Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy‐related cognitive impairment in patients with breast cancer who receive chemotherapy

Senbang Yao; Wen Li; Shaochun Liu; Yinlian Cai; Qianqian Zhang; Lingxue Tang; Sheng Yu; Yanyan Jing; Xiangxiang Yin; Huaidong Cheng

doi:10.1002/cam4.5319

. 2022 Oct 6;12(5):5209–5221. doi: 10.1002/cam4.5319

Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy‐related cognitive impairment in patients with breast cancer who receive chemotherapy

Senbang Yao ^1,², Wen Li ^1,², Shaochun Liu ^1,², Yinlian Cai ^1,², Qianqian Zhang ^1,², Lingxue Tang ^1,², Sheng Yu ^1,², Yanyan Jing ^1,², Xiangxiang Yin ^1,², Huaidong Cheng ^1,^2,^✉

PMCID: PMC10028021 PMID: 36200595

Abstract

Background

Chemotherapy‐related cognitive impairment (CRCI) is a common but easily overlooked condition that markedly affects the quality of life (QOL) of patients with breast cancer. The rs671 is a common gene polymorphism of aldehyde dehydrogenase 2 (ALDH2) in Asia that is involved in aldehyde metabolism and may be closely related to CRCI. However, no study has yet summarised the association between ALDH2 and CRCI.

Methods

This study enrolled one hundred and twenty‐four patients diagnosed with breast cancer according to the pathology results, genotyped for ALDH2 single‐nucleotide polymorphisms (SNP) to explore these. The mini‐mental state exam (MMSE), verbal fluency test (VFT), and digit span test (DST) results were compared in these patients before and after chemotherapy (CT).

Results

We found that patients with ALDH2 gene genotypes of rs671_GG, rs886205_GG, rs4648328_CC, and rs4767944_TT polymorphisms were more likely to suffer from cognitive impairment during chemotherapy. A trend toward statistical significance was observed for rs671_GG of DST (z = 2.769, p = 0.006), VFT (t = 4.624, P<0.001); rs886205_GG of DST (z = 3.663, P<0.001); rs4648328_CC of DST (z = 2.850, p = 0.004), VFT (t = 3.477, p = 0.001); and rs4767944_TT of DST (z = 2.967, p = 0.003), VFT (t = 2.776, p = 0.008). The cognitive indicators of these patients significantly decreased after chemotherapy (p < 0.05). The difference in ALDH2 rs671 was most obvious.

Conclusion

Our results showed what kinds of ALDH2 genotyped patients that are more likely to develop CRCI. In the future, it may be possible to infer the risk of CRCI by detecting the single‐nucleotide locus of ALDH2 that is conducive to strengthening clinical interventions for these patients and improving their QOL. More importantly, this study has important implications for Asian women with breast cancer as ALDH2 rs671 is a common polymorphism in Asians.

Keywords: breast cancer survivors, chemotherapy, cognitive impairment, CRCI

It may be possible to infer the risk of CRCI by detecting the single‐nucleotide locus of ALDH2 in patients with breast cancer who receive chemotherapy, which is conducive to strengthening clinical interventions for these patients and improving their QOL.

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1. INTRODUCTION

Breast cancer is the most common type of malignant tumour in women worldwide, ¹ representing nearly 25% of all cases ² and accounting for 6.5% of mortalities globally. ³ In China, the incidence of breast cancer is 7.33%, which ranks first among malignant tumours in females, with a death rate of approximately 6.9%. ⁴ , ⁵ , ⁶ Patients with breast cancer often need multiple chemotherapy treatments. ⁷ , ⁸ The physical health of patients with breast cancer is severely affected by the somatic side effects of chemotherapy. ⁹ However, a cognitive decline caused by chemotherapy also affects these patients' quality of life (QOL). Chemotherapy‐related cognitive impairment (CRCI) is used to define chemotherapy‐induced cognitive impairment in patients with cancer. ¹⁰ Currently, many countries and scientific research institutions are committed to exploring the neurobiological mechanisms of CRCI. ¹¹ , ¹² Further study is required on how to predict which patients' cognitive function is more likely to be affected by chemotherapy. Functional MRI is effective for exploring patient cognition; however, it is expensive and not widely available.

