Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer’s disease

Panagiota Pagoni; Christina Dardani; Beate Leppert; Roxanna S Korologou-Linden; George Davey Smith; Laura D Howe; Emma L Anderson; Evangelia  Stergiakouli

doi:10.1038/s41398-022-02150-2

Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer’s disease

Panagiota Pagoni, Christina Dardani, Beate Leppert, Roxanna S Korologou-Linden, George Davey Smith, Laura D Howe, Emma L Anderson, Evangelia Stergiakouli

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

Abstract

Background There are very few studies investigating possible links between Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Alzheimer’s disease and these have been limited by small sample sizes, diagnostic and recall bias. However, neurocognitive deficits affecting educational attainment in individuals with ADHD could be risk factors for Alzheimer’s later in life while hyper plasticity of the brain in ASD and strong positive genetic correlations of ASD with IQ and educational attainment could be protective against Alzheimer’s.

Methods We estimated the bidirectional total causal effects of genetic liability to ADHD and ASD on Alzheimer’s disease through two-sample Mendelian randomization. We investigated their direct effects, independent of educational attainment and IQ, through Multivariable Mendelian randomization.

Results There was limited evidence to suggest that genetic liability to ADHD (OR=1.00, 95% CI: 0.98 to 1.02, p=0.39) or ASD (OR=0.99, 95% CI: 0.97 to 1.01, p=0.70) was associated with risk of Alzheimer’s disease. Similar causal effect estimates were identified when the direct effects, independent of educational attainment (ADHD: OR=1.00, 95% CI: 0.99 to 1.01, p=0.07; ASD: OR=0.99, 95% CI: 0.98 to 1.00, p=0.28) and IQ (ADHD: OR=1.00, 95% CI: 0.99 to 1.02. p=0.29; ASD: OR=0.99, 95% CI: 0.98 to 1.01, p=0.99), were assessed. Finally, genetic liability to Alzheimer’s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR=1.12, 95% CI: 0.86 to 1.44, p=0.37; ASD: OR=1.19, 95% CI: 0.94 to 1.51, p=0.14).

Conclusions In the first study to date investigating the causal associations between genetic liability to ADHD, ASD and Alzheimer’s, within an MR framework, we found limited evidence to suggest a causal effect. It is important to encourage future research using ADHD and ASD specific subtype data, as well as longitudinal data in order to further elucidate any associations between these conditions.

Original language	English
Article number	422
Journal	Translational Psychiatry
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41398-022-02150-2
Publication status	Published - 1 Oct 2022

Bibliographical note

Funding Information:
This work was supported by a grant from the BRACE Alzheimer’s charity (BR16/028). PP, BL, RKL, ELA, GDS, LDH and ES work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3 and MC_UU_00011/6). CD is funded by the Wellcome Trust (grant ref: 108902/B/15/Z). BL was supported by a research grant from the Wellcome Trust (grant ref: 204895/Z/16/Z). RKL is supported by a Wellcome Trust PhD studentship (Grant ref: 215193/Z18/Z). LDH and ELA are funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1 and MR/P014437/1, respectively). This publication is the work of the authors, and ES will serve as a guarantor for the contents of this paper.

Publisher Copyright:
© 2022, The Author(s).

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Bristol Population Health Science Institute

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. & Davey Smith, G.
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Life course aetiology of dementia and cognitive decline: improving causal inference
Anderson, E. L.
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Cite this

