Sex differences in the association between AD biomarkers and cognitive decline
Open accessAbstract
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.
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After diagnosis, women progress faster with more rapid cognitive and functional declines.
“After diagnosis, women also progress faster with more rapid cognitive and functional declines [3–8]”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [3]
The Discussion reports faster decline in memory and executive function among women with biomarker levels indicating greater AD pathology. It does not report functional decline, and the finding is conditional on biomarker levels rather than a general finding that women progress faster after diagnosis; the reported sex difference was most pronounced among participants with MCI. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSex is an important factor that contributes to clinical and biological heterogeneity in Alzheimer's disease.
“Sex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer’s disease (AD)”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [3]
It is reasonable to expect that further sex differences will be found in digital biomarkers for Alzheimer's disease and other clinical conditions, given significant sex differences in neurodegenerative, physiological and cognitive aspects during preclinical stages of AD.
“Considering that several studies have shown that there are significant sex differences on neurodegenerative, physiological and cognitive aspects during the preclinical stages of AD45, it is reasonable to expect that further sex differences will be found in the digital biomarkers for this and other clinical conditions.”
From Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare (2020) · cites this paper as [45]
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Cites
Desikan, R. S., Ségonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker, D., Buckner, R. L., Dale, A. M., Maguire, R. P., Hyman, B. T., et al. (2006) · NeuroImage · doi:10.1016/j.neuroimage.2006.01.021 · Cited by 13,324 · see citing works
Cortical Surface-Based Analysis
Dale, A. M., Fischl, B., & Sereno, M. I. (1999) · NeuroImage · doi:10.1006/nimg.1998.0395 · Cited by 10,910 · see citing works
Cortical Surface-Based Analysis
Fischl, B., Sereno, M. I., & Dale, A. M. (1999) · NeuroImage · doi:10.1006/nimg.1998.0396 · Cited by 6,147 · see citing works
The Alzheimer’s disease neuroimaging initiative (ADNI): MRI methods
Jack, C. R., Bernstein, M. A., Fox, N. C., Thompson, P., Alexander, G., Harvey, D., Borowski, B., Britson, P. J., L. Whitwell, J., Ward, C., et al. (2008) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.21049 · Cited by 4,347 · see citing works
Measurement of Functional Activities in Older Adults in the Community
PFEFFER, R. I., Kurosaki, T., Harrah, C. H., Chance, J. M., & Filos, S. (1982) · Journal of Gerontology · doi:10.1093/geronj/37.3.323 · Cited by 2,978 · see citing works
Alzheimer disease in the United States (2010–2050) estimated using the 2010 census
Hebert, L. E., Weuve, J., Scherr, P. A., & Evans, D. A. (2013) · Neurology · doi:10.1212/wnl.0b013e31828726f5 · Cited by 2,642 · see citing works
Within-subject template estimation for unbiased longitudinal image analysis
Reuter, M., Schmansky, N. J., Rosas, H. D., & Fischl, B. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.02.084 · Cited by 2,356 · see citing works
Rates and risk factors for dementia and Alzheimer’s disease: Results from EURODEM pooled analyses
Launer, L. J., Andersen, K., Dewey, M. E., Letenneur, L., Ott, A., Amaducci, L. A., Brayne, C., Copeland, J. R. M., Dartigues, J.-F., Kragh-Sorensen, P., et al. (1999) · Neurology · doi:10.1212/wnl.52.1.78 · Cited by 758 · see citing works
Episodic memory loss is related to hippocampal-mediated -amyloid deposition in elderly subjects
Mormino, E. C., Kluth, J. T., Madison, C. M., Rabinovici, G. D., Baker, S. L., Miller, B. L., Koeppe, R. A., Mathis, C. A., Weiner, M. W., Jagust, W. J., et al. (2009) · Brain · doi:10.1093/brain/awn320 · Cited by 684 · see citing works
