Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau
Open accessAbstract
Importance: The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner. Objective: To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. Design, Setting, and Participants: This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017. Main Outcomes and Measures: Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer's Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles. Results: Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55; P < .001) and phosphorylated tau (β = 0.24; 95% CI, 0.09-0.38; P = .001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (β = 0.41; 95% CI, 0.20-0.62; P < .001) but not among amyloid-negative individuals (β = 0.06; 95% CI, -0.18 to 0.31; P = .62). We did not observe sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden. Conclusions and Relevance: We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In clinically normal older adults and individuals with mild cognitive impairment, higher cerebrospinal fluid tau levels have been observed in female APOE ε4 carriers compared with male carriers.
“In clinically normal older adults9,10 and individuals with mild cognitive impairment,11 higher cerebrospinal fluid (CSF) tau levels have been observed in female apolipoprotein E (APOE) ε4 carriers compared with male carriers.”
From Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults (2019) · cites this paper as [10]
The Results (Sex × APOE Interactions) report a stronger association between APOE ε4 and CSF tau in females than in males. The Materials and Methods say an included cohort contained people with mild cognitive impairment, but the reported result is pooled rather than specific to that group. Post hoc Results also indicate that the sex difference was observed in amyloid-positive, not amyloid-negative, individuals. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe APOE-e4 genotype may have a stronger association with Alzheimer's dementia and neurodegeneration in women than in men.
“the APOE-e4 genotype, the best known common genetic risk factor for Alzheimer's dementia, may have a stronger association with Alzheimer's dementia 285,286 and neurodegeneration 287 in women than in men.”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [287]
Sex differences may be more likely to appear downstream after the onset of Aβ accumulation.
“supporting the notion that sex differences may be more likely to appear downstream after the onset of Aβ accumulation.5,10”
From Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults (2019) · cites this paper as [10]
Female APOE ε4 carriers with abnormal levels of CSF Aβ also exhibit higher CSF tau than male carriers.
“Female APOE ε4 carriers with abnormal levels of CSF Aβ also exhibit higher CSF tau than male carriers.10”
From Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults (2019) · cites this paper as [10]
Few if any previous studies that investigated the association of sex with AD pathologies have examined menopausal factors.
“Few if any of the previous studies which investigated the association of sex with AD pathologies have examined menopausal factors [25,41,43,53].”
From Sex differences in Alzheimer’s disease and common neuropathologies of aging (2018) · cites this paper as [25]
The Introduction describes prior research on sex differences in APOE-associated Alzheimer’s pathology, and the Discussion proposes hormonal changes around menopause as a possible mechanism. Neither passage says whether few, if any, previous studies examined menopausal factors. Searches for menopausal status and hormone measures did not establish that claim. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Several additional loci, including APOE, have been identified as exhibiting sex-specific association with AD endophenotypes.
