Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease

Jaclyn M Eissman^{1

2}, Logan Dumitrescu^{1

2}, Emily R Mahoney^{1

2}, Alexandra N Smith^{1

2}, Shubhabrata Mukherjee³, Michael L Lee³, Phoebe Scollard³, Seo Eun Choi³, William S Bush⁴, Corinne D Engelman⁵, Qiongshi Lu^{6

7}, David W Fardo^{8

9}, Emily H Trittschuh^{10

11}, Jesse Mez¹², Catherine C Kaczorowski¹³, Hector Hernandez Saucedo¹⁴, Keith F Widaman¹⁵, Rachel F Buckley^{16

17

18}, Michael J Properzi¹⁶, Elizabeth C Mormino¹⁹, Hyun Sik Yang^{16

17}, Theresa M Harrison²⁰, Trey Hedden²¹, Kwangsik Nho^{22

23}, Shea J Andrews²¹, Douglas Tommet²⁴, Niran Hadad¹³, R Elizabeth Sanders³, Douglas M Ruderfer², Katherine A Gifford¹, Xiaoyuan Zhong^{6

7}, Neha S Raghavan^{25

26

27}, Badri N Vardarajan^{25

26

27}; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); A4 Study Team; Margaret A Pericak-Vance²⁸, Lindsay A Farrer^{12

29

30}, Li San Wang³¹, Carlos Cruchaga³², Gerard D Schellenberg³¹, Nancy J Cox², Jonathan L Haines⁴, C Dirk Keene³³, Andrew J Saykin³⁴, Eric B Larson^{3

35}, Reisa A Sperling¹⁶, Richard Mayeux^{25

26

27}, Michael L Cuccaro²⁸, David A Bennett³⁶, Julie A Schneider³⁶, Paul K Crane³, 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, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Medicine, University of Washington, Seattle, WA, USA.
⁴ Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁵ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁶ Department of Statistics, University of Wisconsin-Madison, Madison, WI, USA.
⁷ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
⁸ Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
⁹ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
¹¹ VA Puget Sound Health Care System, GRECC, Seattle, WA, USA.
¹² Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹³ The Jackson Laboratory, Bar Harbor, ME, USA.
¹⁴ UC Davis Alzheimer's Disease Research Center, Department of Neurology, University of California Davis Medical Center, Sacramento, CA, USA.
¹⁵ University of California at Riverside, Riverside, CA, USA.
¹⁶ Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
¹⁷ Center for Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.
¹⁸ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia.
¹⁹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
²⁰ Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
²¹ Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
²² Department of Radiology and Imaging Sciences, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
²³ Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
²⁴ Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, RI, USA.
²⁵ Department of Neurology, Columbia University, New York, NY, USA.
²⁶ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University, New York, NY, USA.
²⁷ The Institute for Genomic Medicine, Columbia University Medical Center and The New York Presbyterian Hospital, New York, NY, USA.
²⁸ John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
²⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³⁰ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
³¹ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³² Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
³³ Department of Pathology, University of Washington, Seattle, WA, USA.
³⁴ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁵ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

PMID: 35552371
PMCID: PMC9337804
DOI: 10.1093/brain/awac177

Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease

Jaclyn M Eissman et al. Brain. 2022.

. 2022 Jul 29;145(7):2541-2554.

doi: 10.1093/brain/awac177.

Authors

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Medicine, University of Washington, Seattle, WA, USA.
⁴ Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁵ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁶ Department of Statistics, University of Wisconsin-Madison, Madison, WI, USA.
⁷ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
⁸ Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
⁹ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
¹¹ VA Puget Sound Health Care System, GRECC, Seattle, WA, USA.
¹² Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹³ The Jackson Laboratory, Bar Harbor, ME, USA.
¹⁴ UC Davis Alzheimer's Disease Research Center, Department of Neurology, University of California Davis Medical Center, Sacramento, CA, USA.
¹⁵ University of California at Riverside, Riverside, CA, USA.
¹⁶ Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
¹⁷ Center for Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.
¹⁸ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia.
¹⁹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
²⁰ Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
²¹ Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
²² Department of Radiology and Imaging Sciences, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
²³ Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
²⁴ Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, RI, USA.
²⁵ Department of Neurology, Columbia University, New York, NY, USA.
²⁶ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University, New York, NY, USA.
²⁷ The Institute for Genomic Medicine, Columbia University Medical Center and The New York Presbyterian Hospital, New York, NY, USA.
²⁸ John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
²⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³⁰ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
³¹ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³² Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
³³ Department of Pathology, University of Washington, Seattle, WA, USA.
³⁴ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁵ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

PMID: 35552371
PMCID: PMC9337804
DOI: 10.1093/brain/awac177

Abstract

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.

Keywords: Alzheimer’s disease; GWAS; genetics; resilience; sex differences.

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Figures

**Figure 1**
**Cognitive and biomarker data harmonization and cognitive resilience model.** Memory, executive function, and Preclinical Alzheimer Cognitive Composite (PACC) scores were harmonized across cohorts. Additionally, *in vivo* amyloid PET SUVRs were harmonized with Gaussian mixture modelling. (A) Harmonized *in vivo* amyloid PET SUVR by harmonized memory scores are plotted by sex. (B) Linear models leveraging harmonized cognitive and amyloid data (harmonized *in vivo* PET or autopsy measures of amyloid plaque burden, CERAD scores) were residualized and fed as indicators into a residual cognitive resilience latent variable model. The combined resilience latent variable model included educational attainment as an additional indicator.

**Figure 2**
**Minor allele of female-specific genome-wide significant locus on chromosome 10 (with rs827389) associated with higher combined resilience scores among cognitively normal females.** (A) Miami plot with female variant associations on the top in pink and male variant associations on the bottom in blue. (B) Forest plot of rs827389 by cohort and by sex, including fixed-effects meta-analysis estimates. (C) Locus Zoom plots displaying the genomic region surrounding the chromosome 10 locus, by sex.

**Figure 3**
**Sex-specific shared genetic architecture between resilience and complex traits.** Genetic covariance estimates with 95% confidence intervals are shown in the figure, with female estimates in pink and male estimates in blue. Grey confidence intervals denote a non-significant covariance estimate irrespective of sex. (A) Genetic covariance estimates with residual cognitive resilience, by sex, for Alzheimer’s disease and for FTD. (B) Genetic covariance estimates with combined resilience, by sex, for three HRV traits and for two autoimmune traits.

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Comment in

Do genetic factors contribute to sex-specific differences in resilience to amyloid pathology?
Groot C, Holstege H, Ossenkoppele R. Groot C, et al. Brain. 2022 Jul 29;145(7):2239-2241. doi: 10.1093/brain/awac216. Brain. 2022. PMID: 35726881 Free PMC article.

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Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease

Affiliations

Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease

Authors

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Abstract

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