Sex Differences in the Clinical Manifestations of Alzheimer Disease Pathology
Barnes, L. L., Wilson, R. S., Bienias, J. L., Schneider, J. A., Evans, D. A., & Bennett, D. A. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.685 · Cited by 643 · see citing works
Initiative, A. D. N., Crane, P. K., Carle, A. C., Gibbons, L. E., Insel, P. S., Mackin, R. S., Gross, A. L., Jones, R. N., Mukherjee, S., Curtis, S. M., et al. (2012) · Brain Imaging and Behavior · doi:10.1007/s11682-012-9186-z · Cited by 615 · see citing works
Initiative, A. D. N., Gibbons, L. E., Carle, A. C., Mackin, R. S., Harvey, D. J., Mukherjee, S., Insel, P. S., Curtis, S. M., Mungas, D., & Crane, P. K. (2012) · Brain Imaging and Behavior · doi:10.1007/s11682-012-9176-1 · Cited by 495 · see citing works
Estradiol and cognitive function: Past, present and future
Luine, V. N. (2014) · Hormones and Behavior · doi:10.1016/j.yhbeh.2014.08.011 · Cited by 457 · see citing works
Relationships between biomarkers in aging and dementia
Jagust, W. J., Landau, S. M., Shaw, L. M., Trojanowski, J. Q., Koeppe, R. A., Reiman, E. M., Foster, N. L., Petersen, R. C., Weiner, M. W., Price, J. C., et al. (2009) · Neurology · doi:10.1212/wnl.0b013e3181bc010c · Cited by 456 · see citing works
Marked gender differences in progression of mild cognitive impairment over 8 years
Lin, K. A., Choudhury, K. R., Rathakrishnan, B. G., Marks, D. M., Petrella, J. R., Doraiswamy, P. M., & Initiative, A. D. N. (2015) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2015.07.001 · Cited by 396 · see citing works
Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI
Initiative, T. A. D. N., Shaw, L. M. J., Vanderstichele, H., Knapik-Czajka, M. E., Figurski, M., Coart, E., Blennow, K., Soares, H. D., Simon, A. J., Lewczuk, P., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0808-0 · Cited by 297 · see citing works
3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer's disease
Apostolova, L. G., Dinov, I. D., Dutton, R. A., Hayashi, K. M., Toga, A. W., Cummings, J. L., & Thompson, P. M. (2006) · Brain · doi:10.1093/brain/awl274 · Cited by 252 · see citing works
Tschanz, J. T., Corcoran, C. D., Schwartz, S., Treiber, K., Green, R. C., Norton, M. C., Mielke, M. M., Piercy, K., Steinberg, M., Rabins, P. V., et al. (2011) · The American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e3181faec23 · Cited by 244 · cited 2× · see citing works
“males with AD appear to show more rapid cognitive decline than males with AD (Tschanz et al. 2011), likely driven by the tighter coupling of cognition and neuropathology previously highlighted.”
BackgroundSex and age differences in atrophic rates: an ADNI study with n=1368 MRI scans
Hua, X., Hibar, D. P., Lee, S., Toga, A. W., Jack, C. R., Weiner, M. W., & Thompson, P. M. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.04.033 · Cited by 234 · see citing works
Nilsen, J., Chen, S., Irwin, R. W., Iwamoto, S. J., & Brinton, R. D. (2006) · BMC Neuroscience · doi:10.1186/1471-2202-7-74 · Cited by 175 · see citing works
Cognitive deficits of men and women with Alzheimer's disease
Henderson, V. W., & Buckwalter, J. G. (1994) · Neurology · doi:10.1212/wnl.44.1.90 · Cited by 170 · see citing works
Estradiol Prevents Neural Tau Hyperphosphorylation Characteristic of Alzheimer's Disease
Rodríguez, M. Á. D. L. R., Silva, I., Nilsen, J., Pérez, M., García‐Segura, L. M., Ávila, J., & Naftolin, F. N. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1347.016 · Cited by 153 · see citing works
<i>APOE</i>-by-sex interactions on brain structure and metabolism in healthy elderly controls
Sampedro, F., Initiative, F. T. A. D. N., Vilaplana, E., de Leon, M. J., Alcolea, D., Pegueroles, J., Montal, V., Carmona-Iragui, M., Sala, I., Sánchez-Saudinos, M.-B., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5185 · Cited by 135 · see citing works
Self-citationFarrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · cited 1× · see citing works
“Previous work has also demonstrated that the APOE ε4 risk allele has a more potent effect in females than in males (Farrer et al. 1997).”
