Invest Clin 66(4): 349 - 364, 2025 https://doi.org/10.54817/IC.v66n4a01
Correspondence author: Yingchun Ling. Department of Clinical Laboratory, Shaoxing Seventh People’s Hospital,
Shaoxing, Zhejiang Province. China. Email: sxdqrm2025@hotmail.com
The role of amyloid and tau biomarkers
in assessing the effectiveness of drug
treatment for Alzheimer’s disease.
Jiao Sun¹, Yingchun Ling², Jie Chen² and Mingyong Zhao³
¹Department of Pharmacy, Shaoxing Seventh People’s Hospital, Shaoxing, Zhejiang
Province, China.
²Department of Clinical Laboratory, Shaoxing Seventh People’s Hospital, Shaoxing,
Zhejiang Province, China.
³Department of Geriatrics Shaoxing Seventh People’s Hospital, Shaoxing, Zhejiang
Province.
Keywords: Amyloid Beta-Peptides; Tau Proteins; Phosphorylated Tau; P-Tau-181,
Alzheimer Disease; Drug Therapy.
Abstract. This study aimed to explore the role of amyloid and tau biomark-
ers in evaluating the effectiveness of drug therapy for Alzheimer’s disease (AD). A
retrospective analysis was performed in 150 AD patients admitted to our hospital
from October 2022 to January 2024, and 50 healthy people were selected as the
control group. The basic information of patients, including cognitive function and
daily living ability, as well as amyloid and tau biomarkers, was compared between the
two groups. AD patients were treated with donepezil hydrochloride and memantine
tablets, and were divided into valid and invalid groups based on efficacy. Binary logis-
tic regression analysis was used to identify factors affecting the effectiveness of AD
drug treatment, with the predictive accuracy being assessed using ROC curves. This
study revealed that compared with the control group, the MMSE (Mini-Mental State
Examination), MoCA (Montreal Cognitive Assessment), and Aβ1-42 in the AD group
decreased, while T-tau and P-Tau-181 increased (p<0.05). Drug treatment was con-
sidered effective in 107 out of 150 AD patients. Education years, daily exercise,
Aβ1-42, T-tau, and P-Tau-181 are all factors that affect the effectiveness of AD drug
treatment. The changes in serum levels of Aβ1-42, T-tau, and P-Tau-181 can all be
used to evaluate the effectiveness of AD drug treatment, with AUC values of 0.869,
0.815, and 0.800, respectively. The combined evaluation of the three factors has an
AUC of 0.977. Drug therapy can improve the clinical efficacy of most AD patients.
The years of education, exercise, Aβ1-42, T-tau and P-Tau-181 are the influencing
factors of the efficacy of AD drug treatment. The efficacy of AD drug treatment can
be evaluated by detecting the changes of serum Aβ1-42, T-tau and P-Tau-181 levels
in clinical practice, and the combined evaluation value of the three is higher than
the individual values.
350 Sun et al.
Investigación Clínica 66(4): 2025
El papel de los biomarcadores de amiloide y tau en la
evaluación de la eficacia del tratamiento farmacológico
para la enfermedad de Alzheimer.
Invest Clin 2025; 66 (4): 349 – 364
Palabras clave: Péptidos Beta-Amiloide; Proteínas Tau; Proteína Tau Fosforilada;
P-Tau- 181; Enfermedad de Alzheimer; Terapia Farmacológica.
Resumen. El objetivo de este estudio es explorar el papel de los biomar-
cadores de amiloide y tau en la evaluación de la eficacia de la farmacoterapia
para la enfermedad de Alzheimer (EA). Se realizó un análisis retrospectivo de
150 pacientes con EA ingresados en nuestro hospital entre octubre de 2022
y enero de 2024, y se seleccionaron 50 personas sanas como grupo control.
Se compararon la información básica, la función cognitiva, la capacidad para
realizar las actividades de la vida diaria, así como los biomarcadores de ami-
loide y tau entre ambos grupos. Los pacientes con EA fueron tratados con
tabletas de hidrocloruro de donepezilo y memantina, y se dividieron en un
grupo de pacientes que respondieron al tratamiento y otro grupo de pacien-
tes que no respondieron, en función de la eficacia del mismo. Se utilizó un
análisis de regresión logística binaria para identificar los factores que afectan
la eficacia del tratamiento farmacológico de la EA, y se evaluó la precisión
predictiva mediante curvas ROC. Los resultados de este estudio revelan que,
en comparación con el grupo control, en el grupo de EA, las puntuaciones en
las escalas MMSE, MoCA y los niveles de Aβ1-42 disminuyeron, mientras que
los niveles de T-tau y P-Tau-181 aumentaron (p<0,05). Después del tratamien-
to farmacológico, 107 de los 150 pacientes con EA mostraron una respuesta
favorable. Los años de educación, el ejercicio diario, los niveles de Aβ1-42,
T-tau y P-Tau-181 son todos factores que afectan la eficacia del tratamiento
farmacológico de la EA. Los cambios en los niveles séricos de Aβ1-42, T-tau y
P-Tau-181 pueden servir para evaluar la eficacia del tratamiento farmacológi-
co de la EA, con valores de área bajo la curva (AUC) de 0,869, 0,815 y 0,800,
respectivamente. La evaluación combinada de estos tres factores tiene un
AUC de 0,977. La farmacoterapia puede mejorar la eficacia clínica en la mayo-
ría de los pacientes con EA. Los años de educación, el ejercicio, los niveles de
Aβ1-42, T-tau y P-Tau-181 son los factores que influyen en la eficacia del trata-
miento farmacológico de la EA. La eficacia del tratamiento farmacológico de
la EA puede evaluarse detectando los cambios en los niveles séricos de Aβ1-
42, T-tau y P-Tau-181 en la práctica clínica. Además, el valor de la evaluación
combinada de estos tres biomarcadores es mayor que la evaluación de estos
factores individualmente.
Received: 02-07-2025 Accepted: 12-07-2025
Amyloid and tau biomarkers in Alzheimer’disease 351
Vol. 66(4): 349 - 364, 2025
INTRODUCTION
Alzheimer’s disease (AD) is a degen-
erative neurological disorder, clinically
manifested as memory impairment and ir-
reversible progressive memory loss, among
others. In addition, patients may also expe-
rience language and visual-spatial disorders,
which mainly affect the elderly 1, 2. With the
increase of aging, the incidence rate of AD
is increasing year by year, and its impact on
the social economy is also increasingly sig-
nificant 3. At present, AD is mainly relying
on drug treatment supplemented by com-
prehensive measures such as psychologi-
cal and cognitive interventions 4. In terms
of drug therapy, cholinesterase inhibitors,
glutamate receptor antagonists, and other
cognitive enhancement drugs are mainly
used 5. However, due to the complexity and
multifactorial nature of AD disease, as well
as the challenges faced in evaluating the ef-
fectiveness and safety of drugs 6, 7, and that
drug therapy can alleviate patients’ clinical
symptoms, the clinical efficacy is not satis-
factory, and additional methods are needed
to improve patients’ quality of life and cogni-
tive abilities 8, 9. Therefore, it is necessary to
explore biomarkers to evaluate the effective-
ness of drugs in order to develop personal-
ized treatment plans tailored to the specific
conditions of patients and enhance their
clinical efficacy.