Studies have found that the effects of chemotherapy on cognition may be due to the accumulation of metabolites such as aldehyde, tau protein, ¹³ conjugated dienes, ¹⁴ hydroperoxides, ¹⁵ , ¹⁶ and so on. Among these, the aldehyde is more important in inducing oxidative stress and neuroinflammation. Because oxidative stress is one important mechanism for CRCI, ¹⁷ the normal metabolism of aldehyde can reduce neuroinflammation responses and maintain normal cognitive function. The protein encoded by the ALDH2 (aldehyde dehydrogenase 2) gene is a key enzyme in toxic aldehyde metabolism that converts aldehyde into acid. ¹⁸ Therefore, ALDH2 may be involved in influencing the extent of cognitive impairment in patients with breast cancer who receive chemotherapy. The ALDH2 single‐nucleotide polymorphisms (SNP) in rs671 is significant in Asian populations as 70% of these patients possess ALDH2 wild‐type (GG, rs671), while 30% have ALDH2 variants (G/A or A/A, rs671). Those with ALDH2 variants have greatly reduced ability to metabolise aldehydes and are more susceptible to cognitive impairment. ¹⁹ , ²⁰ Therfore, ALDH2 has received extensive attention in cancer and cardiovascular disease. ²¹ , ²² The cognitive regulatory function of ALDH2 in Alzheimer's disease (AD), ²³ Parkinson's disease, ²⁴ and diabetes‐associated cognitive impairments ²⁵ has received extensive attention. Yu et al. found that the ALDH2 rs671 genotype was correlated with cognitive status in patients with Parkinson's disease. ²⁴ Ying et al. found that ALDH2 upregulation can significantly improve cognitive function in AD mice. ²³ A Stanford University study found that low ALDH2 activity could contribute to increased cytotoxicity by producing more reactive oxygen species (ROS) during chemotherapy, ²⁶ and ROS is an important factor affecting cognitive function. ²⁷ Therefore, it is worth exploring whether ALDH2 plays a similar role in CRCI.

Previous studies on the genetic risk of CRCI have focused on the catechol‐O‐methyltransferase (COMT) gene. The COMT (rs165599) polymorphism has been reported to contribute to CRCI in patients with breast cancer. ²⁸ Recent studies have also found that three SNPs in genes related to cognitive function (APOE rs429358, ANKK1 rs1800497, and TOMM40 rs10119) are closely associated with CRCI. ²⁹ As ALDH2 rs671 is an important site that determines its functional activity, it is of great significance to explore the activity of its related sites.

The current study confirmed that ALDH2's role in cognitive function is important. The ALDH2 genotype may be associated with cognitive function after chemotherapy. Currently, no studies have explored this topic. This study was conducted to determine whether ALDH2 genotyping can identify which groups are more likely to be affected by cognitive function during chemotherapy. Positive results will have important implications for improving their QOL.

2. MATERIALS AND METHODS

2.1. Patients

This study enrolled one hundred and twenty‐four patients diagnosed with breast cancer according to pathology results. The histopathological type of breast cancer was determined on the basis of the WHO classification criteria of breast tumours. The tumour specimens were histologically graded depending on the Nottingham grading system. IHC staining was performed in all the cases for ER, PR, HER‐2, and Ki‐67 biomarkers for molecular pathology examination. The corresponding reference guide containing the WHO classification of breast tumours ³⁰ are the AJCC TNM staging system for breast cancer, ³¹ the NCCN Guidelines for Breast Cancer, ³² and St. Gallen International Expert Consensus. ³³ The patient cohort consisted of 124 females with an average age of 49.5 ± 10.50 years (mean and standard deviation). The baseline clinical and demographic characteristics of enrolled patients are presented in Table 1. The patients were recruited at the Second Affiliated Hospital of Anhui Medical University between September 2017 and August 2021. The exclusion criteria were as follows:(1) received radiotherapy and other treatments in the past; (2) had brain metastasis or cachexia; (3) suffered from bipolar disorders such as depression and anxiety; and (4) had impaired cognition as a result of other diseases, such as Alzheimer's disease, vascular dementia, and cerebral trauma. All patients provided informed consent before participating in this study.

TABLE 1.