BackgroundAnastasio, T. J. (2013) · Frontiers in Pharmacology · doi:10.3389/fphar.2013.00016 · Cited by 49 · see citing works
Alzheimer's & Dementia: Translational Research & Clinical Interventions
(2020) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/(issn)2352-8737 · Cited by 12 · see citing works
High-resolution intersubject averaging and a coordinate system for the cortical surface
Fischl, B., Sereno, M. I., Tootell, R. B. H., & Dale, A. M. (1999) · Human Brain Mapping · doi:10.1002/(sici)1097-0193(1999)8:4
Flagged first, then by citations
Cited by
Sorted by citations
Nichols, E., Steinmetz, J. D., Vollset, S. E., Fukutaki, K., Chalek, J., Abd-Allah, F., Abdoli, A., Abualhasan, A., Abu-Gharbieh, E., Akram, T. T., et al. (2022) · The Lancet Public Health · doi:10.1016/s2468-2667(21)00249-8 · Cited by 5,575 · see citing works
2020 Alzheimer's disease facts and figures
(2020) · Alzheimer's & Dementia · doi:10.1002/alz.12068 · Cited by 2,353 · see citing works
Global estimates on the number of persons across the Alzheimer's disease continuum
Gustavsson, A., Norton, N., Fast, T., Frölich, L., Georges, J., Holzapfel, D., Kirabali, T., Krolak‐Salmon, P., Rossini, P. M., Ferretti, M. T., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12694 · Cited by 895 · see citing works
Understanding the impact of sex and gender in Alzheimer’s disease: A call to action
Nebel, R. A., Aggarwal, N. T., Barnes, L. L., Gallagher, A., Goldstein, J. M., Kantarci, K., Mallampalli, M. P., Mormino, E. C., Scott, L., Yu, W. H., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.04.008 · Cited by 839 · see citing works
Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare
Cirillo, D., Catuara-Solarz, S., Morey, C., Guney, E., Subirats, L., Mellino, S., Gigante, A., Valencia, A., Rementeria, M. J., Chadha, A. S., et al. (2020) · npj Digital Medicine · doi:10.1038/s41746-020-0288-5 · Cited by 553 · see citing works
Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau
Hohman, T. J., Dumitrescu, L., Barnes, L. L., Thambisetty, M., Beecham, G., Kunkle, B., Gifford, K. A., Bush, W. S., Chibnik, L. B., Mukherjee, S., et al. (2018) · JAMA Neurology · doi:10.1001/jamaneurol.2018.0821 · Cited by 340 · see citing works
Self-citationSex and gender differences in cognitive resilience to aging and Alzheimer's disease
Arenaza‐Urquijo, E. M., Boyle, R., Casaletto, K., Anstey, K. J., Vila‐Castelar, C., Colverson, A., Palpatzis, E., Eissman, J. M., Kheng Siang Ng, T., Raghavan, S., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13844 · Cited by 223 · see citing works
Self-citationGene-environment interactions in Alzheimer's disease: A potential path to precision medicine
Eid, A., Mhatre, I., & Richardson, J. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.03.005 · Cited by 164 · see citing works
Sayed, F. A., Kodama, L., Fan, L., Carling, G. K., Udeochu, J. C., Le, D., Li, Q., Zhou, L., Wong, M. Y., Horowitz, R., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe3947 · Cited by 155 · see citing works
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
“cognitive decline in women, increased susceptibility to neuropathology such that each unit increase of AD pathology confers a 22-fold increase in risk for AD in women compared to a 3-fold increase in males, as well as important differences in clinical and pathological disease presentation [262].”
