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) epsilon 4 status and beta-amyloid (A beta). 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 A beta 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 A beta 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 F-18 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 A beta as well as sex and APOE epsilon 4 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 epsilon 4 carriers [31%]; 89 individuals [30%] with high A beta. 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: beta [male] = -0.11 [0.05]; 95% CI,-0.21 to -0.02; P=.02), which was associated with individuals with higher AB burden. A sex by APOE epsilon 4 interaction was not associated with regional tau (meta-analytic estimate: beta [male, APOE epsilon 4+] = -0.15 [0.09]; 95% Cl, -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.
| Original language | English |
|---|---|
| Pages (from-to) | 542-551 |
| Number of pages | 10 |
| Journal | JAMA Neurology |
| Volume | 76 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 2019 |
Keywords
- APOLIPOPROTEIN-E GENOTYPE
- ALZHEIMER-DISEASE
- APOE EPSILON-4
- GENDER-DIFFERENCES
- COGNITIVE DECLINE
- PRECURSOR PROTEIN
- RISK-FACTORS
- BETA
- DEMENTIA
- PET
Access to Document
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: JAMA Neurology, Vol. 76, No. 5, 05.2019, p. 542-551.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults
AU - Buckley, Rachel F.
AU - Mormino, Elizabeth C.
AU - Rabin, Jennifer S.
AU - Hohman, Timothy J.
AU - Landau, Susan
AU - Hanseeuw, Bernard J.
AU - Jacobs, Heidi I. L.
AU - Papp, Kathryn V.
AU - Amariglio, Rebecca E.
AU - Properzi, Michael J.
AU - Schultz, Aaron P.
AU - Kirn, Dylan
AU - Scott, Matthew R.
AU - Hedden, Trey
AU - Farrell, Michelle
AU - Price, Julie
AU - Chhatwal, Jasmeer
AU - Rentz, Dorene M.
AU - Villemagne, Victor L.
AU - Johnson, Keith A.
AU - Sperling, Reisa A.
N1 - Funding Information: preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). The ADNI was launched in 2003 as a public-private partnership, led by principal investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging, positron emission tomography, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment and early Alzheimer disease. For up-to-date information, see www.adni-info.org. This work was supported with funding from the National Institutes of Health (grants P01 AG036694 [Drs Sperling and Johnson], R01 AG053509 [Dr Hedden], P50 AG005134 [Drs Sperling, Johnson, and Hedden], K23 AG049087 [Dr Chhatwal], and K24 AG035007 [Dr Sperling]). This research was carried out in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies (grant P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health). This work also involved the use of instrumentation supported by the National Institutes of Health Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program (grants S10RR021110, S10RR023401, and S10RR023043). For ADNI, data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (National Institutes of Health grant U01 AG024904) and US Department of Defense ADNI (award W81XWH-12-2-0012). The Alzheimer’s Disease Neuroimaging Initiative is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from AbbVie; Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica Inc; Biogen; Bristol-Myers Squibb; CereSpir Inc; Cogstate; Eisai Inc; Elan Pharmaceuticals Inc; Eli Lilly; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Lumosity; Lundbeck; Merck & Co; Meso Scale Diagnostics; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals; Pfizer; Piramal Imaging; Servier; Takeda Pharmaceutical; and Transition Therapeutics. The Canadian Institutes of 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 (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. Alzheimer’s Disease Neuroimaging Initiative data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: 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. Publisher Copyright: © 2019 American Medical Association. All rights reserved.
PY - 2019/5
Y1 - 2019/5
N2 - 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) epsilon 4 status and beta-amyloid (A beta). 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 A beta 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 A beta 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 F-18 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 A beta as well as sex and APOE epsilon 4 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 epsilon 4 carriers [31%]; 89 individuals [30%] with high A beta. 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: beta [male] = -0.11 [0.05]; 95% CI,-0.21 to -0.02; P=.02), which was associated with individuals with higher AB burden. A sex by APOE epsilon 4 interaction was not associated with regional tau (meta-analytic estimate: beta [male, APOE epsilon 4+] = -0.15 [0.09]; 95% Cl, -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.
AB - 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) epsilon 4 status and beta-amyloid (A beta). 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 A beta 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 A beta 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 F-18 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 A beta as well as sex and APOE epsilon 4 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 epsilon 4 carriers [31%]; 89 individuals [30%] with high A beta. 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: beta [male] = -0.11 [0.05]; 95% CI,-0.21 to -0.02; P=.02), which was associated with individuals with higher AB burden. A sex by APOE epsilon 4 interaction was not associated with regional tau (meta-analytic estimate: beta [male, APOE epsilon 4+] = -0.15 [0.09]; 95% Cl, -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.
KW - APOLIPOPROTEIN-E GENOTYPE
KW - ALZHEIMER-DISEASE
KW - APOE EPSILON-4
KW - GENDER-DIFFERENCES
KW - COGNITIVE DECLINE
KW - PRECURSOR PROTEIN
KW - RISK-FACTORS
KW - BETA
KW - DEMENTIA
KW - PET
U2 - 10.1001/jamaneurol.2018.4693
DO - 10.1001/jamaneurol.2018.4693
M3 - Article
C2 - 30715078
SN - 2168-6149
VL - 76
SP - 542
EP - 551
JO - JAMA Neurology
JF - JAMA Neurology
IS - 5
ER -