Skip to main content

Sex differences in the association between AD biomarkers and cognitive decline

Brain Imaging and Behavior volume 11, pages 205–213 (2017)Cite this article

Abstract

Women are disproportionately affected by Alzheimer’s disease (AD) in terms of both disease prevalence and severity. Previous autopsy work has suggested that, in the presence of AD neuropathology, females are more susceptible to the clinical manifestation of AD. This manuscript extends that work by evaluating whether sex alters the established associations between cerebrospinal fluid (CSF) biomarker levels and brain aging outcomes (hippocampal volume, cognition). Participants were drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and included individuals with normal cognition (n = 348), mild cognitive impairment (n = 565), and AD (n = 185). We leveraged mixed effects regression models to assess the interaction between sex and baseline cerebrospinal fluid biomarker levels of amyloid-β42 (Aβ-42) and total tau on cross-sectional and longitudinal brain aging outcomes. We found a significant interaction between sex and Aβ-42 on longitudinal hippocampal atrophy (p = 0.002), and longitudinal decline in memory (p = 0.017) and executive function (p = 0.025). Similarly, we observed an interaction between sex and total tau level on longitudinal hippocampal atrophy (p = 0.008), and longitudinal decline in executive function (p = 0.034). Women with Aβ-42 and total tau levels indicative of worse pathological changes showed more rapid hippocampal atrophy and cognitive decline. The sex difference was particularly pronounced among individuals with MCI, with lower education, and varied by APOE ε4 allele. These results suggest females may be more susceptible to the clinical manifestation of AD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  • Alvarez-de-la-Roza, M., Silva, I., Nilsen, J., Perez, M., Garcia-Segura, L. M., Ávila, J., & Naftolin, F. (2005). Estradiol prevents neural tau hyperphosphorylation characteristic of Alzheimer’s disease. Annals of the New York Academy of Sciences, 1052(1), 210–224.

    Article  Google Scholar 

  • Anastasio, T. J. (2013). Exploring the contribution of estrogen to amyloid-beta regulation: a novel multifactorial computational modeling approach. Frontiers in Pharmacology, 4. doi:10.3389/fphar.2013.00016.

  • Apostolova, L. G., Dinov, I. D., Dutton, R. A., Hayashi, K. M., Toga, A. W., Cummings, J. L., & Thompson, P. M. (2006). 3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer’s disease. Brain, 129(11), 2867–2873.

    Article  PubMed  Google Scholar 

  • Barnes, L. L., Wilson, R. S., Bienias, J. L., Schneider, J. A., Evans, D. A., & Bennett, D. A. (2005). Sex differences in the clinical manifestations of Alzheimer disease pathology. Archives of General Psychiatry, 62(6), 685–691.

    Article  PubMed  Google Scholar 

  • Crane, P. K., Carle, A., Gibbons, L. E., Insel, P., Mackin, R. S., Gross, A., et al. (2012). Development and assessment of a composite score for memory in the Alzheimer’s disease neuroimaging initiative (ADNI). Brain Imaging and Behavior, 6(4), 502–516.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dale, A. M., Fischl, B., & Sereno, M. I. (1999). Cortical surface-based analysis: I. Segmentation and surface reconstruction. NeuroImage, 9(2), 179–194.

    CAS  Article  PubMed  Google Scholar 

  • Desikan, R. S., Segonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker, D., et al. (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage, 31(3), 968–980.

    Article  PubMed  Google Scholar 

  • Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., Mayeux, R., et al. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. Jama, 278(16), 1349–1356.

    CAS  Article  PubMed  Google Scholar 

  • Fischl, B., Sereno, M. I., Tootell, R. B. H., & Dale, A. M. (1999a). High-resolution intersubject averaging and a coordinate system for the cortical surface. Human Brain Mapping, 8(4), 272–284.

    CAS  Article  PubMed  Google Scholar 

  • Fischl, B., Sereno, M. I., & Dale, A. M. (1999b). Cortical surface-based analysis: II: inflation, flattening, and a surface-based coordinate system. NeuroImage, 9(2), 195–207.

    CAS  Article  PubMed  Google Scholar 

  • Gibbons, L. E., Carle, A. C., Mackin, R. S., Harvey, D., Mukherjee, S., Insel, P., et al. (2012). A composite score for executive functioning, validated in Alzheimer’s disease neuroimaging initiative (ADNI) participants with baseline mild cognitive impairment. Brain Imaging and Behavior, 6(4), 517–527.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hebert, L. E., Weuve, J., Scherr, P. A., & Evans, D. A. (2013). Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology, 80(19), 1778–1783.

    Article  PubMed  PubMed Central  Google Scholar 

  • Henderson, V. W., & Buckwalter, J. G. (1994). Cognitive deficits of men and women with Alzheimer’s disease. Neurology, 44(1), 90–90.