Research has shown that the exces-
sive deposition of amyloid-β (Aβ) in cere-
bral blood vessels and the aggregation of
tau protein to form neurofibrillary tangles
are the primary pathological mechanisms
of AD 10,11. Aβ is a peptide generated by the
amyloid precursor protein (APP) 12, 13, and its
primary forms are Aβ1-42 and Aβ1-40, which
are important biomarkers in AD 14. Studies
have shown that excessive deposition of Aβ1-
42 promotes neuroinflammation, neuronal
death and cognitive dysfunction 15. For mild
AD patients, Aβ begins to accumulate abnor-
mally in the early stages of the disease, and
soluble Aβ1-42 levels decrease; however, the
damage to nerve cells and neural networks
is relatively mild at this time. Timely anti-
amyloid treatment can effectively prevent
the progression of the disease 16. Tau protein
plays a crucial role in maintaining the stabil-
ity of the microtubule structure, facilitating
axonal transport, and regulating neuronal
function 17. However, in AD patients, the ab-
normal phosphorylation and aggregation of
the Tau protein lead to the formation of neu-
rofibrillary tangles, which destroy the cellu-
lar structure and trigger neuronal death 18.
Among them, phosphorylated tau protein
181 (P-Tau-181) is a phosphorylated form
of T-tau 19. Under normal circumstances,
the content of P-Tau-181 in blood or spinal
fluid is minimal. Therefore, detection of P-
Tau-181 levels can reflect neural or cognitive
function 20.
However, there is currently no report
on whether amyloid protein and tau bio-
markers can be used to evaluate the effec-
tiveness of drug therapy. Therefore, this
study examines the role of serum Aβ1-42, P-
Tau-181, and T-tau biomarkers in evaluating
the effectiveness of AD drug therapy, aim-
ing to provide personalized treatment plans
for patients and thereby improve treatment
outcomes, to provide further laboratory
evidence for drug treatment and clinical
reference for saving patients’ lives and im-
proving prognosis.
MATERIALS AND METHODS
Subjects
Regression analysis was conducted on
150 AD patients admitted to our hospital
between February 2023 and January 2024.
Fifty healthy individuals were included as the
control group. Through multidisciplinary
consultations in neurology, psychiatry, reha-
bilitation, and other fields, comprehensive
evaluations and confirmations of AD pa-
tients were conducted using EEG and head
MRI examinations (Fig. 1).
Inclusion criteria: ①Meet the diagnos-
tic criteria for AD 21, age≥55 years; ②Com-
352 Sun et al.
Investigación Clínica 66(4): 2025
plete clinical data; ③Could communicate
fluently in Mandarin, understand the ques-
tionnaire content, and complete various sur-
vey evaluations; ④Good compliance; ⑤Ex-
pected survival period≥6 months; ⑥Tolerate
the treatment plan related to this study; ⑦A
score of≥27 on the Mini Mental State Exam-
ination (MMSE) and/or≥26 on the Montre-
al Cognitive Assessment Scale (M0CA) for
healthy individuals during the same period.
Exclusion criteria: ①Patients with
comorbidities of other mental illnesses;
②Long-term use of sedatives and sleeping
pills; ③Individuals who are allergic to the
medication used in this study; ④Serious in-
fectious diseases of body organs; ⑤Not will-
ing to comply with the follow-up and evalua-
tion plan of this study.
Ethical considerations
This study strictly adheres to the prin-
ciples of the Declaration of Helsinki, and
all research procedures comply with inter-
national ethical standards. Has obtained
approval from the ethics committee of Sha-
oxing Seventh People’s Hospital. All partici-
pants have signed an informed consent form.
In emergencies, the consent form may be
signed by a representative or guardian of the
individual. All data involved in the research
process has been anonymized to ensure the
privacy and confidentiality of participants’
identities.
Therapeutic approaches
All AD patients received drug treat-
ment: oral donepezil hydrochloride (Shaanxi
Fangzhou Pharmaceutical Co., Ltd., GYZZ
H20030583, specification: 5 mg), one tab-
let per day. The dose was adjusted four weeks
later, the maximum dose was two tablets/
per day. if severe insomnia occurred, they
were administered in the morning. Oral ad-
ministration of Meijingang tablets (Hang-
zhou Baishan Technology Co., Ltd., national
drug approval number H20213931, specifi-
Fig. 1. Study design drawing.
Amyloid and tau biomarkers in Alzheimer’disease 353
Vol. 66(4): 349 - 364, 2025
cation: 5mg), one tablet/per day, increas-
ing by one tablet/per day per week, the
maximum dose was four tablets/per day.
Regular monitoring of the patient’s blood
pressure and provision of medication guid-
ance and education was carried out during
nursing. Appropriate sleep schedules were
arranged to ensure adequate sleep. The diet
was guided to be light, to avoid overeating,
stimulating foods, and smoking and alcohol
consumption. Moreover, specific psycho-
logical counselling was provided, tailored
to the patient’s situation and treatment for
three months.
Detection of indicators
Clinical data: Relevant indicators and
clinical data of patients were collected with-
in 24 hours after admission, including gen-
der, age, BMI, clinical symptoms, imaging
data, and relevant laboratory examination
indicators, as well as basic diseases. Using
an electronic blood pressure measuring de-
vice (model: HEM-7124, Manufacturer: Om-
ron Company), systolic and diastolic blood
pressure values were recorded. Five mL of
venous blood was extracted from the pa-
tient, the serum separated and an automat-
ed chemical analyzer used to detect blood
calcium, fasting blood glucose, homocyste-
ine (Hcy), and creatinine (Cr), Urea (BUN),
total cholesterol (TC), triglycerides (TG),
low-density and high-density lipoprotein
cholesterol (LDL, HDL). Jinan Xinrun Med-
ical Equipment Co., Ltd, provided the in-
struments and supporting reagent kits. The
ELISA method was used to detect serum
neuregulin1 (NRGl) and Klotho protein.
The kit was purchased from Tinglai Biologi-
cal Company with item number J19117 and
validated by at least two intermediate-level
pathologists. If there was any objection,
the result was reviewed and confirmed by
a physician with a senior professional title
or above to ensure the reliability of the re-
sults.
