Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline

Rachel F. Buckley; Matthew R. Scott; Heidi I. L. Jacobs; Aaron P. Schultz; Michael J. Properzi; Rebecca E. Amariglio; Timothy J. Hohman; Danielle V. Mayblyum; Zoe B. Rubinstein; Lyssa Manning; Bernard J. Hanseeuw; Elizabeth C. Mormino; Dorene M. Rentz; Keith A. Johnson; Reisa A. Sperling

doi:10.1002/ana.25878

Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline

Rachel F. Buckley, Matthew R. Scott, Heidi I. L. Jacobs, Aaron P. Schultz, Michael J. Properzi, Rebecca E. Amariglio, Timothy J. Hohman, Danielle V. Mayblyum, Zoe B. Rubinstein, Lyssa Manning, Bernard J. Hanseeuw, Elizabeth C. Mormino, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Objective The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. Methods Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined(18)F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*A beta-PET positive / negative (+ / -) and sex*apolipoprotein epsilon 4 (APOE epsilon 4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. Results Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p<0.007). beta-amyloid (A beta)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p<0.007); A beta + women exhibited greater FTP-signal than other groups. APOE epsilon 4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p= 0.04). Interpretation Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and A beta were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020

Original language	English
Pages (from-to)	921-932
Number of pages	12
Journal	Annals of Neurology
Volume	88
Issue number	5
Early online date	31 Aug 2020
DOIs	https://doi.org/10.1002/ana.25878
Publication status	Published - Nov 2020

Keywords

ALZHEIMERS-DISEASE
APOE EPSILON-4
AMYLOID-BETA
PET
RISK

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10.1002/ana.25878

Cite this

Buckley, R. F., Scott, M. R., Jacobs, H. I. L., Schultz, A. P., Properzi, M. J., Amariglio, R. E., Hohman, T. J., Mayblyum, D. V., Rubinstein, Z. B., Manning, L., Hanseeuw, B. J., Mormino, E. C., Rentz, D. M., Johnson, K. A., & Sperling, R. A. (2020). Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline. Annals of Neurology, 88(5), 921-932. https://doi.org/10.1002/ana.25878

@article{f60dc35e5be841cfa6cee1f7a4b94ce0,

title = "Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline",

abstract = "Objective The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. Methods Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined(18)F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*A beta-PET positive / negative (+ / -) and sex*apolipoprotein epsilon 4 (APOE epsilon 4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. Results Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p<0.007). beta-amyloid (A beta)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p<0.007); A beta + women exhibited greater FTP-signal than other groups. APOE epsilon 4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p= 0.04). Interpretation Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and A beta were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020",

keywords = "ALZHEIMERS-DISEASE, APOE EPSILON-4, AMYLOID-BETA, PET, RISK",

author = "Buckley, {Rachel F.} and Scott, {Matthew R.} and Jacobs, {Heidi I. L.} and Schultz, {Aaron P.} and Properzi, {Michael J.} and Amariglio, {Rebecca E.} and Hohman, {Timothy J.} and Mayblyum, {Danielle V.} and Rubinstein, {Zoe B.} and Lyssa Manning and Hanseeuw, {Bernard J.} and Mormino, {Elizabeth C.} and Rentz, {Dorene M.} and Johnson, {Keith A.} and Sperling, {Reisa A.}",

note = "Funding Information: The Harvard Aging Brain Study is funded by the National Institute on Aging (P01AG036694) with additional support from several philanthropic organizations. The Alzheimer's Disease Neuroimaging Initiative is funded by the NIA (U19AG024904), the NIBIB, the Canadian IHR, and several philanthropic organizations. Several co‐authors{\textquoteright} contributions were also supported by career development awards: R.F.B. is supported by a K99/R00 award from NIA; H.I.L. is supported by a Marie‐Sklodowska‐Curie Global Fellowship within the European Union's Horizon 2020 Research and Innovation Programme; and T.J.H. is supported by a K01 award from NIA. Publisher Copyright: {\textcopyright} 2020 American Neurological Association",

year = "2020",

month = nov,

doi = "10.1002/ana.25878",

language = "English",

volume = "88",

pages = "921--932",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "Wiley",

number = "5",

}

Buckley, RF, Scott, MR, Jacobs, HIL, Schultz, AP, Properzi, MJ, Amariglio, RE, Hohman, TJ, Mayblyum, DV, Rubinstein, ZB, Manning, L, Hanseeuw, BJ, Mormino, EC, Rentz, DM, Johnson, KA & Sperling, RA 2020, 'Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline', Annals of Neurology, vol. 88, no. 5, pp. 921-932. https://doi.org/10.1002/ana.25878

TY - JOUR

T1 - Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline

AU - Buckley, Rachel F.

AU - Scott, Matthew R.

AU - Jacobs, Heidi I. L.

AU - Schultz, Aaron P.

AU - Properzi, Michael J.

AU - Amariglio, Rebecca E.

AU - Hohman, Timothy J.

AU - Mayblyum, Danielle V.

AU - Rubinstein, Zoe B.

AU - Manning, Lyssa

AU - Hanseeuw, Bernard J.

AU - Mormino, Elizabeth C.

AU - Rentz, Dorene M.

AU - Johnson, Keith A.

AU - Sperling, Reisa A.

N1 - Funding Information: The Harvard Aging Brain Study is funded by the National Institute on Aging (P01AG036694) with additional support from several philanthropic organizations. The Alzheimer's Disease Neuroimaging Initiative is funded by the NIA (U19AG024904), the NIBIB, the Canadian IHR, and several philanthropic organizations. Several co‐authors’ contributions were also supported by career development awards: R.F.B. is supported by a K99/R00 award from NIA; H.I.L. is supported by a Marie‐Sklodowska‐Curie Global Fellowship within the European Union's Horizon 2020 Research and Innovation Programme; and T.J.H. is supported by a K01 award from NIA. Publisher Copyright: © 2020 American Neurological Association

PY - 2020/11

Y1 - 2020/11

N2 - Objective The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. Methods Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined(18)F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*A beta-PET positive / negative (+ / -) and sex*apolipoprotein epsilon 4 (APOE epsilon 4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. Results Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p<0.007). beta-amyloid (A beta)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p<0.007); A beta + women exhibited greater FTP-signal than other groups. APOE epsilon 4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p= 0.04). Interpretation Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and A beta were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020

AB - Objective The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. Methods Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined(18)F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*A beta-PET positive / negative (+ / -) and sex*apolipoprotein epsilon 4 (APOE epsilon 4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. Results Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p<0.007). beta-amyloid (A beta)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p<0.007); A beta + women exhibited greater FTP-signal than other groups. APOE epsilon 4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p= 0.04). Interpretation Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and A beta were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020

KW - ALZHEIMERS-DISEASE

KW - APOE EPSILON-4

KW - AMYLOID-BETA

KW - PET

KW - RISK

U2 - 10.1002/ana.25878

DO - 10.1002/ana.25878

M3 - Article

C2 - 32799367

SN - 0364-5134

VL - 88

SP - 921

EP - 932

JO - Annals of Neurology

JF - Annals of Neurology

IS - 5

ER -