Self-reported and device-based physical activity and risk of Alzheimer’s disease and related dementias: a Mendelian randomization study

1. Self-reported and device-based physical activity and risk of Alzheimer’s disease and related
dementias: a Mendelian randomization study
Gayatri Arania, Tingting Thompsona, Michelle S. Newellj, Karmel W. Choib,c,d,e, Chia-Yen Chend,e,f, David A. Raichleng, Gene E. Alexanderh,i, Yann C.
Klimentidisa*
aDepartment of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona, USA, bDepartment of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA
cHarvard T.H. Chan School of Public Health, Boston, Massachusetts, USA, dPsychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
eStanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts, USA, fAnalytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
gSchool of Anthropology, University of Arizona, Tucson, Arizona, USA hDepartments of Psychology and Psychiatry, Neuroscience and Physiological Sciences Interdisciplinary Programs, BIO5 Institute, and Evelyn F. McKnight Brain Institute, University
of Arizona, Tucson, Arizona, USA iArizona Alzheimer's Consortium, Phoenix, Arizona, USA jVeteran’s Affairs Administration, Arizona, USA
Background
• Current observational studies suggest that physical activity (PA) may have a
protective role in Alzheimer’s disease and related dementias (ADD). 1,2 However,
these may be prone to residual confounding, bias, and reverse causation.
• Additionally, Educational Attainment (EA) and PA may have a common genetic
correlation with other exercises.3,6 Therefore EA may be confounding the
relationship between PA and health outcomes.
• Mendelian randomization (MR) is an alternative approach that may avoid these
limitations to better assess the causal role of PA in ADD and to consider the role of
EA in this relationship.
• Primary aim: To examine whether genetically- predicted levels of PA are
associated with ADD.
• Secondary aim: To examine whether genetically-predicted EA is associated with
PA.
Methods
Results
Figure 2. IVW estimates of the effect of genetically
predicted educational attainment on the physical
activity phenotypes
Figure 1. IVW estimates of the effect of genetically
predicted physical activity phenotypes on Alzheimer’s
disease
Discussion
• We leveraged both self-reported and objective measures of PA
and the largest ADD GWAS to date in our Mendelian
randomization analyses.
• We did not find any evidence to support that the genetic
propensity for different types of physical activity is associated
with the risk of Alzheimer’s disease and related dementias with
IVW and sensitivity analyses.
• These results are consistent with previous MR results using
MVPA and sedentary behavior and Alzheimer’s Disease, and
with MR using the previous AD GWAS and device-based PA
phenotypes.7,8
• Our results for the EA on SSOE emphasize that EA, given its
shared genetics with PA, needs to be accounted for using MVMR
in future studies.3
• Our research uses the robust methodology of MR for causal
inference that can inform the development of public health
recommendations for the primary prevention of Alzheimer’s and
related dementia. Most importantly, the results for the
association of EA with SSOE could have implications in tailoring
public health communications and interventions to prevent ADD.
References
1. IhiraH, Sawada N, Inoue M, et al. AssociationBetweenPhysicalActivityand Riskof DisablingDementiainJapan. JAMA Network Open. 2022;5(3):e224590. doi:10.1001/jamanetworkopen.2022.4590
2. Yoon M, Yang PS, JinMN, et al. Associationof PhysicalActivityLevel WithRiskof Dementiaina Nationwide Cohort inKorea. JAMA Network Open. 2021;4(12):e2138526. doi:10.1001/jamanetworkopen.2021.38526
3. Iso-MarkkuP, Kujala UM, Knittle K, Polet J, VuoksimaaE, Waller K. Physical activityas aprotective factor for dementiaandAlzheimer’s disease:systematic review, meta-analysis andqualityassessment of cohortand case-controlstudies. Br J SportsMed. 2022;56(12):701-709. doi:10.1136/bjsports-2021-104981
4. KlimentidisYC, RaichlenDA, Bea J, et al. Genome-wide associationstudyof habitual physical activityinover 377,000 UK Biobank participants identifiesmultiplevariants includingCADM2 and APOE. Int J Obes (Lond). 2018;42(6):1161-1176. doi:10.1038/s41366-018-0120-3
5. BellenguezC, Küçükali F, JansenIE, et al. New insights intothe geneticetiologyof Alzheimer’s disease andrelateddementias. Nat Genet. 2022;54(4):412-436. doi:10.1038/s41588-022-01024-z
6. Okbay A, Beauchamp JP, Fontana MA, et al. Genome-wide associationstudyidentifies74 lociassociatedwitheducational attainment. Nature. 2016;533(7604):539-542. doi:10.1038/nature17671
7. Wang Z, EmmerichA, PillonNJ, et al. Genome-wide associationanalyses ofphysical activityand sedentarybehavior provide insightsinto underlyingmechanismsandroles indiseaseprevention.Nat Genet. 2022;54(9):1332-1344. doi:10.1038/s41588-022-01165-1
8. BaumeisterSE, Karch A, Bahls M, Teumer A, LeitzmannMF, Baurecht H. Physical activityand riskof Alzheimerdisease. Neurology. 2020;95(13):e1897-e1905. doi:10.1212/WNL.0000000000010013.
9. Aaltonen S, Latvala A, Jelenkovic A, et al. Physical Activity and Academic Performance: Genetic and Environmental Associations. Med Sci Sports Exerc. 2020;52(2):381-390. doi:10.1249/MSS.0000000000002124
Three self-reported measures
(nmax=377,234) GWAS3
• - Moderate-to-vigorous
physical activity (MVPA)
• - Vigorous physical activity
(VPA)
• - Strenuous sports or
exercises (SSOE)
Two accelerometry-based
measures (nmax=91,084)4
• Acceleration average
(AAv)
• A fraction of accelerations
>425 mg (AF)
GWAS of ADD from the
European Alzheimer’s &
Dementia Biobank (EADB)5
N = 111,326 cases and
677,633 controls.
GWAS of EA from Okbay et
al., 2022
N max = 293,723, mean=
14.3, sd= 3.6.
PA
traits
ADD
EA
PA
traits
MR
MR
Statistical analyses – Inverse variance weighted and sensitivity analyses
(MR Egger, Simple mode, weighted mode, and weighted median)
• Primary aim: The direction of associations for ADD was
inconsistent across the PA phenotypes. We didn’t find evidence for
the associations between genetically predicted physical activity
and Alzheimer’s and related dementias
• Secondary aim: We found the higher genetically predicted EA is
associated with higher SSOE (0.88, 95% CI: 0.47,1.30)