Clinical and demographic characteristics of the research groups

	N/Mean ± SD	Percentage
Total number of patients	124	100%
Age (years)	49.5 ± 10.50	/
Education (years)	10.3 ± 3.86	/
Molecular classification
Luminal A	23	18.55%
Luminal B	47	37.90%
HER‐2 overexpression	34	27.42%
TNBC	20	16.13%
Pathological type
Invasive Carcinoma No Special Type	115	92.74%
Invasive Carcinoma Special Type	1	0.81%
Noninvasive carcinoma	7	5.65%
Other type	1	0.81%
KPS
100	2	1.61%
90	71	57.26%
80	33	26.61%
70	18	14.52%

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Abbreviations: KPS, Karnofsky performance status; TNBC, triple‐negative breast cancer.

2.2. Genotyping

The collected peripheral venous blood (3–5 ml) was stored in an ethylenediamine tetraacetic acid dipotassium salt (EDTA‐K2) tube at −80°C. A genomic QIAGENE kit (Cat#69504, Shanghai Genesky Bio‐Tech Co, Ltd) was used to extract genomic DNA from the blood. The DNA samples were kept at −20°C. An improved multiplex ligase detection reaction (iMLDR) was used for genotyping. Different fluorescently labelled allele‐specific oligonucleotide probe pairs were used to distinguish the alleles of each SNP. Different SNPs were recognised by distinct extended lengths at the 3'end. Two negative controls were used; one was a double‐distilled water template and the other was a DNA sample without primers, with other conditions remaining the same. Repeated tests were conducted, and the results were consistent. Finally, 5% of the total DNA samples were randomly selected and repeated for iMLDR genotyping using an ABI3730XL automated sequencer (Applied Biosystems), and the results were consistent to confirm the iMLDR results. The sequencing results were uploaded as supplementary raw data which can be opened with GeneMapper 4.1 (AppliedBiosystems, USA) software. The picture of the iMLDR SNP genotyping schematic diagram was uploaded in the manuscript as Figure S1. The picture of iMLDR (Sample 110) was uploaded in the manuscript as Figure S2, and other samples can also be opened with GeneMapper.

2.3. Cognitive screening test

The mini‐mental state exam (MMSE) was used to assess cognizant ability, including spatial and time recognition, calculation, short‐term memory, language, and visual–spatial abilities. It is mainly used to quickly check whether the subject has intellectual disabilities such as mental retardation and dementia. MMSE is one of the most influential cognitive screening tools. It has been widely used in families and communities because of its simple and convenient characteristics.

2.4. Neuropsychological tests

Programmatic neuropsychological tests were performed after starting chemotherapy and after six cycles of postoperative adjuvant chemotherapy to evaluate memory and cognitive function. The verbal fluency test (VFT) was used, in which patients were required to say as many animal names as possible within 60 s. The digit span test (DST) was used to evaluate short‐term memory, in which patients were asked to repeat a random sequence of numbers. The number of digits repeated in the correct order determined the score.

2.5. The expression of ALDH2 in brain

The Human Protein Atlas (HPA) has been used to explore the expression of ALDH2 in the brain. ³⁴ HPA was launched in 2003 as a project initiated by the Swedish scientific research sector to explore and summarise the expression of all human proteins in tissues and organs using ‐omics techniques (https://www.proteinatlas.org). The expression of ALDH2 in the brain was explored using the BRAIN section of the HPA. ALDH2 was also analysed in hippocampal formation and amygdala.

2.6. Statistical analysis

The proportions of qualitative variables were calculated. Means and standard deviations (SD) of quantitative variables were calculated. The data were tested for normality. The paired t‐test and paired Wilcoxon signed‐rank test were performed for normal and non‐normal distributions in continuous variable data, respectively. The independent‐samples t‐test and Mann–Whitney U‐test were performed for normal and non‐normal distribution in continuous variable data, respectively. Differences were considered statistically significant when the probability value was <0.05. The mean and SD of cognitive outcomes from similar studies and our previous pre‐experimental tests were used for sample size estimation. ²⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ With the test level of 0.05 on both sides and 80% power (1–β), the sample size was estimated using PASS (Power Analysis and Sample Size Software, version 15). GraphPad Prism 5.0, R language, and SPSS software (version 21.0) were used for statistical analysis and visualisation.

3. RESULTS

3.1. Process and enrolled patient profiles of the research

A flow diagram of our research strategy and the analytical method is shown in Figure 1. The baseline clinical and demographic characteristics of the 124 enrolled patients are presented in Table 1. General information about the four genotyped SNPs loci of the ALDH2 gene is shown in Table 2.