BackgroundSex differences in the genetic predictors of Alzheimer’s pathology
Dumitrescu, L., Barnes, L. L., Thambisetty, M., Beecham, G., Kunkle, B., Bush, W. S., Gifford, K. A., Chibnik, L. B., Mukherjee, S., De Jager, P. L., et al. (2019) · Brain · doi:10.1093/brain/awz206 · Cited by 93 · see citing works
Udeh-Momoh, C., & Watermeyer, T. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101459 · Cited by 67 · see citing works
Sex-specific DNA methylation differences in Alzheimer’s disease pathology
Zhang, L., Young, J. I., Gomez, L., Silva, T. C., Schmidt, M. A., Cai, J., Chen, X., Martin, E. R., & Wang, L. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01177-8 · Cited by 58 · see citing works
Mayeda, E. R. (2019) · American Journal of Epidemiology · doi:10.1093/aje/kwz047 · Cited by 52 · see citing works
Sex differences in the genetic architecture of Alzheimer’s disease
Dumitrescu, L., Mayeda, E. R., Sharman, K., Moore, A. M., & Hohman, T. J. (2019) · Current Genetic Medicine Reports · doi:10.1007/s40142-019-0157-1 · Cited by 48 · see citing works
Self-citationHobel, Z., ageing, F. T. A. D. N. I. A. T. A. I. B. A. L. F. S. O., Isenberg, A. L., Raghupathy, D., Mack, W., & Pa, J. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-180859 · Cited by 40 · see citing works
The association between white matter hyperintensities and amyloid and tau deposition
Alban, S. L., Lynch, K. M., Ringman, J. M., Toga, A. W., Chui, H. C., Sepehrband, F., & Choupan, J. (2023) · NeuroImage: Clinical · doi:10.1016/j.nicl.2023.103383 · Cited by 35 · see citing works
Distinct sex-specific DNA methylation differences in Alzheimer’s disease
C. Silva, T., Zhang, W., Young, J. I., Gomez, L., Schmidt, M. A., Varma, A., Chen, X. S., Martin, E. R., & Wang, L. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01070-z · Cited by 33 · see citing works
Enhancing brain health in the global south through a sex and gender lens
Baez, S., Castro-Aldrete, L., Britton, G. B., Ibañez, A., & Santuccione-Chadha, A. (2024) · Nature Mental Health · doi:10.1038/s44220-024-00339-6 · Cited by 15 · see citing works
Oh, D. J., Bae, J. B., Lipnicki, D. M., Han, J. W., Sachdev, P. S., Kim, T. H., Kwak, K. P., Kim, B. J., Kim, S. G., Kim, J. L., et al. (2023) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13561 · Cited by 8 · see citing works
- Authors
- Initiative, F. T. A. N., Koran, M. E. I., Wagener, M., & Hohman, T. J.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Hohman, Timothy J.
- Venue
- Brain Imaging and Behavior
- Published
- 2016-02-03
- Volume
- 11
- Issue
- 1
- Pages
- 205-213
- ISSN
- 1931-7557 (ISSN-L)
- 1931-7565
- PMC
- PMC4972701
- OpenAlex
- W2270987730
- Cited by
- 339
- References
- 27
- Citations by year
- 2026: 33 · 2025: 50 · 2024: 36 · 2023: 49 · 2022: 53 · 2021: 43 · 2020: 28 · 2019: 19 · 2018: 16 · 2017: 5 · 2016: 6
- FWCI
- 13.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Imaging and Behavior (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (K12 HD043483)
- National Institute of General Medical Sciences (T32 GM07347)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- sex differences, Alzheimer's disease, cerebrospinal fluid biomarkers, amyloid-beta 42, total tau, cognitive decline, hippocampal atrophy, mild cognitive impairment, executive function, memory decline, APOE ε4, brain aging, women
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Atrophy, Brain, Cross-Sectional Studies, Female, Humans, Longitudinal Studies, Male, Middle Aged, Peptide Fragments, Regression Analysis, Sex Characteristics, Biomarkers, Amyloid beta-Peptides, tau Proteins, Apolipoprotein E4, Cognitive Dysfunction
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