Cognitive function: Evaluated with
the MMSE test (Mini-Mental State Examina-
tion)22, with 1 point for correct answers and
0 point for incorrect answers. The score is
proportional to cognitive function. Scores
higher than 26 indicate normal cognition.
At least one day later, the MoCA test 23 was
performed, which covers eight cognitive do-
mains related to visual spatial execution abil-
ity, naming, memory, abstract thinking, etc.
Scores above 25 indicate normal cognitive.
The total score for both tables is 30 points.
Daily living ability: The AD Patient
Activities of Daily Living Cooperative Study
Scale (ADCS-ADL) was used to evaluate it24.
The scale encompasses Basic Activities of
Daily Living (BADL) and Instrumental Ac-
tivities of Daily Living (IADL). The BADL
section evaluates more basic activities such
as dressing, eating, and toileting. The IADL
section encompasses complex daily or so-
cial activities, such as visiting, working, and
performing household chores, that require
more cognitive function. The total score is
22 and 56 points. The lower the score, the
lower the activity ability.
Amyloid and Tau biomarkers: venous
blood was collected from all participants on an
empty stomach and measured in real-time us-
ing an ELISA method according to diagnosis
and treatment needs. The kit was purchased
from Fujirebio Corporation in Japan and oper-
ated strictly according to the kit instructions.
Follow-up
After three months of drug treatment,
a clinical efficacy evaluation was conducted
on 150 patients 25, who were divided into
three groups: significantly effective (with
basic recovery of mental symptoms, com-
plete orientation, MMSE and MoCA scores
increased by≥4 points, and self-care abil-
ity); effective (with improvement of main
mental symptoms, basic orientation, MMSE
and MoCA scores increased by 1-3 points,
slightly delayed response, and basic self-
care ability); and ineffective (not meeting
the above criteria). The significant and ef-
fective were included in the valid group,
and the ineffective in the invalid group.
354 Sun et al.
Investigación Clínica 66(4): 2025
Outcome measures
Clinical data, cognitive function, and
biomarker levels (amyloid and tau) were
compared between AD patients and healthy
individuals. The effectiveness of drug ther-
apy compared the indicators of cognitive
and self-care abilities between the effective
and ineffective treatment groups. Factors in-
fluencing the effectiveness of drug therapy
were evaluated by determining the values of
serum Aβ1-42, T-tau, and P-Tau-181 levels in
predicting the effectiveness of drug therapy
in AD patients.
Statistical analysis
SPSS25.0 software package was used
to analyze the data; the count data were
expressed as an example (%), and the chi-
square test was applied. Measurement data
were presented as mean ± SD (±s), and a
t-test was conducted. An ROC curve was con-
structed, and the corresponding AUC was
computed to assess the effectiveness of drug
therapy in AD patients. p<0.05 was consid-
ered statistically significant.
RESULTS
Baseline data
No statistical difference was observed
in the baseline characteristics between the
two groups (p>0.05, Table 1).
Cognitive function and biological
indicators
The AD group exhibited decreased
MMSE, MoCA, and Aβ1-42 levels, as well as in-
creased T-tau and p-tau-181 levels, compared
to the control group (p<0.05, Table 2).
Clinical efficacy
After three months of drug treatment,
among the 150 AD patients, significant ef-
fective, effective and ineffective cases were
62, 45 and 43 cases, respectively, so 107 cas-
Table 1. Baseline comparison between Alzheimer’s Disease patients and controls.
Group nAge
(years)
Gender BMI
(kg/m2)
Years of Education
(years)
Male Female
Control group 50 66.30±6.08** 24 *(48.00) *26 (52.00) 23.24±1.10** 9.04±2.99**
AD group 150 65.45±5.81** *91 (60.67) *59 (39.33) 23.53±1.76** 9.22±4.08**
t/χ2-value -0.890 2.462 1.362 0.334
p-value 0.375 0.117 0.175 0.739
AD: Alzheimer’s Disease; BMI: Body Mass Index. The data is presented as * n (%), or** mean ± SD
Table 2. Comparison of indicators between Alzheimer’s Disease and control groups.
Group nMMSE MoCA Aβ1-40 Aβ1-42 T-tau P-Tau-181
Control
group 50 28.50±0.99 27.74±0.83 317.79±17.38 188.66±17.77 461.68±26.01 49.77±6.48
AD group 150 12.50±1.65 11.51±1.71 322.89±31.29 163.76±26.03 497.59±46.13 62.11±12.67
t-value -82.144 -89.167 1.439 -7.567 6.746 8.929
p<0.001 <0.001 0.152 <0.001 <0.001 <0.001
Abbreviations: AD: Alzheimer’s Disease; MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive As-
sessment; Aβ1-40: Amyloid-beta 1-40; Aβ1-42: Amyloid-beta 1-42; T-tau: Total tau protein; P-Tau-181: Phosphoryla-
ted tau protein at threonine 181. Data Expression: The data is presented as mean ± standard deviation (SD).
Amyloid and tau biomarkers in Alzheimer’disease 355
Vol. 66(4): 349 - 364, 2025
es were included in the valid group, account-
ing for 71.33%. There were 43 cases in the
invalid group, accounting for 28.67%.
Cognitive function and self-care ability
The MMSE, MoCA, BADL, and IADL
scores of the valid group were higher than
those of the invalid group (p<0.05, Table 3).
Univariate analysis of factors affecting
the effectiveness of drug therapy in AD
Compared with the invalid group, the
valid group had longer years of education,
engaged in daily exercise, had higher levels
of Aβ1-42, and lower levels of T-tau and P-
Tau-181 (p<0.05, Table 4).
Logistic regression analysis of factors
influencing the effectiveness of AD drug
therapy
Analyzing the statistically significant
factors in univariate analysis, with the ef-
fectiveness of AD drug treatment as the de-
pendent variable (effectiveness=0, ineffec-
tiveness=1), education years (actual value),
daily exercise (yes=1, no=0), Aβ1-42 (actu-
al value), T-tau (actual value), P-Tau-181 (ac-
tual value) as independent variables, binary
logistic regression analysis was conducted.
The results showed that education years,
daily exercise, Aβ1-42, T-tau, and P-Tau-181
were all factors affecting the effectiveness of
AD drug treatment (p<0.05, Table 5).
The predictive value of Aβ1-42, T-tau,
P-Tau-181 in AD drug therapy
The AUC values for predicting the effica-
cy of AD drug treatment using serum Aβ1-42,
T-tau, and P-Tau-181 levels were 0.869, 0.815,
and 0.800, respectively, with cut-off values
of 154.67 (ng/L), 517.95 (ng/L), and 63.66
(ng/L). The sensitivities were 76.74%, 69.77%,
and 72.09%, respectively, and the specificities
were 83.18%, 81.31%, and 71.03%. The AUC
of the joint prediction of the three factors is
0.954, with a cut-off value of 0.292, a sensitiv-
ity of 90.70%, and a specificity of 93.46%, See
Fig. 2 and Table 6.