“Several additional loci, including APOE [264], have been identified as exhibiting sex-specific association with AD endophenotypes”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [264]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · cited 2× · see citing works
“Tau positive 38 (43) 51 (31) 4 (8) 14 (14) 217 (33) 224 (41) 33 (31) 21 (41)”
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Self-citationMirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961 · see citing works
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · see citing works
Naj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · see citing works
Self-citationCSF markers for incipient Alzheimer's disease
Blennow, K., & Hampel, H. (2003) · The Lancet Neurology · doi:10.1016/s1474-4422(03)00530-1 · Cited by 1,291 · see citing works
Self-citationApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220 · see citing works
Sex modifies the <i>APOE</i> ‐related risk of developing Alzheimer disease
Altmann, A., Tian, L., Henderson, V. W., Greicius, M. D., & Alzheimer's Disease Neuroimaging Initiative Investigators (2014) · Annals of Neurology · doi:10.1002/ana.24135 · Cited by 891 · see citing works
Overview and Findings from the Rush Memory and Aging Project
Bennett, D. A., Schneider, J. A., Buchman, A. S., Barnes, L. L., Boyle, P. A., & Wilson, R. S. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322663 · Cited by 837 · see citing works
Self-citation<i>APOE</i> predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., & Mintun, M. A. (2010) · Annals of Neurology · doi:10.1002/ana.21843 · Cited by 830 · see citing works
Dementia and Alzheimer Disease Incidence: A Prospective Cohort Study
Kukull, W. A., Higdon, R., Bowen, J. D., McCormick, W. C., Teri, L., Schellenberg, G. D., van Belle, G., Jolley, L., & Larson, E. B. (2002) · Archives of Neurology · doi:10.1001/archneur.59.11.1737 · Cited by 806 · see citing works
Self-citationReiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., Langbaum, J. B. S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900345106 · Cited by 785 · see citing works
Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis
Neu, S. C., Pa, J., Kukull, W., Beekly, D., Kuzma, A., Gangadharan, P., Wang, L.-S., Romero, K., Arneric, S. P., Redolfi, A., et al. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2017.2188 · Cited by 674 · see citing works
Self-citationOverview and Findings from the Religious Orders Study
Bennett, D. A., Schneider, J. A., Arvanitakis, Z., & Wilson, R. S. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322573 · Cited by 647 · see citing works
Self-citationEstrogen reduces neuronal generation of Alzheimer β-amyloid peptides
Xu, H., Gouras, G. K., Greenfield, J. P., Vincent, B., Näslund, J., Mazzarelli, L., Fried, G., Jovanovic, J. N., Seeger, M., Relkin, N. R., et al. (1998) · Nature Medicine · doi:10.1038/nm0498-447 · Cited by 557 · see citing works
Verghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., & Holtzman, D. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220484110 · Cited by 556 · see citing works
Gender and incidence of dementia in the Framingham Heart Study from mid‐adult life
Chêne, G., Beiser, A., Au, R., Preis, S. R., Wolf, P. A., Dufouil, C., & Seshadri, S. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.10.005 · Cited by 499 · 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
Age, Sex, andAPOEε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span
Jack, C. R., Wiste, H. J., Weigand, S. D., Knopman, D. S., Vemuri, P., Mielke, M. M., Lowe, V. J., Senjem, M. L., Gunter, J. L., Machulda, M. M., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.4821 · Cited by 382 · see citing works
