidase 9 modulates Tau expression and phosphorylation: possible implications for tauopathies. Mol Neurobiol 54:7979–7993

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Kovacs GG, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Capellari S et al (2008) Mixed brain pathologies in dementia: the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord 26:343–350

    Article  PubMed  Google Scholar 

  35. 35.

    Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY (2002) Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci USA 99:7705–7710

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Maynard CJ, Cappai R, Volitakis I, Cherny RA, Masters CL, Li QX et al (2006) Gender and genetic background effects on brain metal levels in APP transgenic and normal mice: implications for Alzheimer beta-amyloid pathology. J Inorg Biochem 100:952–962

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Melnikova T, Savonenko A, Wang Q, Liang X, Hand T, Wu L et al (2006) Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer’s disease in a sex-dimorphic pattern. Neurosci 141:1149–1162

    CAS  Article  Google Scholar 

  39. 39.

    Miech RA, Breitner JC, Zandi PP, Khachaturian AS, Anthony JC, Mayer L (2002) Incidence of AD may decline in the early 90 s for men, later for women: the Cache County study. Neurology 58:209–218

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 6:37–48

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Miller FD, Hicks SP, D’Amato CJ, Landis JR (1984) A descriptive study of neuritic plaques and neurofibrillary tangles in an autopsy population. AmJ Epidemiol 120:331–341

    CAS  Article  Google Scholar 

  42. 42.

    Nag S, Yu L, Capuano AW, Wilson RS, Leurgans SE, Bennett DA et al (2015) Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease. Ann Neurol 77:942–952

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Nelson PT, Schmitt FA, Jicha GA, Kryscio RJ, Abner EL, Smith CD et al (2010) Association between male gender and cortical Lewy body pathology in large autopsy series. J Neurol 257:1875–1881

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Oikawa N, Ogino K, Masumoto T, Yamaguchi H, Yanagisawa K (2010) Gender effect on the accumulation of hyperphosphorylated tau in the brain of locus-ceruleus-injured APP-transgenic mouse. Neurosci Lett 468:243–247

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Oveisgharan S, Buchman AS, Yu L, Farfel J, Hachinski V, Gaiteri C et al (2018) APOE epsilon2epsilon4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology 92(24):e2127–e2134

    Article  CAS  Google Scholar 

  46. 46.

    Petersen RC, Roberts RO, Knopman DS, Geda YE, Cha RH, Pankratz VS et al (2010) Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging. Neurology 75:889–897

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Placanica L, Zhu L, Li YM (2009) Gender- and age-dependent gamma-secretase activity in mouse brain and its implication in sporadic Alzheimer disease. PLoS ONE 4:e5088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Plassman BL, Langa KM, McCammon RJ, Fisher GG, Potter GG, Burke JR (2011) Incidence of dementia and cognitive impairment, not dementia in the United States. Ann Neurol 70:418–426

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Reynolds WF, Rhees J, Maciejewski D, Paladino T, Sieburg H, Maki RA et al (1999) Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer’s disease. Exp Neurol 155:31–41

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M et al (2007) Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 69:1074–1083

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Rocca WA, Grossardt BR, Shuster LT (2011) Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity. Brain Res 1379:188–198

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Rocca WA, Grossardt BR, Shuster LT, Stewart EA (2012) Hysterectomy, oophorectomy, estrogen, and the risk of dementia. Neurodegener Dis 10:175–178

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Sandberg G, Stewart W, Smialek J, Troncoso JC (2001) The prevalence of the neuropathological lesions of Alzheimer’s disease is independent of race and gender. Neurobiol Aging 22:169–175

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C et al (2009) Age, neuropathology, and dementia. N Eng J Med 360:2302–2309

    CAS  Article  Google Scholar 

  55. 55.

    Schafer S, Wirths O, Multhaup G, Bayer TA (2007) Gender dependent APP processing in a transgenic mouse model of Alzheimer’s disease. J Neural Transm (Vienna) 114:387–394

    CAS  Article  Google Scholar 

  56. 56.

    Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69:2197–2204

    Article  PubMed  Google Scholar 

  57. 57.

    Schneider JA, Arvanitakis Z, Yu L, Boyle PA, Leurgans SE, Bennett DA (2012) Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies. Brain 135:3005–3014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Schneider JA, Wilson RS, Cochran EJ, Bienias JL, Arnold SE, Evans DA et al (2003) Relation of cerebral infarctions to dementia and cognitive function in older persons. Neurology 60:1082–1088

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Scott EL, Zhang QG, Vadlamudi RK, Brann DW (2014) Premature menopause and risk of neurological disease: basic mechanisms and clinical implications. Mol Cell Endocrinol 389:2–6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Seshadri S, Wolf PA, Beiser A, Au R, McNulty K, White R et al (1997) Lifetime risk of dementia and Alzheimer’s disease. The impact of mortality on risk estimates in the Framingham Study. Neurology 49:1498–1504

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    National Center for Health Statistics (2017) Health, United States, 2016: With chartbook on long-term trends in Health. Hyattsville, MD

  62. 62.

    Wilson RS, Beckett LA, Barnes LL, Schneider JA, Bach J, Evans DA et al (2002) Individual differences in rates of change in cognitive abilities of older persons. Psychol Aging 17:179–193

    Article  PubMed  Google Scholar 

  63. 63.

    Wilson RS, Yu L, Trojanowski JQ, Chen EY, Boyle PA, Bennett DA, Schneider JA (2013) TDP-43 pathology, cognitive decline, and dementia in old age. JAMA Neurol 70:1418–1424

    Article  PubMed  Google Scholar 

  64. 64.

    Yu L, Boyle PA, Leurgans S, Schneider JA, Bennett DA (2014) Disentangling the effects of age and APOE on neuropathology and late life cognitive decline. Neurobiol Aging 35:819–826

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Yu L, Lutz MW, Wilson RS, Burns DK, Roses AD, Saunders AM et al (2017) TOMM40′523 variant and cognitive decline in older persons with APOE epsilon3/3 genotype. Neurology 88:661–668

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Zhang QG, Wang RM, Scott E, Han D, Dong Y, Tu JY et al (2013) Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause. Brain 136:1432–1445

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the participants in the ROS and MAP. We also thank the staff and faculty of the Rush Alzheimer’s Disease Center. This work was supported by the National Institute of Health grants R01AG17917, P30AG10161, R01AG15819, and RO1NS084965.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Shahram Oveisgharan.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 49 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Oveisgharan, S., Arvanitakis, Z., Yu, L. et al. Sex differences in Alzheimer’s disease and common neuropathologies of aging. Acta Neuropathol 136, 887–900 (2018). https://doi.org/10.1007/s00401-018-1920-1

Download citation

Keywords

  • Alzheimer disease
  • Sex
  • Pathology
  • Tau proteins
  • Amyloid
  • Arteriolosclerosis