Table 3. Comparison of MMSE, MoCA, BADL, IADL between valid and invalid groups.
Group nMMSE MoCA
Before treatment After treatment Before treatment After treatment
Valid group 107 12.44±1.67 20.33±5.20* 11.59±1.79 19.26±4.81*
Invalid group 43 12.65±1.60 12.21±2.65 11.33±1.49 11.05±2.47
t-value -0.710 12.580 0.854 13.735
p 0.471 <0.001 0.395 <0.001
Group nBADL IADL
Before treatment After treatment Before treatment After treatment
Valid group 107 8.32±1.47 16.43±3.06* 18.71±1.41 29.56±5.56*
Invalid group 43 8.16±1.79 9.28±1.32* 19.02±1.54 21.35±2.40*
t-value 0.505 19.996 -1.200 12.625
p value 0.616 <0.001 0.232 <0.001
Compared with before the treatment, *p<0.05.
Abbreviations: AD: Alzheimer’s Disease; MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive As-
sessment; BADL: Basic Activities of Daily Living; IADL: Instrumental Activities of Daily Living. Data Expression:
The data is presented as mean ± standard deviation (SD).
356 Sun et al.
Investigación Clínica 66(4): 2025
Table 4. Univariate analysis of factors affecting the effectiveness of drug therapy
in Alzheimer’s disease patients.
Factors n Valid group
(n=107)
Invalid group
(n=43) t/χ2-value p
Age (years) 65.30±5.97 65.81±5.43 -0.490 0.625
Gender
Male 91 68 (63.55) 23 (53.49)
Female 59 39 (66.45) 20 (46.51)
Duration of disease (years) 3.14±0.44 3.23±0.57 -0.952 0.345
BMI (kg/m2) 23.51±1.76 23.59±1.78 -0.247 0.805
Systolic pressure (mmHg) 130.04±16.01 128.81±12.28 0.450 0.653
Diastolic pressure (mmHg) 79.21±8.08 79.51±10.48 -0.167 0.868
Years of Education (years) 10.93±3.82 4.95±2.42 12.298 <0.001
Drinking
Ye s 109 80 (74.77) 29 (67.44) 2.511 0.113
No 41 27 (25.23) 14 (32.56)
Family history
Ye s 15 10 (9.35) 5 (11.63) 0.177 0.674
No 135 97 (90.65) 38 (88.37)
Diabetes
Ye s 34 21 (19.63) 13 (30.23) 1.969 0.161
No 116 86 (80.37) 30 (69.77)
Hyperlipidemia
Ye s 50 32 (29.91) 18 (41.86) 1.972 0.160
No 100 75 (70.09) 25 (58.14)
Marital status
Married 117 87 (81.31) 30 (69.77) 2.381 0.123
Other 33 20 (18.69) 13 (30.23)
Daily exercise
Ye s 100 85 (79.44) 15 (34.88) 27.402 <0.001
No 50 22 (20.56) 28 (65.12)
Blood calcium (mmol/L) 2.28±0.17 2.32±0.14 -1.499 0.136
Fasting blood glucose
(mmol/L) 4.95±1.01 4.98±0.79 -0.144 0.886
Hcy (μmol/L) 17.72±3.11 17.96±2.90 -0.436 0.664
Cr (μmol/L) 57.66±6.31 57.73±4.60 -0.073 0.942
BUN (mmol/L) 5.38±1.28 5.28±0.89 0.551 0.582
TC (mmol/L) 4.92±1.04 4.97±0.69 -0.382 0.703
TG (mmol/L) 1.28±0.18 1.30±0.20 -0.557 0.579
Amyloid and tau biomarkers in Alzheimer’disease 357
Vol. 66(4): 349 - 364, 2025
Factors n Valid group
(n=107)
Invalid group
(n=43) t/χ2-value p
LDL (mmol/L) 2.75±0.32 2.76±0.39 -0.289 0.773
HDL (mmol/L) 1.26±0.14 1.27±0.10 -0.352 0.726
NRGl (ng/L) 340.62±27.22 332.20±30.48 1.665 0.100
Aβ1-40 (ng/L) 321.83±29.51 325.53±35.56 -0.653 0.515
Aβ1-42 (ng/L) 173.90±24.76 138.50±24.76 8.464 <0.001
T-tau (ng/L) 483.43±41.57 532.83±37.49 12.298 <0.001
P-Tau-181 (ng/L) 57.97±9.96 72.41±12.91 -6.590 <0.001
Abbreviations: BMI: Body Mass Index; Hcy: Homocysteine; Cr: Creatinine; BUN: Blood Urea Nitrogen; TC: Total
Cholesterol; TG: Triglycerides; LDL: Low-Density Lipoprotein; HDL: High-Density Lipoprotein; NRGl: Neurogranin;
Aβ1-40: Amyloid-beta 1-40; Aβ1-42: Amyloid-beta 1-42; T-tau: Total tau protein; P-Tau-181: Phosphorylated tau pro-
tein at threonine 181. Data Expression: The data is presented as mean ± standard deviation (SD) or n(%).
Table 4. CONTINUATION
Table 5. Logistic regression analysis of factors influencing the efficacy of drug treatment
in Alzheimer’s disease patients.
Factors B SE Wald/χ2 p OR 95%CI
Years of Education -0.487 0.146 11.125 0.001 0.614 0.461-0.818
Daily exercise -2.148 0.939 5.235 0.022 0.117 0.019-0.735
Aβ1-42 -0.065 0.022 8.400 0.004 0.937 0.897-0.979
T-tau 0.032 0.012 7.841 0.005 1.033 1.010-1.056
P-Tau-181 0.107 0.039 7.691 0.006 1.113 1.032-1.200
Abbreviations: AD: Alzheimer’s Disease; B: Regression Coefficient; SE: Standard Error; OR: Odds Ratio; 95% CI:
95% Confidence Interval; Aβ1-42: Amyloid-beta 1-42; T-tau: Total Tau Protein; P-Tau-181: Phosphorylated Tau Pro-
tein at Threonine 181.
Fig. 2. ROC curves for predicting the therapeutic effect of AD drugs using Aβ1-42, T-tau, P-Tau-181.
Sensitivity
100-Specificity (%)
358 Sun et al.
Investigación Clínica 66(4): 2025
DISCUSSION
AD is a global public health and social
care issue, with 10 million AD patients in Chi-
na 26, and the patient population is becoming
younger. Early prevention and treatment, as
well as improving the effectiveness and safe-
ty of drug therapy, are important means to
delay disease progression and enhance qual-
ity of life. Aβ1-42 is a protein fragment pro-
duced by enzymatic hydrolysis of APP, which
can be used as an effective indicator of cog-
nitive function 27. Tau protein can stabilize
microtubules in nerve cells and is closely
associated with cognitive impairment28.