The Wisconsin Registry for Alzheimer's Prevention: A review of findings and current directions
Johnson, S., Koscik, R., Jonaitis, E., Clark, L. R., Mueller, K., Berman, S. E., Bendlin, B., Engelman, C., Okonkwo, O., Hogan, K., et al. (2017) · bioRxiv · doi:10.1016/j.dadm.2017.11.007 · Cited by 350 · see citing works
Self-citationBeecham, G. W., Hamilton, K., Naj, A. C., Martin, E. R., Huentelman, M., Myers, A. J., Corneveaux, J. J., Hardy, J., Vonsattel, J.-P., Younkin, S. G., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004606 · Cited by 343 · see citing works
Self-citationSex differences in the association between AD biomarkers and cognitive decline
Initiative, F. T. A. N., Koran, M. E. I., Wagener, M., & Hohman, T. J. (2017) · Brain Imaging and Behavior · doi:10.1007/s11682-016-9523-8 · Cited by 339 · see citing works
Self-citationJack, C. R., Wiste, H. J., Weigand, S. D., Therneau, T. M., Knopman, D. S., Lowe, V., Vemuri, P., Mielke, M. M., Roberts, R. O., Machulda, M. M., et al. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30077-7 · Cited by 333 · see citing works
Damoiseaux, J. S., Seeley, W. W., Zhou, J., Shirer, W. R., Coppola, G., Karydas, A., Rosen, H. J., Miller, B. L., Kramer, J. H., Greicius, M. D., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0305-12.2012 · Cited by 267 · see citing works
Self-citationSex, Apolipoprotein E ε4 Status, and Hippocampal Volume in Mild Cognitive Impairment
Fleisher, A. (2005) · Archives of Neurology · doi:10.1001/archneur.62.6.953 · Cited by 256 · see citing works
CORDER, E. H., GHEBREMEDHIN, E., TAYLOR, M. G., THAL, D. R., OHM, T. G., & BRAAK, H. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1297.005 · Cited by 254 · see citing works
Assessment of the genetic variance of late-onset Alzheimer's disease
Ridge, P. G., Hoyt, K. B., Boehme, K., Mukherjee, S., Crane, P. K., Haines, J. L., Mayeux, R., Farrer, L. A., Pericak-Vance, M. A., Schellenberg, G. D., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.02.024 · Cited by 236 · see citing works
Self-citationEstradiol protects against β-amyloid (25–35)-induced toxicity in SK-N-SH human neuroblastoma cells
Green, P. S., Gridley, K. E., & Simpkins, J. W. (1996) · Neuroscience Letters · doi:10.1016/s0304-3940(96)13148-7 · Cited by 234 · see citing works
Srivastava, R. A. K., Srivastava, N., Averna, M. R., Lin, R. C., Korach, K. S., Lubahn, D. B., & Schonfeld, G. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.52.33360 · Cited by 187 · see citing works
The ARIC-PET amyloid imaging study
Gottesman, R. F., Schneider, A. L. C., Zhou, Y., Chen, X., Green, E., Gupta, N., Knopman, D. S., Mintz, A., Rahmim, A., Sharrett, A. R., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002914 · Cited by 172 · see citing works
APOE genotype and MRI markers of cerebrovascular disease
Schilling, S., DeStefano, A. L., Sachdev, P. S., Choi, S. H., Mather, K. A., DeCarli, C. S., Wen, W. X., Høgh, P., Raz, N., Au, R., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e31829bfda4 · Cited by 171 · see citing works
Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging
Jagust, W. J., Landau, S. M., & Initiative, F. T. A. D. N. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.3266-12.2012 · Cited by 162 · see citing works
Self-citationAlbert, M., Soldan, A., Gottesman, R. F., McKhann, G. M., Sacktor, N. C., Farrington, L., Grega, M. A., Turner, R. S., Lu, Y., Li, S., et al. (2014) · Current Alzheimer Research · doi:10.2174/156720501108140910121920 · Cited by 160 · see citing works
Self-citationEstradiol 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
Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects
Toledo, J. B., Zetterberg, H., van Harten, A. C., Glodzik, L., Martinez-Lage, P., Bocchio-Chiavetto, L., Rami, L., Hansson, O., Sperling, R., Engelborghs, S., et al. (2015) · Brain · doi:10.1093/brain/awv199 · Cited by 136 · see citing works
