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. 2019 May 1;76(5):542-551.
doi: 10.1001/jamaneurol.2018.4693.

Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults

Rachel F Buckley  1   2   3   4 , Elizabeth C Mormino  5 , Jennifer S Rabin  6 , Timothy J Hohman  7 , Susan Landau  8 , Bernard J Hanseeuw  1   9 , Heidi I L Jacobs  10   11 , Kathryn V Papp  1   2 , Rebecca E Amariglio  1   2 , Michael J Properzi  1 , Aaron P Schultz  1   2 , Dylan Kirn  1   2 , Matthew R Scott  1 , Trey Hedden  12 , Michelle Farrell  1 , Julie Price  12 , Jasmeer Chhatwal  1   2 , Dorene M Rentz  1   2 , Victor L Villemagne  13 , Keith A Johnson  1   2   11 , Reisa A Sperling  1   2
Affiliations

Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults

Rachel F Buckley et al. JAMA Neurol. .

Abstract

Importance: Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.

Objective: To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET).

Design, setting and participants: This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET.

Main outcomes and measures: A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined.

Results: The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = -0.11 [0.05]; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = -0.15 [0.09]; 95% CI, -0.32 to 0.01; P = .07).

Conclusions and relevance: Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Buckley is funded with the National Health and Medical Research Council Dementia Research Fellowship (APP1105576). Dr Mormino reports grants from the National Institutes of Health during the conduct of the study and personal fees from Eli Lilly and Biogen outside the submitted work. Dr Rabin is funded by the Canadian Institutes of Health Research Postdoctoral Fellowship. Dr Hohman is funded by the National Institutes of Health/National Institute on Aging (K01 AG049164). Dr Landau reports grants from the National Institutes of Health during the conduct of the study and personal fees from Cortexyme outside the submitted work. Dr Hanseeuw reports grants from the Belgian National Fund for Scientific Research, Belgian Foundation for Scientific Research (FNRS grant SPD28094292), and the Belgian Foundation for Alzheimer Research (SAO-FRA grant P16.008) during the conduct of the study and nonfinancial support from GE Healthcare outside the submitted work. Dr Jacobs received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant agreement (IF-2015-GF, 706714). Dr Papp has been a paid consultant for Biogen. Dr Schultz has been a paid consultant for Janssen Pharmaceuticals and Biogen. Dr Hedden reports grants from the National Institutes of Health during the conduct of the study and outside the submitted work. Dr Chhatwal is funded by the National Institutes of Health (K23 AG049087). Dr Rentz served as a consultant for Eli Lilly, Biogen, and Lundbeck Pharmaceuticals and serves as a member of the scientific advisory board for Neurotrack. Dr Johnson has served as a paid consultant for Bayer, GE Healthcare, Janssen Alzheimer Immunotherapy, Siemens Medical Solutions, Sanofi Genzyme, Novartis, Biogen, Roche, ISIS Pharma (now Ionis Pharmaceuticals Inc), AZTherapies, Lundberg, and AbbVie; is a site coinvestigator for Eli Lilly/Avid Radiopharmaceuticals, Pfizer, Janssen Immunotherapy, and Navidea; has spoken at symposia sponsored by Janssen Alzheimer Immunotherapy and Pfizer; and receives funding from the National Institutes of Health (grants R01EB014894, R21 AG038994, R01 AG026484, R01 AG034556, P50 AG00513421, U19 AG10483, P01 AG036694, R13 AG042201174210, R01 AG027435, and R01 AG037497) and the Alzheimer’s Association (grant ZEN-10-174210). Dr Sperling has served as a paid consultant for AbbVie, Biogen, Bracket, Genentech, Lundbeck, Roche, and Sanofi; has served as a coinvestigator for Avid Radiopharmaceuticals, Eli Lilly, and Janssen Alzheimer Immunotherapy clinical trials; has spoken at symposia sponsored by Eli Lilly, Biogen, and Janssen Pharmaceuticals; receives research support from Janssen Pharmaceuticals and Eli Lilly (these relationships are not related to the content in the manuscript); and also receives research support from the following grants: P01 AG036694, U01 AG032438, U01 AG024904, R01 AG037497, R01 AG034556, K24 AG035007, P50 AG005134, U19 AG010483, R01 AG027435, Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer’s Association.

Figures

Figure 1.
Figure 1.. Sex Differences in the Association Between Regional Temporal Tau and Global β-Amyloid in Clinically Normal Older Adults
DVR indicates distribution volume ratio; EC, entorhinal cortex; PVC, partial volume corrected; ROI, region of interest; SUVr, standard uptake value ratio.
Figure 2.
Figure 2.. Sex–Apolipoprotein E (APOE) Differences in Regional Tau in Clinically Normal Older Adults
EC indicates entorhinal cortex; IT, inferior temporal cortex; PVC, partial volume corrected.
Figure 3.
Figure 3.. Exemplification of the Magnitude of the Sex × Aβ Differences in Regional Tau in Clinically Normal Adults Represented by the Predicted Male:Female Ratio of Standard Uptake Value Ratio (SUVR) at a Given Level of β-Amyloid
The y-axis represents the predicted ratio of tau–positron emission tomography (PET) SUVr between women and men given a level of β-amyloid burden. Orange indicates the percentage male:female ratio for EC tau SUVR, and blue indicates the percentage male:female ratio for IT tau SUVR. Error bands represent an uncertainty parameter, which was calculated from the following estimates from the model: ([the upper 95% CI bound for men − the lower 95% CI bound for women] / the regional tau PET SUVR for men) × 100. P values represent a floodlight analysis of the point at which the association between β-amyloid and tau PET diverge between the sexes. ADNI, indicates Alzheimer’s Disease Neuroimaging Initiative; DVR, distribution volume ratio; HABS, Harvard Aging Brain Study; ns, not significant.
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