    CAS  Article  PubMed  Google Scholar 

  • Hua, X., Hibar, D. P., Lee, S., Toga, A. W., Jack, C. R., Weiner, M. W., et al. (2010). Sex and age differences in atrophic rates: an ADNI study with n = 1368 MRI scans. Neurobiology of Aging, 31(8), 1463–1480.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jack, C. R., Bernstein, M. A., Fox, N. C., Thompson, P., Alexander, G., Harvey, D., et al. (2008). The Alzheimer’s disease neuroimaging initiative (ADNI): MRI methods. Journal of Magnetic Resonance Imaging, 27(4), 685–691.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jagust, W. J., Landau, S. M., Shaw, L. M., Trojanowski, J. Q., Koeppe, R. A., Reiman, E. M., et al. (2009). Relationships between biomarkers in aging and dementia. Neurology, 73(15), 1193–1199.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Launer, L., Andersen, K., Dewey, M., Letenneur, L., Ott, A., Amaducci, L., et al. (1999). Rates and risk factors for dementia and Alzheimer’s disease results from EURODEM pooled analyses. Neurology, 52(1), 78–78.

    CAS  Article  PubMed  Google Scholar 

  • Lin, K. A., Choudhury, K. R., Rathakrishnan, B. G., Marks, D. M., Petrella, J. R., Doraiswamy, P. M., & Initiative, A. S. D. N. (2015). Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimer’s & Dementia: translational Research & Clinical Interventions, 1(2), 103–110.

    Google Scholar 

  • Luine, V. N. (2014). Estradiol and cognitive function: past, present and future. Hormones and Behavior, 66(4), 602–618. doi:10.1016/j.yhbeh.2014.08.011.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Mormino, E. C., Kluth, J. T., Madison, C. M., Rabinovici, G. D., Baker, S. L., Miller, B. L., et al. (2009). Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain, 132(5), 1310–1323.

    CAS  Article  PubMed  Google Scholar 

  • Nilsen, J., Chen, S., Irwin, R. W., Iwamoto, S., & Brinton, R. D. (2006). Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC Neuroscience, 7(1), 74.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pfeffer, R., Kurosaki, T., Harrah, C., Chance, J., & Filos, S. (1982). Measurement of functional activities in older adults in the community. Journal of Gerontology, 37(3), 323–329.

    CAS  Article  PubMed  Google Scholar 

  • Reuter, M., Schmansky, N. J., Rosas, H. D., & Fischl, B. (2012). Within-subject template estimation for unbiased longitudinal image analysis. NeuroImage, 61(4), 1402–1418.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sampedro, F., Vilaplana, E., de Leon, M. J., Alcolea, D., Pegueroles, J., Montal, V., et al. (2015). APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls. Oncotarget, 6(29), 26663–26674. doi:10.18632/oncotarget.5185.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shaw, L. M., Vanderstichele, H., Knapik-Czajka, M., Figurski, M., Coart, E., Blennow, K., et al. (2011). Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathologica, 121(5), 597–609.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Tschanz, J. T., Corcoran, C. D., Schwartz, S., Treiber, K., Green, R. C., Norton, M. C., et al. (2011). Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the cache county dementia progression study. The American Journal of Geriatric Psychiatry, 19(6), 532–542.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors report no conflicts of interest. Dr. Hohman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This research was supported in part by the Building Interdisciplinary Research Careers in Women’s Health program (K12 HD043483), the Vanderbilt Medical Scientist Training Program (T32 GM07347), and the Vanderbilt Memory & Alzheimer’s Center.

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; ; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Rev. December 5, 2013 Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Affiliations

  1. Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University School of Medicine, 1207 17th Ave S, Suite 204F, Nashville, TN, 37212, USA

    Mary Ellen I. Koran, Madison Wagener & Timothy J. Hohman

Authors
  1. Mary Ellen I. Koran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Madison Wagener
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Timothy J. Hohman
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Alzheimer’s Neuroimaging Initiative

Corresponding author

Correspondence to Timothy J. Hohman.

Ethics declarations

This research was supported in part by the Building Interdisciplinary Research Careers in Women’s Health program (K12 HD043483), the Vanderbilt Medical Scientist Training Program (T32 GM07347), and the Vanderbilt Memory & Alzheimer’s Center. The authors report no conflicts of interest. Informed consent was obtained from all participants included in the study.

Additional information

Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Koran, M.E.I., Wagener, M., Hohman, T.J. et al. Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging and Behavior 11, 205–213 (2017). https://doi.org/10.1007/s11682-016-9523-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11682-016-9523-8

Keywords

  • Biomarkers
  • Hippocampus
  • Sex differences
  • Alzheimer’s disease
  • Cognition