@article{cbbbdfc02e6f4388a8b44b2dcb13f0ee,

title = "Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer{\textquoteright}s disease",

abstract = "Background There are very few studies investigating possible links between Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Alzheimer{\textquoteright}s disease and these have been limited by small sample sizes, diagnostic and recall bias. However, neurocognitive deficits affecting educational attainment in individuals with ADHD could be risk factors for Alzheimer{\textquoteright}s later in life while hyper plasticity of the brain in ASD and strong positive genetic correlations of ASD with IQ and educational attainment could be protective against Alzheimer{\textquoteright}s.Methods We estimated the bidirectional total causal effects of genetic liability to ADHD and ASD on Alzheimer{\textquoteright}s disease through two-sample Mendelian randomization. We investigated their direct effects, independent of educational attainment and IQ, through Multivariable Mendelian randomization.Results There was limited evidence to suggest that genetic liability to ADHD (OR=1.00, 95% CI: 0.98 to 1.02, p=0.39) or ASD (OR=0.99, 95% CI: 0.97 to 1.01, p=0.70) was associated with risk of Alzheimer{\textquoteright}s disease. Similar causal effect estimates were identified when the direct effects, independent of educational attainment (ADHD: OR=1.00, 95% CI: 0.99 to 1.01, p=0.07; ASD: OR=0.99, 95% CI: 0.98 to 1.00, p=0.28) and IQ (ADHD: OR=1.00, 95% CI: 0.99 to 1.02. p=0.29; ASD: OR=0.99, 95% CI: 0.98 to 1.01, p=0.99), were assessed. Finally, genetic liability to Alzheimer{\textquoteright}s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR=1.12, 95% CI: 0.86 to 1.44, p=0.37; ASD: OR=1.19, 95% CI: 0.94 to 1.51, p=0.14).Conclusions In the first study to date investigating the causal associations between genetic liability to ADHD, ASD and Alzheimer{\textquoteright}s, within an MR framework, we found limited evidence to suggest a causal effect. It is important to encourage future research using ADHD and ASD specific subtype data, as well as longitudinal data in order to further elucidate any associations between these conditions.",

author = "Panagiota Pagoni and Christina Dardani and Beate Leppert and Korologou-Linden, {Roxanna S} and {Davey Smith}, George and Howe, {Laura D} and Anderson, {Emma L} and Evangelia Stergiakouli",

note = "Funding Information: This work was supported by a grant from the BRACE Alzheimer{\textquoteright}s charity (BR16/028). PP, BL, RKL, ELA, GDS, LDH and ES work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3 and MC_UU_00011/6). CD is funded by the Wellcome Trust (grant ref: 108902/B/15/Z). BL was supported by a research grant from the Wellcome Trust (grant ref: 204895/Z/16/Z). RKL is supported by a Wellcome Trust PhD studentship (Grant ref: 215193/Z18/Z). LDH and ELA are funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1 and MR/P014437/1, respectively). This publication is the work of the authors, and ES will serve as a guarantor for the contents of this paper. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = oct,

day = "1",

doi = "10.1038/s41398-022-02150-2",

language = "English",

volume = "12",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Springer Nature",

number = "1",

}

TY - JOUR

T1 - Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer’s disease

AU - Pagoni, Panagiota

AU - Dardani, Christina

AU - Leppert, Beate

AU - Korologou-Linden, Roxanna S

AU - Davey Smith, George

AU - Howe, Laura D

AU - Anderson, Emma L

AU - Stergiakouli , Evangelia

N1 - Funding Information: This work was supported by a grant from the BRACE Alzheimer’s charity (BR16/028). PP, BL, RKL, ELA, GDS, LDH and ES work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3 and MC_UU_00011/6). CD is funded by the Wellcome Trust (grant ref: 108902/B/15/Z). BL was supported by a research grant from the Wellcome Trust (grant ref: 204895/Z/16/Z). RKL is supported by a Wellcome Trust PhD studentship (Grant ref: 215193/Z18/Z). LDH and ELA are funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1 and MR/P014437/1, respectively). This publication is the work of the authors, and ES will serve as a guarantor for the contents of this paper. Publisher Copyright: © 2022, The Author(s).

