Sex differences in the genetic predictors of Alzheimer's pathology

Logan Dumitrescu^{1

2}, Lisa L Barnes³, Madhav Thambisetty⁴, Gary Beecham^{5

6}, Brian Kunkle⁶, William S Bush⁷, Katherine A Gifford¹, Lori B Chibnik^{8

9}, Shubhabrata Mukherjee¹⁰, Philip L De Jager^{11

12}, Walter Kukull¹³, Paul K Crane¹⁰, Susan M Resnick⁴, C Dirk Keene¹⁴, Thomas J Montine¹⁵, Gerard D Schellenberg¹⁶, Yuetiva Deming¹⁷, Michael J Chao¹⁸, Matt Huentelman¹⁹, Eden R Martin^{5

6}, Kara Hamilton-Nelson⁶, Leslie M Shaw¹⁶, John Q Trojanowski¹⁶, Elaine R Peskind²⁰, Carlos Cruchaga¹⁷, Margaret A Pericak-Vance⁶, Alison M Goate¹⁸, Nancy J Cox², Jonathan L Haines⁷, Henrik Zetterberg^{21

22

23

24}, Kaj Blennow^{21

22}, Eric B Larson^{10

25}, Sterling C Johnson²⁶, Marilyn Albert²⁷; Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative; David A Bennett³, Julie A Schneider³, Angela L Jefferson¹, Timothy J Hohman^{1

2}

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Vanderbilt Genetics Institute, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁴ Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
⁵ John T MacDonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
⁶ John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
⁷ Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
¹² Cell Circuits Program, Broad Institute, Cambridge MA, USA.
¹³ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
¹⁴ Department of Pathology, University of Washington, Seattle, WA, USA.
¹⁵ Department of Pathology, Stanford University, Stanford, CA, USA.
¹⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
¹⁸ Ronald M Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
²¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
²² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²³ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
²⁴ UK Dementia Research Institute at UCL, London, UK.
²⁵ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
²⁶ Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
²⁷ Department of Neurology, the Johns Hopkins University School of Medicine, Baltimore, MD.

PMID: 31497858
PMCID: PMC6736148
DOI: 10.1093/brain/awz206

Sex differences in the genetic predictors of Alzheimer's pathology

Logan Dumitrescu et al. Brain. 2019.

. 2019 Sep 1;142(9):2581-2589.

doi: 10.1093/brain/awz206.

Authors

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Vanderbilt Genetics Institute, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁴ Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
⁵ John T MacDonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
⁶ John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
⁷ Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
¹² Cell Circuits Program, Broad Institute, Cambridge MA, USA.
¹³ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
¹⁴ Department of Pathology, University of Washington, Seattle, WA, USA.
¹⁵ Department of Pathology, Stanford University, Stanford, CA, USA.
¹⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
¹⁸ Ronald M Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
²¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
²² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²³ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
²⁴ UK Dementia Research Institute at UCL, London, UK.
²⁵ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
²⁶ Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
²⁷ Department of Neurology, the Johns Hopkins University School of Medicine, Baltimore, MD.

PMID: 31497858
PMCID: PMC6736148
DOI: 10.1093/brain/awz206

Abstract

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

Keywords: Alzheimer’s disease; beta-amyloid; genome-wide association study; neuropathology; tau.

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Figures

**Figure 1**
**Sex-stratified genome-wide association results for tangle positivity.** (A) Miami plot illustrating neurofibrillary tangle positivity genome-wide association results stratified by males and females. Male findings are plotted in blue and grey on the *top* and female results are plotted in pink and grey at the *bottom.* The red lines represent the genome-wide threshold for statistical significance (P < 5 × 10⁻⁸). Regional association plots for the rs34331204 association with neurofibrillary tangle positivity within (B) males and (C) females.

**Figure 2**
**Male-specific SNP (rs34331204) associated with protection from neurofibrillary tangles also relates to hippocampal volume and executive function.** Sex-specific association of rs34331204 with (A) NFT, (B) hippocampal volume, and (C) executive function. Within each panel, males are presented on the *left* and females on the *right.* Outcomes are presented on the y-axes. Bar colours represent rs34331204 genotype. Homozygous carriers of the A allele are presented in dark green on the *left*, heterozygotes in light green in the *middle*, and homozygous carriers of the C allele in the lightest green on the *right.* A neuroprotective effect of the rs34331204 C allele is observed among males, but not females.

See this image and copyright information in PMC

Comment in

Reply: rs34331204 regulates TSPAN13 expression and contributes to Alzheimer's disease with sex differences.
Dumitrescu L, Hohman TJ. Dumitrescu L, et al. Brain. 2020 Dec 5;143(11):e96. doi: 10.1093/brain/awaa303. Brain. 2020. PMID: 33175951 No abstract available.
rs34331204 regulates TSPAN13 expression and contributes to Alzheimer's disease with sex differences.
Hu Y, Zhang H, Liu B, Gao S, Wang T, Han Z; International Genomics of Alzheimer’s Project (IGAP); Ji X, Liu G. Hu Y, et al. Brain. 2020 Dec 5;143(11):e95. doi: 10.1093/brain/awaa302. Brain. 2020. PMID: 33175954 Free PMC article. No abstract available.

References

1. Altmann A, Tian L, Henderson VW, Greicius MD. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 2014; 75: 563–73. - PMC - PubMed
1. Apostolova LG, Dinov ID, Dutton RA, Hayashi KM, Toga AW, Cummings JL et al. . 3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer’s disease. Brain 2006; 129: 2867–73. - PubMed
1. Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 2005; 62: 685–91. - PubMed
1. Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ et al. . Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet 2014; 10: e1004606. - PMC - PubMed
1. Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003; 2: 605–13. - PubMed

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Sex differences in the genetic predictors of Alzheimer's pathology

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Sex differences in the genetic predictors of Alzheimer's pathology

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