Relevant studies have shown 29, 30, that the
Aβ1-42, T-tau and P-tau-181 proteins can be
used to evaluate the occurrence of cognitive
impairment in AD patients. Compared with
healthy individuals, serum Aβ1-42 levels are
decreased, and T-tau and P-Tau-181 levels are
increased in AD patients, which is consistent
with the results of this study. This suggests
that the changes in the above proteins can
serve as potential biomarkers for predicting
AD patients. However, there is currently no
report on whether they can evaluate the ef-
fectiveness of drug therapy in AD patients.
This study demonstrated effective
clinical efficacy in 107 of 150 AD patients
(71.33%) after three months of drug treat-
ment, while in 43 cases, it was ineffective,
accounting for 28.67%. The MMSE, MoCA,
BADL, and IADL scores of the valid group
were higher than those of the invalid group.
This suggests that donepezil hydrochloride
and memantine tablets can enhance the ef-
ficacy, cognitive function, and self-care abili-
ties of most patients. It is speculated that
donepezil hydrochloride is an acetylcholin-
esterase inhibitor, which increases the con-
centration of acetylcholine by inhibiting its
activity and reducing its breakdown, thereby
improving patients’ cognitive function and
neurotransmission function 31. Moreover,
this process is reversible and can help stabi-
lize the level of acetylcholine in the body32.
Meijingang tablets are a non-competitive
NMDA antagonist that can reduce neurotox-
icity by blocking excessive glutamate activa-
tion of NMDA receptors, thereby protecting
neurons and enhancing cognitive function33.
The combination of the two can exert a syn-
ergistic effect, further improving the clini-
cal efficacy, cognitive function, and self-care
ability of AD patients. However, there are
still a few patients with unsatisfactory treat-
ment outcomes. Therefore, we need to ex-
plore further the factors that affect the
effectiveness of drug therapy, such as edu-
cation level, physical activity, and severity of
the disease, so that the medical staff can ad-
just the dosage and type of drugs according
to the patient’s condition on time, in order
to improve the efficacy of drug treatment.
Logistic regression analysis showed
that education years, daily exercise, Aβ1-42,
T-tau, and P-Tau-181 are influencing factors
on the effectiveness of AD drug treatment.
It is speculated that this may be because the
length of education is closely related to the
cognitive reserve of the brain, which is the
Table 6. Diagnostic Value of A β1-42, T-tau, P-Tau-181 in the Efficacy of Alzheimer’s
disease drug therapy.
Indicators AUC p Best Cut-off Value Sensitivity (%) Specificity (%) 95% CI
Aβ1-42 0.869 <0.001 154.67 76.74 83.18 0.805-0.919
T-tau 0.815 <0.001 517.95 69.77 81.31 0.743-0.874
P-tau-181 0.800 <0.001 63.66 72.09 71.03 0.727-0.861
Unite 0.954 <0.001 0.292 90.70 93.46 0.908-0.982
Abbreviations: AUC: Area Under the Curve; 95% CI: 95% Confidence Interval; Aβ1-42: Amyloid-beta 1-42; T-tau:
Total Tau Protein; P-Tau-181: Phosphorylated Tau Protein at Threonine 181.
Amyloid and tau biomarkers in Alzheimer’disease 359
Vol. 66(4): 349 - 364, 2025
brain’s ability to maintain cognitive abili-
ties by activating and utilizing previously
experienced neural networks, and serves as
a resource for processing information and
solving problems 34. Patients with longer ed-
ucational years are tipically able to accumu-
late more knowledge and problem-solving
skills, have higher cognitive reserves, main-
tain higher treatment compliance when fac-
ing treatment, better understand the im-
portance of medication treatment, and take
medication according to medical orders,
thereby improving treatment effectiveness35.
Furthermore, patients with higher education
are more likely to seek ways to obtain sup-
port from their families and society 36, and
to receive more help and encouragement
during the treatment process. Patients with
lower education may have poorer cognitive
function and self-care abilities, lack under-
standing of the disease, have greater disease
uncertainty, and thus lack attention and co-
operation in treatment, which affects treat-
ment efficacy 37. Daily exercise is considered
an important non-pharmacological interven-
tion that can improve brain health, enhance
neuroplasticity, promote blood circulation,
increase oxygen supply to the brain 38, en-
hance muscle strength, and improve cardio-
vascular function. It helps dementia patients
maintain good physical fitness, reduce func-
tional decline caused by physical reasons,
and improve functional outcomes. Exercise
also promotes the recovery of the endocrine
and immune system function 39, and helps
reduce AD-related pathological processes
such as inflammation and oxidative stress,
improving clinical outcomes. Studies have
shown that for AD patients receiving medi-
cation treatment, regular physical exercise
can not only alleviate potential side effects
such as fatigue and depression caused by
medication, but also improve patients’ com-
pliance with treatment. For example, dance,
as a physical and mental exercise method,
emphasizes calmness and relaxation during
movement, and requires concentration to
achieve a harmonious unity of conscious-
ness and movement, thereby achieving the
effects of physical and mental balance and
spiritual relaxation 40. In addition, exercise
can enhance dopamine binding ability in the
brain, delay neurodegenerative changes, de-
lay memory decline symptoms, and regulate
the secretion of neurotransmitters such as
norepinephrine. This can promote memory
recovery and enhance sensory input, reac-
tion speed, and other cognitive functions,
thereby achieving cognitive improvement 41.
In addition, exercise can reduce NLRP3 in-
flammation and improve the redox balance,
which together slow the progression of AD42.
Therefore, higher education levels and daily
exercise are factors that affect the effective-
ness of AD drug treatment.
Aβ deposition is one of the pathologi-
cal changes in AD, which can easily cause
neurotoxicity, inflammatory reactions, etc.,
leading to neuronal dysfunction, death, and
other phenomena 43. Moreover, Aβ1-42 is a
protein fragment produced by enzymatic hy-
drolysis of APP, the abnormal processing of
APP in AD patients reduces the production
of soluble Aβ1-42, leading to neuroinflam-
mation and neuronal damage, including in-
terference with nerve signal transmission,
triggering inflammatory reactions, damag-
ing the stability of neurons and synaptic
connections, ultimately resulting in patho-
logical changes and degenerative damage
to the nervous system, causing cognitive
impairment and other symptoms 44. The
reduction of Aβ1-42 may also affect the
pathological state of other key molecules,
such as the Tau protein, further accelerat-
ing disease progression. In addition, the re-
duction of Aβ1-42 also inhibits the activity
of gamma-secretase, thereby reducing the
clearance of Aβ deposition and forming a vi-
cious cycle45. Under normal circumstances,
tau protein maintains the stability and func-
tion of neuronal microtubules 46. However,
in AD, the T-tau protein undergoes exces-
sive phosphorylation, transforming it from
a microtubule-binding protein to the pri-
mary component of neurofibrillary tangles,
360 Sun et al.
Investigación Clínica 66(4): 2025
which in turn causes neuronal degenera-
tion and cognitive dysfunction. P-Tau-181, a
phosphorylated T-tau form, exhibits neuro-
toxicity, promoting neuronal death and dys-
function, thus impacting AD progression 47.