PY - 2022/10/1

Y1 - 2022/10/1

N2 - Background There are very few studies investigating possible links between Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Alzheimer’s disease and these have been limited by small sample sizes, diagnostic and recall bias. However, neurocognitive deficits affecting educational attainment in individuals with ADHD could be risk factors for Alzheimer’s later in life while hyper plasticity of the brain in ASD and strong positive genetic correlations of ASD with IQ and educational attainment could be protective against Alzheimer’s.Methods We estimated the bidirectional total causal effects of genetic liability to ADHD and ASD on Alzheimer’s disease through two-sample Mendelian randomization. We investigated their direct effects, independent of educational attainment and IQ, through Multivariable Mendelian randomization.Results There was limited evidence to suggest that genetic liability to ADHD (OR=1.00, 95% CI: 0.98 to 1.02, p=0.39) or ASD (OR=0.99, 95% CI: 0.97 to 1.01, p=0.70) was associated with risk of Alzheimer’s disease. Similar causal effect estimates were identified when the direct effects, independent of educational attainment (ADHD: OR=1.00, 95% CI: 0.99 to 1.01, p=0.07; ASD: OR=0.99, 95% CI: 0.98 to 1.00, p=0.28) and IQ (ADHD: OR=1.00, 95% CI: 0.99 to 1.02. p=0.29; ASD: OR=0.99, 95% CI: 0.98 to 1.01, p=0.99), were assessed. Finally, genetic liability to Alzheimer’s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR=1.12, 95% CI: 0.86 to 1.44, p=0.37; ASD: OR=1.19, 95% CI: 0.94 to 1.51, p=0.14).Conclusions In the first study to date investigating the causal associations between genetic liability to ADHD, ASD and Alzheimer’s, within an MR framework, we found limited evidence to suggest a causal effect. It is important to encourage future research using ADHD and ASD specific subtype data, as well as longitudinal data in order to further elucidate any associations between these conditions.

AB - Background There are very few studies investigating possible links between Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Alzheimer’s disease and these have been limited by small sample sizes, diagnostic and recall bias. However, neurocognitive deficits affecting educational attainment in individuals with ADHD could be risk factors for Alzheimer’s later in life while hyper plasticity of the brain in ASD and strong positive genetic correlations of ASD with IQ and educational attainment could be protective against Alzheimer’s.Methods We estimated the bidirectional total causal effects of genetic liability to ADHD and ASD on Alzheimer’s disease through two-sample Mendelian randomization. We investigated their direct effects, independent of educational attainment and IQ, through Multivariable Mendelian randomization.Results There was limited evidence to suggest that genetic liability to ADHD (OR=1.00, 95% CI: 0.98 to 1.02, p=0.39) or ASD (OR=0.99, 95% CI: 0.97 to 1.01, p=0.70) was associated with risk of Alzheimer’s disease. Similar causal effect estimates were identified when the direct effects, independent of educational attainment (ADHD: OR=1.00, 95% CI: 0.99 to 1.01, p=0.07; ASD: OR=0.99, 95% CI: 0.98 to 1.00, p=0.28) and IQ (ADHD: OR=1.00, 95% CI: 0.99 to 1.02. p=0.29; ASD: OR=0.99, 95% CI: 0.98 to 1.01, p=0.99), were assessed. Finally, genetic liability to Alzheimer’s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR=1.12, 95% CI: 0.86 to 1.44, p=0.37; ASD: OR=1.19, 95% CI: 0.94 to 1.51, p=0.14).Conclusions In the first study to date investigating the causal associations between genetic liability to ADHD, ASD and Alzheimer’s, within an MR framework, we found limited evidence to suggest a causal effect. It is important to encourage future research using ADHD and ASD specific subtype data, as well as longitudinal data in order to further elucidate any associations between these conditions.

U2 - 10.1038/s41398-022-02150-2

DO - 10.1038/s41398-022-02150-2

M3 - Article (Academic Journal)

C2 - 36182936

VL - 12

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

IS - 1

M1 - 422

ER -

Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer’s disease

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Life course aetiology of dementia and cognitive decline: improving causal inference

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