Introduction: The potential influence of age at menarche (AM) on cognitive aging remains inadequate, partly because of the difficulties presented by multiple confounders. To address this issue, Mendelian randomization (MR) analysis was used to explore the causal impacts of AM on cognitive aging. Methods: Using the publicly accessible Taiwan Biobank, we identified single nucleotide polymorphisms (SNPs) significantly associated with AM as instrumental variables to estimate the effects of instruments on cognitive function assessed with the Mini-Mental State Examination (MMSE). We employed several MR methods, including two-stage least squares, inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and constrained maximum likelihood (cML) MR methods, to ensure the stability and reliability of the results. Results: MR analyses indicated no significant causal relationship between genetically determined AMs and total and subdomain MMSE scores, except the G5 subdomain (βIVW = 0.156, 95% confidence interval [CI]: 0.005, 0.307; βcML = 0.161, 95% CI: 0.014, 0.309). However, in a leave-one-out sensitivity analysis, we found a significant relationship between AM and cognitive aging after eliminating rs157863 and rs6758290, thus demonstrating the potential pleiotropic effects of these two SNPs. After these two SNPs were eliminated, we found a significant causal relationship between AM and overall MMSE scores (βIVW = 0.425, 95% CI: 0.011, 0.839), though. Conclusion: Evidence from the present MR study did not fully support a causal relationship between AM and cognitive function decline in later life. Potential pleiotropic effects of the genes underlying these two traits are worthy of further investigation.

1.
Cantarero-Prieto
D
,
Leon
PL
,
Blazquez-Fernandez
C
,
Juan
PS
,
Cobo
CS
.
The economic cost of dementia: a systematic review
.
Dementia
.
2020
;
19
(
8
):
2637
57
.
2.
Núñez
F
,
Maraver
MJ
,
Colzato
LS
.
Sex hormones as cognitive enhancers
.
J Cogn Enhanc
.
2020
;
4
(
2
):
228
33
.
3.
Najar
J
,
Ostling
S
,
Waern
M
,
Zettergren
A
,
Kern
S
,
Wetterberg
H
, et al
.
Reproductive period and dementia: a 44-year longitudinal population study of Swedish women
.
Alzheimers Dement
.
2020
;
16
(
8
):
1153
63
.
4.
Gilsanz
P
,
Lee
C
,
Corrada
MM
,
Kawas
CH
,
Quesenberry
CP
,
Whitmer
RA
.
Reproductive period and risk of dementia in a diverse cohort of health care members
.
Neurology
.
2019
;
92
(
17
):
2005
14
.
5.
Song
YJ
,
Li
SRL
,
Li
X
,
Chen
X
,
Wei
Z
,
Liu
Q
, et al
.
The effect of estrogen replacement therapy on alzheimer’s disease and Parkinson’s disease in postmenopausal women: a meta-analysis
.
Front Neurosci
.
2020
;
14
:
14
.
6.
Shumaker
SA
,
Legault
C
,
Rapp
SR
,
Thal
L
,
Wallace
RB
,
Ockene
JK
, et al
.
Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial
.
JAMA
.
2003
;
289
(
20
):
2651
62
.
7.
Henderson
VW
,
Paganini-Hill
A
,
Miller
BL
,
Elble
RJ
,
Reyes
PF
,
Shoupe
D
, et al
.
Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial
.
Neurology
.
2000
;
54
(
2
):
295
301
.
8.
Ramezani Tehrani
F
,
Mirmiran
P
,
Gholami
R
,
Moslehi
N
,
Azizi
F
.
Factors influencing menarcheal age: results from the cohort of tehran lipid and glucose study
.
Int J Endocrinol Metab
.
2014
;
12
(
3
):
e16130
.
9.
Charalampopoulos
D
,
McLoughlin
A
,
Elks
CE
,
Ong
KK
.
Age at menarche and risks of all-cause and cardiovascular death: a systematic review and meta-analysis
.
Am J Epidemiol
.
2014
;
180
(
1
):
29
40
.
10.
Burgess
S
,
Thompson
SG
.
Mendelian randomization: methods for causal inference using genetic variants
. 2nd ed.
Chapman & Hall/CRC Interdisciplinary Statistics Series
.
2021
:
Boca Raton London New York
;
CRC Press
. p.
225
.
11.
Li
M
,
Lin
J
,
Liang
S
,
Chen
Z
,
Bai
Y
,
Long
X
, et al
.
The role of age at menarche and age at menopause in Alzheimer’s disease: evidence from a bidirectional mendelian randomization study
.
Stress and The Aging Brain
.
2021
;
13
(
15
):
19722
49
.
12.
Fan
CT
,
Hung
TH
,
Yeh
CK
.