Self-citationAssociation of APOE with tau-tangle pathology with and without β-amyloid
Farfel, J. M., Yu, L., Jager, P. L. D., Schneider, J. A., & Bennett, D. A. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.09.011 · Cited by 135 · see citing works
Self-citation<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 · see citing works
Zhao, L., Yao, J., Mao, Z., Chen, S., Wang, Y., & Brinton, R. D. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.12.010 · Cited by 124 · see citing works
Differential effect of <i>APOE</i> genotype on amyloid load and glucose metabolism in AD dementia
Ossenkoppele, R., van der Flier, W. M., Zwan, M. D., Adriaanse, S. F., Boellaard, R., Windhorst, A. D., Barkhof, F., Lammertsma, A. A., Scheltens, P., & van Berckel, B. N. M. (2013) · Neurology · doi:10.1212/wnl.0b013e31827f0889 · Cited by 112 · see citing works
Gender and age modify the association between APOE and AD-related neuropathology
Ghebremedhin, E., Schultz, C., Thal, D. R., Rüb, U., Ohm, T. G., Braak, E., & Braak, H. (2001) · Neurology · doi:10.1212/wnl.56.12.1696 · Cited by 108 · see citing works
CSF biomarker changes precede symptom onset of mild cognitive impairment
Moghekar, A., Li, S., Lu, Y., Li, M., Wang, M.-C., Albert, M., O’Brien, R., & For the BIOCARD Research Team (2013) · Neurology · doi:10.1212/01.wnl.0000435558.98447.17 · Cited by 103 · see citing works
Self-citationThe APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice
Cacciottolo, M., Christensen, A., Moser, V. A., Liu, J., Pike, C. J., Smith, C. C., LaDu, M. J., Sullivan, P. M., Morgan, T. E., Dolzhenko, E., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.10.010 · Cited by 94 · see citing works
Bendlin, B. B., Carlsson, C. M., Johnson, S. C., Zetterberg, H., Blennow, K., Willette, A. A., Okonkwo, O. C., Sodhi, A., Ries, M. L., Birdsill, A. C., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037720 · Cited by 91 · see citing works
Self-citationEstrogen receptor-α is localized to neurofibrillary tangles in Alzheimer’s disease
Wang, C., Zhang, F., Jiang, S., Siedlak, S. L., Shen, L. H., Perry, G. L., Wang, X., Tang, B., & Zhu, X. (2016) · Scientific Reports · doi:10.1038/srep20352 · Cited by 69 · see citing works
The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview
Jefferson, A. L., Gifford, K. A., Acosta, L. M. Y., Bell, S. P., Donahue, M. J., Davis, L. T., Gottlieb, J., Gupta, D. K., Hohman, T. J., Lane, E., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150914 · Cited by 67 · see citing works
Self-citationDubal, D. B., Broestl, L., & Worden, K. (2012) · Biology of Sex Differences · doi:10.1186/2042-6410-3-24 · Cited by 58 · see citing works
Li, G., Shofer, J. B., Petrie, E. C., Yu, C., Wilkinson, C. W., Figlewicz, D. P., Shutes‐David, A., Zhang, J., Montine, T. J., Raskind, M. A., et al. (2017) · Alzheimer s Research & Therapy · doi:10.1186/s13195-017-0271-9 · Cited by 53 · see citing works
Self-citationEquine estrogens induce apolipoprotein E and glial fibrillary acidic protein in mixed glial cultures
Rozovsky, I., Hoving, S., Anderson, C. P., et al. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)00146-5 · Cited by 35 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [48]Farrer LA, Cupples LA, Haines JL, Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA 1997; 278(16): 1349– 1356. 9343467
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
2023 Alzheimer's disease facts and figures
(2023) · Alzheimer's & Dementia · doi:10.1002/alz.13016 · Cited by 3,212 · see citing works
2024 Alzheimer's disease facts and figures
(2024) · Alzheimer's & Dementia · doi:10.1002/alz.13809 · Cited by 2,536 · see citing works
