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Mendelian Randomization Analysis Reveals Causal Factors behind Alzheimer’s Disease Risk: Evidence, Opportunities, and Challenges

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Abstract

Alzheimer’s disease and its comorbidities pose a heavy disease burden globally, and its treatment remains a major challenge. Identifying the protective and risk factors for Alzheimer’s disease, as well as its possible underlying molecular processes, can facilitate the development of interventions that can slow its progression. Observational studies and randomized controlled trials have provided some evidence regarding potential risk factors for Alzheimer’s disease; however, the results of these studies vary. Mendelian randomization is a novel epidemiological methodology primarily used to infer causal relationships between exposures and outcomes. Many Mendelian randomization studies have identified potential causal relationships between Alzheimer’s disease and certain diseases, lifestyle habits, and biological exposures, thus providing valuable data for further mechanistic studies and the development and implementation of clinical prevention strategies. However, the results and data from Mendelian randomization studies must be interpreted based on comprehensive evidence. Moreover, the existing Mendelian randomization studies on the epidemiology of Alzheimer’s disease have some limitations that are worth exploring. Therefore, the aim of this review was to summarize the available evidence on the potential protective and risk factors for Alzheimer’s disease by assessing published Mendelian randomization studies on Alzheimer’s disease, and to provide new perspectives on the etiology of Alzheimer’s disease.

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Abbreviations

IGAP:

the International Genomics of Alzheimer’s Project

FinnGen R4:

the Fin-nGen consortium release 4

CHARGE:

the Cohorts for Heart and Aging Research in Genomic Epidemiology

UKBB(UKB):

the UK Biobank

CGPS:

Copenhagen General Population Study

CCHS:

Copenhagen City Heart Study

HGI:

the COVID-19 Host Genetics Initiative

PGC-ALZ:

the Psychiatric Genomic Consortium Alzheimer’s Disease Workgroup

ADSP:

the Alzheimer’s Disease Sequencing Project

ADGC:

the Alzheimer Disease Genetics Consortium

EADI:

the European Alzheimer’s Disease Initiative

GERAD/PERADES:

the Genetic and Environmental Risk in AD/ Polygenic and Environmental Risk for Alzheimer’s Disease Consortium

Andro:

androsterone sulfate

DHEAS:

dehydroepiandrosterone sulfate

E2:

estradio

Tot T:

total testosterone

LDL-c:

Low-density lipoprotein cholesterol

TG:

triglycerides

TC:

total cholesterol

MFH-UKBB:

maternal UKBB family history of AD

PFH-UKBB:

paternal UKBB family history of AD

CG A:

Chlorogenic Acid

ApoB:

Apolipoprotein B

Ca:

serum Calcium

VD:

Vitamin D

UA:

Uric Acid

Hey:

plasma Homocysteine

MCI:

mitochondrial complex I

AHMS:

AHMS gene (antihypertensive drug targets)

sTREM1:

soluble triggering receptor expressed on myeloid cells 1

GDF-15:

growth differentiation factor 15

glycoprotein acetyls:

GlycA.

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Funding

Funding: This work was supported by a grant from the Shaanxi Provincial Department of Science and Technology (2023-YBSF-152). The funder had no role in the research process or in the writing of the paper.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Shanxi University of Traditional Chinese Medicine, Xianyang, China

    X. Feng, Y. Hou, W. Ma & J. Ma

  2. Xian Hospital of Traditional Chinese Medicine, Xi’an, China

    L. Zhang, X. Chang & Lin Yang

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  2. L. Zhang
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Contributions

Author contributions: XF wrote the main manuscript text and prepared the figures. LZ and YH prepared the table. WM, XC and ZM revised the manuscript. LY provided the concepts and guided this study. All authors reviewed the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Lin Yang.

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Ethics statement: Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Conflict of interest: None.

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Feng, X., Zhang, L., Hou, Y. et al. Mendelian Randomization Analysis Reveals Causal Factors behind Alzheimer’s Disease Risk: Evidence, Opportunities, and Challenges. J Prev Alzheimers Dis 11, 749–758 (2024). https://doi.org/10.14283/jpad.2024.30

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