Taiwan regulation of biobanks
.
J L Med Ethics
.
2015
;
43
(
4
):
816
26
.
13.
Chen
CH
,
Yang
JH
,
Chiang
CWK
,
Hsiung
CN
,
Wu
PE
,
Chang
LC
, et al
.
Population structure of Han Chinese in the modern Taiwanese population based on 10,000 participants in the Taiwan Biobank project
.
Hum Mol Genet
.
2016
;
25
(
24
):
5321
31
.
14.
Shyu
YIL
,
Yip
PK
.
Factor structure and explanatory variables of the Mini-Mental State Examination (MMSE) for elderly persons in Taiwan
.
J Formos Med Assoc
.
2001
;
100
(
10
):
676
83
.
15.
Chou
HT
,
Wu
PY
,
Huang
JC
,
Chen
SC
,
Ho
WY
.
Late Menarche, Not reproductive period, is associated with poor cognitive function in postmenopausal women in taiwan
.
Int J Environ Res Public Health
.
2021
;
18
(
5
):
2345
.
16.
Lin
WY
,
Chan
CC
,
Liu
YL
,
Yang
AC
,
Tsai
SJ
,
Kuo
PH
.
Performing different kinds of physical exercise differentially attenuates the genetic effects on obesity measures: evidence from 18,424 Taiwan Biobank participants
.
PLoS Genet
.
2019
;
15
(
8
):
1008277
.
17.
Purcell
S
,
Neale
B
,
Todd-Brown
K
,
Thomas
L
,
Ferreira
MAR
,
Bender
D
, et al
.
PLINK: a tool set for whole-genome association and population-based linkage analyses
.
Am J Hum Genet
.
2007
;
81
(
3
):
559
75
.
18.
Kamat
MA
,
Blackshaw
JA
,
Young
R
,
Surendran
P
,
Burgess
S
,
Danesh
J
, et al
.
PhenoScanner V2: an expanded tool for searching human genotype–phenotype associations
.
Bioinformatics
.
2019
;
35
(
22
):
4851
3
.
19.
Choi
SW
,
O’Reilly
PF
.
PRSice-2: polygenic Risk Score software for biobank-scale data
.
Gigascience
.
2019
;
8
(
7
):
giz082
.
20.
Burgess
S
,
Butterworth
A
,
Thompson
SG
.
Mendelian randomization analysis with multiple genetic variants using summarized data
.
Genet Epidemiol
.
2013
;
37
(
7
):
658
65
.
21.
Bowden
J
,
Davey Smith
G
,
Burgess
S
.
Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression
.
Int J Epidemiol
.
2015
;
44
(
2
):
512
25
.
22.
Bowden
J
,
Davey Smith
G
,
Haycock
PC
,
Burgess
S
.
Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator
.
Genet Epidemiol
.
2016
;
40
(
4
):
304
14
.
23.
Hartwig
FP
,
Davey Smith
G
,
Bowden
J
.
Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption
.
Int J Epidemiol
.
2017
;
46
(
6
):
1985
98
.
24.
Xue
H
,
Shen
X
,
Pan
W
.
Constrained maximum likelihood-based Mendelian randomization robust to both correlated and uncorrelated pleiotropic effects
.
Am J Hum Genet
.
2021
;
108
(
7
):
1251
69
.
25.
Verbanck
M
,
Chen
CY
,
Neale
B
,
Do
R
.
Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases
.
Nat Genet
.
2018
;
50
(
5
):
693
8
.
26.
Zheng
J
,
Baird
D
,
Borges
MC
,
Bowden
J
,
Hemani
G
,
Haycock
P
, et al
.
Recent developments in mendelian randomization studies
.
Curr Epidemiol Rep
.
2017
;
4
(
4
):
330
45
.
27.
Matsuda
H
,
Okita
K
,
Motoi
Y
,
Mizuno
T
,
Ikeda
M
,
Sanjo
N
, et al
.
Clinical impact of amyloid PET using (18)F-florbetapir in patients with cognitive impairment and suspected Alzheimer’s disease: a multicenter study
.
Ann Nucl Med
.
2022
;
36
(
12
):
1039
49
.
28.
Tombaugh
TN
,
McIntyre
NJ
.
The mini-mental state examination: a comprehensive review
.
J Am Geriatr Soc
.
1992
;
40
(
9
):
922
35
.
29.
Li
J
,
Hao
W
,
Fu
C
,
Zhou
C
,
Zhu
D
.
Sex differences in memory: do female reproductive factors explain the differences
.
Front Endocrinol
.
2022
;
13
:
837852
.
30.
Koedam
EL
,
Lauffer
V
,
van der Vlies
AE
,
van der Flier
WM
,
Scheltens
P
,
Pijnenburg
YA
.