Therefore, low serum Aβ1-42 levels and high
levels of T-tau and P-Tau-181 in patients can
affect the effectiveness of drug treatment.
Consequently, we speculate that the effec-
tiveness of drug therapy can be evaluated
by monitoring changes in the levels of the
three factors. This study confirmed through
ROC curve analysis that the level changes
of the three have a good assessment value,
and the value of joint analysis of the three
is higher. The reason may be that they each
play unique and complementary roles in the
pathogenesis of AD patients, and together
affect cognitive function and drug efficacy.
Combined detection provides a more com-
prehensive reflection of the effectiveness of
drug treatment in patients, thereby improv-
ing their predictive value.
Although this study analyzed clinical
data from AD patients and explored early pre-
dictors of the effectiveness of drug therapy,
it has some limitations. This study is a ret-
rospective analysis with a small sample size
and a relatively short follow-up period of only
three months. While this duration was suffi-
cient to observe initial treatment responses,
it is important to note that AD is a chronic
and progressive condition. A more extended
follow-up period would be essential to fully
capture the dynamic changes in β-amyloid
and tau protein levels, as well as to better
understand the long-term effectiveness and
potential side effects of the drug therapy.
Future research should focus on prospective
studies with larger sample sizes and extend-
ed treatment cycles to improve the reliabil-
ity and applicability of the results.
Additionally, the potential heteroge-
neity of the patient sample is another limi-
tation. This study did not stratify patients
based on the stage of disease progression,
which could influence the observed treat-
ment responses and biomarker levels.
Patients with AD at different stages may
exhibit varying degrees of cognitive im-
pairment, biomarker profiles, and treat-
ment efficacy. Therefore, it is crucial to
consider the disease stage when interpret-
ing the results and to conduct stratified
analyses in future studies to account for
this variability. In the future, a compre-
hensive evaluation should be conducted
based on the influence of multiple bio-
markers and pathological mechanisms.
Moreover, a detailed assessment consider-
ing factors such as clinical manifestations,
genetic background, and disease severity
of patients should be performed to meet
the treatment needs of AD patients and
to develop more personalized therapeutic
strategies.
In conclusion, donepezil hydrochloride
combined with memantine tablets can im-
prove the clinical efficacy, function and self-
care ability of most patients with AD. How-
ever, the efficacy of treatment is not ideal
for some patients. Several factors influence
the effectiveness of Alzheimer’s disease (AD)
drug therapy, including years of education,
daily exercise, and biomarkers such as Aβ1-
42, T-tau, and P-Tau-181. In clinical practice,
the effectiveness of AD drug treatment can
be assessed by monitoring changes in the
levels of these three factors. Additionally, a
combined evaluation of all three factors pro-
vides a more comprehensive assessment of
treatment outcomes.
Acknowledgment
None.
Funding
To explore the mechanism of the NL-
RP3caspase-1GSDMD pathway mediated by
miR-146a-5p to regulate the progression of
Alzheimer’s disease based on the inflamma-
tory microenvironment (No. 2023A14029).
Study on the mechanism of regulat-
ing microglia mitochondria autophagy of
Amyloid and tau biomarkers in Alzheimer’disease 361
Vol. 66(4): 349 - 364, 2025
Ginseng Yangrong Decoction to improve
cognitive ability of Alzheimer’s disease (No.
2024ZL1138).
Conflicts of interest
The authors declare that they have no
financial conflicts of interest.
Consent to publish
The manuscript has neither been previ-
ously published nor is it under consideration
by any other journal. The authors have all ap-
proved the content of the paper.
Consent to participate
We secured a signed informed consent
form from every participant.
Ethic approval
This experiment was approved by the
Shaoxing Seventh People’s Hospital Ethics
Committee.
ORCID number of authors
• Jiao Sun (JS):
0009-0006-4570-0221
• Yingchun Ling (YL):
0009-0003-7630-3753
• Jie Chen (JC):
0009-0009-0661-9449
• Mingyong Zhao (MZ):
0009-0008-8142-2235
Author participation
JS: Developed and planned the study,
performed experiments, and interpreted
results. Edited and refined the manuscript
with a focus on critical intellectual contri-
butions. YL, JC: Participated in collecting,
assessing, and interpreting the data. Made
significant contributions to date interpreta-
tion and manuscript preparation. MZ: Pro-
vided substantial intellectual input during
the drafting and revision of the manuscript.
REFERENCES
1. Lopez-Lee C, Torres ERS, Carling
G, Gan L. Mechanisms of sex differ-
ences in Alzheimer’s disease. Neuron.
2024;112(8):1208-1221. https://doi.org/
10.1016/j.neuron.2024.01.024.
2. Gustavsson A, Norton N, Fast T, Frölich
L, Georges J, Holzapfel D, et al. Global
estimates on the number of persons across
the Alzheimer’s disease continuum. Al-
zheimers Dement. 2023;19(2):658-670.
https://doi.org/10.1002/alz.12694.
3. 2023 Alzheimer’s disease facts and figures.
Alzheimers Dement. 2023;19(4):1598-
1695. https://doi.org/10.1002/alz.13016.
4. Jucker M, Walker LC. Alzheimer’s dis-
ease: From immunotherapy to immunopre-
vention. Cell. 2023;186(20):4260-4270.
https://doi.org/10.1016/j.cell.2023.08.
021.
5. Reuben DB, Kremen S, Maust DT. De-
mentia Prevention and Treatment: A
Narrative Review. JAMA Intern Med.
2024;184(5):563-572. https://doi.org/10.
1001/jamainternmed.2023.8522.
6. Rostagno AA. Pathogenesis of Alzheimer’s
Disease. Int J Mol Sci. 2022;24(1):107.
https://doi.org/10.3390/ijms24010107.
7. Ashrafizadeh M. Cell Death Mechanisms
in Human Cancers: Molecular Pathways,
Therapy Resistance and Therapeutic Per-
spective. JCBT. 2024;1(1):17-40. http://
dx.doi.org/10.62382/jcbt.v1i1.13
8. Majidazar R, Rezazadeh-Gavgani E, Sa-
digh-Eteghad S, Naseri A. Pharmacother-
apy of Alzheimer’s disease: an overview
of systematic reviews. Eur J Clin Pharma-
col. 2022;78(10):1567-1587. https://doi.
org/10.1007/s00228-022-03363-6.