2019 Alzheimer’s disease facts and figures.
Alzheimer's Association (2019) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.01.010 · Cited by 2,461 · 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
Sex and gender: modifiers of health, disease, and medicine
Mauvais-Jarvis, F., Bairey Merz, N., Barnes, P. J., Brinton, R. D., Carrero, J.-J., DeMeo, D. L., De Vries, G. J., Epperson, C. N., Govindan, R., Klein, S. L., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)31561-0 · Cited by 2,001 · see citing works
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward
Belloy, M. E., Napolioni, V., & Greicius, M. D. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.056 · Cited by 570 · see citing works
Buckley, R. F., Mormino, E. C., Rabin, J. S., Hohman, T. J., Landau, S., Hanseeuw, B. J., Jacobs, H. I. L., Papp, K. V., Amariglio, R. E., Properzi, M. J., et al. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2018.4693 · Cited by 373 · see citing works
Self-citationSex differences in Alzheimer’s disease and common neuropathologies of aging
Oveisgharan, S., Arvanitakis, Z., Yu, L., Farfel, J., Schneider, J. A., & Bennett, D. A. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1920-1 · Cited by 330 · see citing works
Self-citationFernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277 · see citing works
Sex 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-citationMielke, M. M., Aggarwal, N. T., Vila‐Castelar, C., Agarwal, P., Arenaza‐Urquijo, E. M., Brett, B., Brugulat‐Serrat, A., DuBose, L. E., Eikelboom, W. S., Flatt, J., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12662 · Cited by 198 · see citing works
Veitch, D. P., Weiner, M. W., Aisen, P. S., Beckett, L. A., DeCarli, C., Green, R. C., Harvey, D., Jack, C. R., Jagust, W., Landau, S. M., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12422 · Cited by 184 · see citing works
Ossenkoppele, R., Lyoo, C. H., Jester-Broms, J., Sudre, C. H., Cho, H., Ryu, Y. H., Choi, J. Y., Smith, R., Strandberg, O., Palmqvist, S., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2019.5154 · Cited by 161 · 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
“Several additional loci, including APOE (Hohman et al., 2018), have been identified as exhibiting sexspecific association with AD endophenotypes, providing insight into biological mechanisms by which females may be at increased risk for AD (Dumitrescu et al.”
BackgroundSex-specific genetic predictors of Alzheimer’s disease biomarkers
(ADNI), A. D. N. I., Deming, Y., The Alzheimer Disease Genetics Consortium (ADGC), Dumitrescu, L., Barnes, L. L., Thambisetty, M., Kunkle, B., Gifford, K. A., Bush, W. S., Chibnik, L. B., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1881-4 · Cited by 110 · see citing works
Sex 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
Bejanin, A., Iulita, M. F., Vilaplana, E., Carmona-Iragui, M., Benejam, B., Videla, L., Barroeta, I., Fernandez, S., Altuna, M., Pegueroles, J., et al. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2021.1893 · Cited by 76 · see citing works
Self-citationAstrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation
Saroja, S. R., Gorbachev, K., Julia, T., Goate, A. M., & Pereira, A. C. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2108870119 · Cited by 75 · 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
Larramona-Arcas, R., González-Arias, C., Perea, G., Gutiérrez, A., Vitorica, J., García-Barrera, T., Gómez-Ariza, J. L., Pascua-Maestro, R., Ganfornina, M. D., Kara, E., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00382-8 · Cited by 56 · see citing works
Sex Difference in the Association of APOE4 with Memory Decline in Mild Cognitive Impairment
Wang, X., Zhou, W., Ye, T., Lin, X., Zhang, J., & Initiative, F. A. D. N. (2019) · Journal of Alzheimer’s Disease · doi:10.3233/jad-181234 · Cited by 51 · see citing works
Self-citationMayeda, 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 Role of Genetic, Environmental, and Dietary Factors in Alzheimer’s Disease: A Narrative Review
Mertaş, B., & Boşgelmez, İ. İ. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031222 · Cited by 35 · see citing works
Vergallo, A., Houot, M., Cavedo, E., Lemercier, P., Vanmechelen, E., De Vos, A., Habert, M., Potier, M., Dubois, B., Lista, S., et al. (2019) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.07.001 · Cited by 32 · see citing works
Azarpazhooh, M. R., Avan, A., Cipriano, L. E., Munoz, D. G., Erfanian, M., Amiri, A., Stranges, S., & Hachinski, V. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2019.101002 · Cited by 32 · see citing works
Nature and implications of sex differences in AD pathology
Babapour Mofrad, R., & van der Flier, W. M. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0115-7 · Cited by 24 · see citing works
- Authors
- 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., De Jager, P. L., Kukull, W., Crane, P. K., Resnick, S. M., Keene, C. D., Montine, T. J., Schellenberg, G. D., Haines, J. L., Zetterberg, H., Blennow, K., Larson, E. B., Johnson, S. C., Albert, M., Bennett, D. A., Schneider, J. A., Jefferson, A. L., & for the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative
- Affiliations
- Vanderbilt University Medical Center (US)
- Rush University Medical Center (US)
- National Institutes of Health (US)
- University of Miami (US)
- Case Western Reserve University (US)
- Brigham and Women's Hospital (US)
- University of Washington (US)
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York
- Stanford Medicine (US)
- University of Pennsylvania (US)
- Harvard University (US)
- Sahlgrenska University Hospital (SE)
- Kaiser Permanente Washington Health Research Institute (US)
- University of Wisconsin–Madison (US)
- Johns Hopkins University (US)
- Corresponding author
- Hohman, Timothy J.