Early-versus late-onset Alzheimer’s disease: more than age alone
.
J Alzheimers Dis
.
2010
;
19
(
4
):
1401
8
.
31.
Ortega-Alonso
A
,
Ekelund
J
,
Sarin
AP
,
Miettunen
J
,
Veijola
J
,
Järvelin
MR
, et al
.
Genome-wide association study of psychosis proneness in the finnish population
.
Schizophr Bull
.
2017
;
43
(
6
):
1304
14
.
32.
Hoffmann
N
,
Peters
J
.
Functions of the (pro)renin receptor (Atp6ap2) at molecular and system levels: pathological implications in hypertension, renal and brain development, inflammation, and fibrosis
.
Pharmacol Res
.
2021
;
173
:
105922
.
33.
Sapouckey
SA
,
Deng
G
,
Sigmund
CD
,
Grobe
JL
.
Potential mechanisms of hypothalamic renin-angiotensin system activation by leptin and DOCA-salt for the control of resting metabolism
.
Physiol Genomics
.
2017
;
49
(
12
):
722
32
.
34.
Cosarderelioglu
C
,
Nidadavolu
LS
,
George
CJ
,
Oh
ES
,
Bennett
DA
,
Walston
JD
, et al
.
Brain renin–angiotensin system at the intersect of physical and cognitive frailty
.
Front Neurosci
.
2020
;
14
:
586314
.
35.
Dong
Y-F
,
Kataoka
K
,
Toyama
K
,
Sueta
D
,
Koibuchi
N
,
Yamamoto
E
, et al
.
Attenuation of brain damage and cognitive impairment by direct renin inhibition in mice with chronic cerebral hypoperfusion
.
Hypertens
.
2011
;
58
(
4
):
635
42
.
36.
Zang
Y
,
Liu
S
,
Rao
Z
,
Wang
Y
,
Zhang
B
,
Li
H
, et al
.
Retinoid X receptor gamma dictates the activation threshold of group 2 innate lymphoid cells and limits type 2 inflammation in the small intestine
.
Immunity
.
2023
;
56
(
11
):
2542
54.e7
.
37.
Leung
AM
,
Rao
MB
,
Raju
N
,
Chung
M
,
Klinger
A
,
Rowe
DJ
, et al
.
A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 ocular retardation J mice
.
Dev Dyn
.
2023
;
252
(
11
):
1338
62
.
38.
Qin
W
,
Ren
Z
,
Xu
C
,
Cao
YN
,
Sun
MA
,
Huang
R
, et al
.
Chromatin accessibility and transcriptional landscape during inhibition of Salmonella enterica by lactobacillus reuteri in IPEC-J2 cells
.
Cells
.
2023
;
12
(
6
):
968
.
39.
Zhao
K
,
Zeng
L
,
Cai
Z
,
Liu
M
,
Sun
T
,
Li
Z
, et al
.
RNA sequencing-based identification of the regulatory mechanism of microRNAs, transcription factors, and corresponding target genes involved in vascular dementia
.
Front Neurosci
.
2022
;
16
:
917489
.
40.
Marchese
A
,
Sawzdargo
M
,
Nguyen
T
,
Cheng
R
,
Heng
HH
,
Nowak
T
, et al
.
Discovery of three novel orphan G-protein-coupled receptors
.
Genomics
.
1999
;
56
(
1
):
12
21
.
41.
Kawasawa
Y
,
Kume
K
,
Nakade
S
,
Haga
H
,
Izumi
T
,
Shimizu
T
.
Brain-specific expression of novel G-protein-coupled receptors, with homologies to Xenopus PSP24 and human GPR45
.
Biochem Biophys Res Commun
.
2000
;
276
(
3
):
952
6
.
42.
Cui
J
,
Ding
Y
,
Chen
S
,
Zhu
X
,
Wu
Y
,
Zhang
M
, et al
.
Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity
.
J Clin Invest
.
2016
;
126
(
9
):
3192
206
.
43.
Cirelli
T
,
Nepomuceno
R
,
Goveia
JM
,
Orrico
SRP
,
Cirelli
JA
,
Theodoro
LH
, et al
.
Association of type 2 diabetes mellitus and periodontal disease susceptibility with genome-wide association-identified risk variants in a Southeastern Brazilian population
.
Clin Oral Investig
.
2021
;
25
(
6
):
3873
92
.
44.
Arvanitakis
Z
,
Tatavarthy
M
,
Bennett
DA
.
The relation of diabetes to memory function
.
Curr Neurol Neurosci Rep
.
2020
;
20
(
12
):
64
.
You do not currently have access to this content.