9. Jun R. Advances in Combination Ther-
apy for Gastric Cancer: Integrating Tar-
geted Agents and Immunotherapy. ACPT.
2024;1(1):1-15. https://doi.org/10.63623
/9k14tf70
10. Söderberg L, Johannesson M, Nygren
P, Laudon H, Eriksson F, Osswald G, et
al. Lecanemab, Aducanumab, and Gan-
tenerumab - Binding Profiles to Different
Forms of Amyloid-Beta Might Explain Ef-
362 Sun et al.
Investigación Clínica 66(4): 2025
ficacy and Side Effects in Clinical Trials for
Alzheimer’s Disease. Neurotherapeutics.
2023;20(1):195-206. https://doi.org/10.
1007/s13311-022-01308-6.
11. Zhang J, Zhang Y, Wang J, Xia Y, Zhang
J, Chen L. Recent advances in Alzheimer’s
disease: Mechanisms, clinical trials and new
drug development strategies. Sig Transduct
Target Ther. 2024;9(1):211. https://doi.
org/10.1038/s41392-024-019 11-3.
12. Jin J, Xu Z, Zhang L, Zhang C, Zhao X,
Mao Y, et al. Gut-derived β-amyloid: Likely
a centerpiece of the gut-brain axis contrib-
uting to Alzheimer’s pathogenesis. Gut mi-
crobes. 2023;15(1):2167172. https://doi.or
g/10.1080/19490976.2023.2167172.
13. Hur JY. γ-Secretase in Alzheimer’s disease.
Exp Mol Med. 2022;54(4):433-446. https://
doi.org/10.1038/s12276-022-007 54-8.
14. Chatterjee P, Pedrini S, Doecke JD, Thota
R, Villemagne VL, Doré V, et al. Plasma
Aβ42/40 ratio, p-tau181, GFAP, and NfL
across the Alzheimer’s disease continu-
um: A cross-sectional and longitudinal
study in the AIBL cohort. Alzheimers De-
ment. 2023;19(4):1117-1134. https://doi.
org/10.1002/alz.12724.
15. Zeng XX, Zeng JB. Systems Medicine as a
Strategy to Deal with Alzheimer’s Disease.
J Alzheimers Dis. 2023;96(4):1411-1426.
https://doi.org/10.3233/JAD-230739.
16. Perneczky R, Dom G, Chan A, Falkai P,
Bassetti C. Anti-amyloid antibody treat-
ments for Alzheimer’s disease. Eur J
Neurol. 2024;31(2):e16049. https://doi.
org/10.1111/ene.16049.
17. Young-Pearse TL, Lee H, Hsieh YC, Chou
V, Selkoe DJ. Moving beyond amyloid and
tau to capture the biological heterogene-
ity of Alzheimer’s disease. Trends Neu-
rosci. 2023;46(6):426-444. https://doi.
org/10.1016/j.tins.2023.03.005.
18. Ossenkoppele R, van der Kant R, Hans-
son O. Tau biomarkers in Alzheimer’s
disease: towards implementation in clini-
cal practice and trials. Lancet Neurol.
2022;21(8):726-734. https://doi.org/10.1
016/S1474-4422(22)00168-5.
19. Brickman AM, Manly JJ, Honig LS, San-
chez D, Reyes-Dumeyer D, Lantigua RA,
et al. Plasma p-tau181, p-tau217, and other
blood-based Alzheimer’s disease biomark-
ers in a multi-ethnic, community study. Al-
zheimers Dement. 2021;17(8):1353-1364.
https://doi.org/10.1002/alz.12301.
20. Dubois B, von Arnim CAF, Burnie N,
Bozeat S, Cummings J. Biomarkers in
Alzheimer’s disease: role in early and dif-
ferential diagnosis and recognition of
atypical variants. Alzheimers Res Ther.
2023;15(1):175. https://doi.org/10.1186/
s13195-023-01314-6.
21. Brooker D, La Fontaine J, Evans S, Bray
J, Saad K. Public health guidance to fa-
cilitate timely diagnosis of dementia:
ALzheimer’s COoperative Valuation in
Europe recommendations. Int J Geriatr
Psychiatry. 2014;29(7):682-693. https://
doi.org/10.1002/gps.4066.
22. Engedal K, Benth J, Gjøra L, Skjellegrind
HK, Nåvik M, Selbæk G. Normative Scores
on the Norwegian Version of the Mini-
Mental State Examination. J Alzheimers
Dis. 2023;92(3):831-842. https://doi.org/
10.3233/JAD-221068.
23. Lima Pereira V, Freitas S, Simões MR,
Gerardo B. Montreal Cognitive Assess-
ment (MoCA): A validation study among
prisoners. Crim Behav Ment Health.
2023;33(5):330-341. https://doi.org/10.
1002/cbm.2306.
24. Monteiro C, Toth B, Brunstein F, Bobbala
A, Datta S, Ceniceros R, et al. Randomized
Phase II Study of the Safety and Efficacy of
Semorinemab in Participants with Mild-to-
Moderate Alzheimer Disease: Lauriet. Neu-
rology. 2023;101(14):e1391-e1401. https://
doi.org/10.1212/WNL.000000000 0207663.
25. Lacorte E, Ancidoni A, Zaccaria V, Re-
moli G, Tariciotti L, Bellomo G, et al.
Safety and Efficacy of Monoclonal Antibod-
ies for Alzheimer’s Disease: A Systematic
Review and Meta-Analysis of Published and
Unpublished Clinical Trials. J Alzheim-
ers Dis. 2022;87(1):101-129. https://doi.
org/10.3233/JAD-220046.
26. Zhang YT, Chen Y, Shang KX, Yu H, Li XF,
Yu H. Effect of Volatile Anesthesia Versus
Intravenous Anesthesia on Postoperative
Pulmonary Complications in Patients Un-
Amyloid and tau biomarkers in Alzheimer’disease 363
Vol. 66(4): 349 - 364, 2025
dergoing Minimally Invasive Esophagec-
tomy: A Randomized Clinical Trial. Anesth
Analg. 2024;139(3):571-580. https://doi.
org/10.1213/ANE.0000000000006814.
27. Zhu M, Xiao B, Xue T, Qin S, Ding J, Wu
Y, et al. Cdc42GAP deficiency contributes
to the Alzheimer’s disease phenotype.
Brain. 2023;146(10):4350-4365. https://
doi.org/10.1093/brain/awad184.