- ORCID
- Hohman, Timothy J.
- Dumitrescu, Logan
- Barnes, Lisa L.
- Thambisetty, Madhav
- Beecham, Gary
- Kunkle, Brian
- Gifford, Katherine A.
- Bush, William S.
- Chibnik, Lori B.
- Mukherjee, Shubhabrata
- Kukull, Walter
- Crane, Paul K.
- Resnick, Susan M.
- Keene, C. Dirk
- Montine, Thomas J.
- Schellenberg, Gerard D.
- Haines, Jonathan L.
- Zetterberg, Henrik
- Blennow, Kaj
- Larson, Eric B.
- Johnson, Sterling C.
- Albert, Marilyn
- Bennett, David A.
- Schneider, Julie A.
- Jefferson, Angela L.
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-08-01
- Volume
- 75
- Issue
- 8
- Pages
- 989
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC6142927
- OpenAlex
- W2802157723
- Cited by
- 340
- References
- 49
- Citations by year
- 2026: 27 · 2025: 49 · 2024: 35 · 2023: 50 · 2022: 50 · 2021: 44 · 2020: 47 · 2019: 30 · 2018: 7
- FWCI
- 21.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- U.S. Department of Defense (U01 AG006781, U01 AG024904, P50 AG005138, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
- Foundation for the National Institutes of Health (P30AG010129, P30 AG010124, W81XWH-12-2-0012, U01AG024904, P50 AG005131, AG016573, AG010124, U24 AG021886, AG024904, P30 AG035982, K12 HD043483, U01 AG016976)
- Alzheimer's Association (P30 AG013854, P30AG010124, U01 HG004610, K24-AG046373, R01 AG027161, K12-HD043483, U24 AG041689, P50 AG023501, R01 AG17917, U01 AG016976, P50 AG025688, R01‐AG034962, P30AG10161, AG010129, U01 AG032984, K01 AG049164, P30AG035982, P50 AG005681, R01 AG30146, P30 AG010161, R01 AG15819, HHSN311201600276P, U01 AG024904, R01 AG037639, P30 AG010129, U01 AG006781, U24AG021886, P50 AG008702, R01-HL111516, U01 AG46152, P30 AG010133, P50 AG005136, RF1 AG15819, W81XWH-12-2-0012, U01 HG006375, R01 NS100980, P50 AG005146, R01 AG019085, R01 AG021155, R01 AG056534)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Eli Lilly and Company (P50 AG005134, U01 AG024904, AG024904, W81XWH-12-2-0012)
- Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
- Massachusetts General Hospital (P50 AG005134)
- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- University of Southern California (P50AG005142, R01 AG15819, W81XWH-12-2-0012, U01 AG006781, P30 AG10161, U01 AG024904)
- Vanderbilt University (R01 AG019085)
- University of Miami (R01 AG019085)
- Brigham Young University
- University of Pennsylvania (AG010124, P30 AG010124)
- Emory University (P50AG025688, AG025688, P50 AG016573)
- F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Northwestern University (P30 AG013854)
- Texas Tech University
- Vanderbilt Memory and Alzheimer's Center
- Cleveland Clinic
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01 AG032984, U01AG024904, AG024904, W81XWH-12-2-, P30 AG010129)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- University of Washington (P50-AG005136, P50 AG005681, P50 AG033514)
- Johns Hopkins University (P50-AG005146, AG005146, P50 AG016574)
- University of Pittsburgh (P50 AG005133, P30 AG010133)
- Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Rush University (P30 AG010161, R01 AG17917, AG17917, R01 AG15819, R01AG30146, R01 AG019085, AG30146)
- University of South Florida
- University of North Texas
- Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012, P30 AG010129)
- National Alzheimer's Coordinating Center (U01AG016976, P30 AG013846)