28. Kashif M, Sivaprakasam P, Vijendra P,
Waseem M, Pandurangan AK. A Recent
Update on Pathophysiology and Therapeu-
tic Interventions of Alzheimer’s Disease.
Curr Pharm Des. 2023;29(43):3428-3441.
https://doi.org/10.2174/0113816128264
355231121064704.
29. Giacomucci G, Mazzeo S, Crucitti C, In-
gannato A, Bagnoli S, Padiglioni S, et
al. Plasma p-tau181 as a promising non-
invasive biomarker of Alzheimer’s Disease
pathology in Subjective Cognitive Decline
and Mild Cognitive Impairment. J Neu-
rol Sci. 2023;453:120805. https://doi.
org/10.1016/j.jns.2023.120805.
30. Yang W, Guan F, Yang L, Shou G, Zhu F, Xu Y,
et al. Highly sensitive blood-based biomark-
ers detection of beta-amyloid and phos-
phorylated-tau181 for Alzheimer’s disease.
Front Neurol. 2024;15:1445479. https://
doi.org/10.3389/fneur.2024.1445479.
31. Guo J, Wang Z, Liu R, Huang Y, Zhang N,
Zhang R. Memantine, Donepezil, or Combi-
nation Therapy-What is the best therapy for
Alzheimer’s Disease? A Network Meta-Anal-
ysis. Brain Behav. 2020;10(11):e01831.
https://doi.org/10.1002/brb3.1831.
32. Buck A, Rezaei K, Quazi A, Goldmeier G,
Silverglate B, Grossberg GT. The donepe-
zil transdermal system for the treatment of
patients with mild, moderate, or severe Al-
zheimer’s disease: a critical review. Expert
Rev Neurother. 2024;24(6):607-614. https://
doi.org/10.1080/14737175.2024.2355981.
33. Zohny SM, Habib MZ, Mohamad MI,
Elayat WM, Elhossiny RM, El-Salam MFA,
et al. Memantine/Aripiprazole Combina-
tion Alleviates Cognitive Dysfunction in
Valproic Acid Rat Model of Autism: Hip-
pocampal CREB/BDNF Signaling and
Glutamate Homeostasis. Neurotherapeu-
tics. 2023;20(2):464-483. https://doi.
org/10.1007/s13311-023-01360-w.
34. Savarimuthu A, Ponniah RJ. Cognition
and Cognitive Reserve. Integr Psychol Be-
hav Sci. 2024;58(2):483-501. https://doi.
org/10.1007/s12124-024-09821-3.
35. Umarova RM, Schumacher LV, Schmidt
CSM, Martin M, Egger K, Urbach H, et
al. Interaction between cognitive reserve
and age moderates effect of lesion load on
stroke outcome. Sci Rep. 2021;11(1):4478.
https://doi.org/10.1038/s41598-021-
83927-1.
36. Hassan M, Fang S, Malik AA, Lak TA, Riz-
wan M. Impact of perceived social support
and psychological capital on university stu-
dents’ academic success: testing the role
of academic adjustment as a moderator.
BMC Psychol. 2023;11(1):340. https://doi.
org/10.1186/s40359-023-01385-y.
37. Rosselli M, Uribe IV, Ahne E, Shihadeh
L. Culture, Ethnicity, and Level of Educa-
tion in Alzheimer’s Disease. Neurothera-
peutics. 2022;19(1):26-54. https://doi.
org/10.1007/s13311-022-01193-z.
38. Iso-Markku P, Kujala UM, Knittle K, Polet
J, Vuoksimaa E, Waller K. Physical activity
as a protective factor for dementia and Al-
zheimer’s disease: systematic review, me-
ta-analysis and quality assessment of co-
hort and case-control studies. Br J Sports
Med. 2022;56(12):701-709. https://doi.
org/10.1136/bjsports-2021-104981.
39. López-Ortiz S, Lista S, Valenzuela PL,
Pinto-Fraga J, Carmona R, Caraci F, et
al. Effects of physical activity and exercise
interventions on Alzheimer’s disease: an
umbrella review of existing meta-analyses.
J Neurol. 2023;270(2):711-725. https://
doi.org/10.1007/s00415-022-11454-8.
40. Fong Yan A, Nicholson LL, Ward RE, Hiller
CE, Dovey K, Parker HM, et al. The Effective-
ness of Dance Interventions on Psychological
and Cognitive Health Outcomes Compared
with Other Forms of Physical Activity: A Sys-
tematic Review with Meta-analysis. Sports
Med. 2024;54(5):1179-1205. https://doi.
org/10.1007/s40279-02 3-01990-2.
41. The 2023 nonhormone therapy posi-
tion statement of The North Ameri-
364 Sun et al.
Investigación Clínica 66(4): 2025
can Menopause Society. Menopause.
2023;30(6):573-590. https://doi.org/10.
1097/GME.0000000000002200.
42. Li X, Jin Y, Ding X, Zhu T, Wei C, Yao
L. Long-term exercise training inhibits
inflammation by suppressing hippocam-
pal NLRP3 in APP/PS1 mice. Sports Med
Health Sci. 2023;5(4):329-335. https://
doi.org/10.1016/j.smhs.2023.09.009.
43. da Rosa MM, de Aguiar Ferreira M, de
Oliveira Lima CA, Santos Mendonça AC,
Silva YM, Sharjeel M, et al. Alzheimer’s
disease: Is there a role for galectins? Eur J
Pharmacol. 2021;909:174437. https://doi.
org/10.1016/j.ejphar.2021.174437.
44. Wu W, Ji Y, Wang Z, Wu X, Li J, Gu F, et al.
The FDA-approved anti-amyloid-β mono-
clonal antibodies for the treatment of Al-
zheimer’s disease: a systematic review and
meta-analysis of randomized controlled
trials. Eur J Med Res. 2023;28(1):544.
https://doi.org/10.1186/s40001-023-
01512-w.
45. Xiao L, Yang X, Sharma VK, Abebe D,
Loh YP. Hippocampal delivery of neuro-
trophic factor-α1/carboxypeptidase E gene
prevents neurodegeneration, amyloidosis,
memory loss in Alzheimer’s Disease male
mice. Mol Psychiatry. 2023;28(8):3332-
3342. https://doi.org/10.1038/s41380-
023-02135-7.
46. Scheltens P, De Strooper B, Kivipelto
M, Holstege H, Chételat G, Teunissen
CE, et al. Alzheimer’s disease. Lancet.
2021;397(10284):1577-1590. https://doi.
org/10.1016/S0140-6736(20)32205-4.
47. Cai H, Pang Y, Fu X, Ren Z, Jia L. Plasma
biomarkers predict Alzheimer’s disease be-
fore clinical onset in Chinese cohorts. Nat
Commun. 2023;14(1):6747. https://doi.
org/10.1038/s41467-023-42596-6.