- York University
- Parkinson's UK (G-0907)
- University of Toronto
- Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
- H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
- IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
- National Institutes of Health (1s10od023680-01, AG028 383, 3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, UL1TR000445, HHSN311201600276P, AG016574, AG016573, AG016976, AG010124, AG023501, U01-AG024904, AG005138, AG005133, AG005131, AG008017, AG010129, AG008051, AG024904, AG005681, AG019610, RF1 AG15819, AG035982, AG10161, AG005134, AG027161, AG010161, AG013854, AG025688, AG013846, AG15819, AG037639, AG005136, AG033514, AG008702, UL1TR002243, UL1TR002369)
- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- University of California, Los Angeles (P50 AG016570)
- University of California, San Diego (P50-AG005131, P50 AG005133)
- Perelman School of Medicine, University of Pennsylvania
- Feinberg School of Medicine
- University of Texas Health Science Center at San Antonio
- University of California, Irvine (P50AG016573)
- Geriatric Research Education and Clinical Center
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012, P50 AG016574, P30 AG010129)
- National Institute on Aging (AG006781, U01-AG-024904, R01AG017917, AG-028383, R01AG056534, AG 016976, P30-AG 10161, AG-016570, P30AG010129, P30AG010133, R01AG019085, K25AG041906, AG-016573, K24AG046373, R01AG030146, W81XWH-12-2–0012, R01‐AG17917, AG021155, AG-010124, AG027161, P30AG028383, R01 AG15819, P30AG012300, AG-005133, AG-17917, AG008017, P50AG005133, AG 024904, U01AG006781, U01AG016976, P50AG005131, AG-013854, AG035982, P50AG005138, K23AG045966, P50AG016570, AG019610, AG010161, P30AG010124, P50AG016573, P50AG047366, AG010129, U19AG033655, R01AG037639, R01AG015819, P30AG008017, AG-033514, P30AG010161, K01AG049164, AG005131, AG019085, U01AG032984, P30AG008051, P50AG008702, P50AG033514, AG023501, P30AG035982, AG032984, AG013846, P50AG005681, P50AG005142, P30AG019610, P50AG005146, P30AG013846, P50AG005136, P50AG005134, P30AG013854, P50AG025688, RF1AG059869, AG‐037639, RF1AG015819, AG021886, AG005681, R01AG034962, R01AG021155, R01AG027161, U24AG041689, U24AG021886, P50AG023501, P50AG016574)
- National Heart, Lung, and Blood Institute (R01HL111516)
- National Human Genome Research Institute (U01HG004610, U01HG006375)
- National Institute of Neurological Disorders and Stroke (R01NS100980)
- National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
- NIH Clinical Center (U01 AG024904, AG025688)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD043483)
- Johnson and Johnson Pharmaceutical Research and Development (W81XWH-12-2-0012, U01 AG024904)
- Janssen Alzheimer Immunotherapy Research And Development (AG024904, U01 AG024904, W81XWH-12-2-0012)
- University of Colorado School of Medicine, Anschutz Medical Campus
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, sex differences, Alzheimer's disease, cerebrospinal fluid biomarkers, total tau, phosphorylated tau, amyloid-beta 42, neurofibrillary tangles, neuritic plaques, Braak staging, Alzheimer's disease staging, neuropathology, genetic risk factors, women's health
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Male, Peptide Fragments, Phosphoproteins, Sex Factors, Cohort Studies, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