TABLE 2.

General information about four genotyped SNP loci of the ALDH2 gene

SNP	ALDH2
SNP	rs671	rs886205	rs4648328	rs4767944
CHR	12	12	12	12
Allele position	111,803,962	111,766,623	111,784,984	111,771,537
Ref allele	G	A	C	C
Alt allele	A	G	T	T
MAF (patients in this study)	0.214	0.102	0.278	0.380
MAF (1000 g‐CHBS)	0.216	0.132	0.272	0.406
P (HWE test)	1.000	1.000	0.103	0.840

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Abbreviations: 1000 g‐CHBS; 1000 Genomes of Han Chinese, Alt allele, alternative allele; CHR, chromosome; HWE, Hardy–Weinberg equilibrium; MAF, minor allele frequency; Ref allele; reference allele; SNP, single‐nucleotide polymorphisms.

3.2. Cognitive abilities of ALDH2_rs671 patients before and after chemotherapy

The comparison results of cognitive function before and after chemotherapy for different SNPs in ALDH2_rs671 are shown in Figure 2 and Table 3. No significant difference was noted in cognitive function between the two groups before chemotherapy. No significant difference was found in cognitive function between the BC and AC groups in rs671(AG/AA) patients. For rs671(GG) patients, the DST and VFT scores after chemotherapy were significantly reduced, suggesting a decline in cognitive ability.

Comparison of cognitive abilities of patients before and after chemotherapy. (A) Score of MMSE of those with *ALDH2*_rs671_GG. (B) Score of DST of those with *ALDH2*_rs671_GG. (C) Score of VFT of those with *ALDH2*_rs671_GG. (D) Score of MMSE of those with *ALDH2*_rs886205_GG. (E) Score of DST of those with *ALDH2*_rs886205_GG. (F) Score of VFT of those with *ALDH2*_rs886205_GG. BC means before chemotherapy, AC means after chemotherapy, *p < 0.05, **p < 0.01, ****p < 0.0001, and p < 0.05 were considered significant

TABLE 3.

Comparison of cognitive abilities before and after chemotherapy based on rs671 type

rs671	N	MMSE	DST	VFT
Before chemotherapy
rs671(GG) group	75	27.4 (1.69)	6.1 (0.72)	11.6 (1.46)
rs671(AG/AA) group	49	27.4 (1.51)	6.3 (0.82)	11.3 (1.59)
t/z		−0.027	−0.927	0.863
p		0.978	0.356	0.390
rs671(GG) patients
BC group	75	27.4 (1.69)	6.1 (0.72)	11.6 (1.46)
AC group	75	26.9 (1.49)	5.8 (0.85)	10.2 (1.85)
t/z		1.919	2.769 ^a	4.624
p		0.059	0.006^**	0.000^***
rs671(AG/AA) patients
BC group	49	27.4 (1.51)	6.3 (0.82)	11.3 (1.59)
AC group	49	26.8 (2.06)	6.0 (0.97)	10.5 (2.20)
t/z		1.641	1.979	1.920
p		0.107	0.054	0.061

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^{^a}

Wilcoxon signed‐rank test.

^**

p < 0.01.

^***

p < 0.001.

3.3. Cognitive abilities of ALDH2_rs886205 patients before and after chemotherapy

The comparison results of cognitive function before and after chemotherapy for different SNPs in ALDH2_rs886205 are shown in Figure 2 and Table 4. Before chemotherapy, the difference between the two groups was statistically significant only for the DST score. A statistically significant difference was found in the VFT scores between the BC and AC groups in rs886205 (AG/AA) patients. For rs886205 (GG) patients, the MMSE, DST, and VFT scores after chemotherapy were significantly reduced, suggesting a decline in cognitive ability.

TABLE 4.

Comparison of cognitive abilities before and after chemotherapy based on rs886205 type

rs886205	N	MMSE	DST	VFT
Before chemotherapy
rs886205 (GG) group	101	27.4 (1.69)	6.27 (0.78)	11.5 (1.51)
rs886205 (AG/AA) group	23	27.5 (1.27)	5.87 (0.57)	11.6 (1.53)
t/z		−0.216	2.346	−0.409
p		0.806	0.016 ^*	0.683
rs886205 (GG) patients
BC group	101	27.4 (1.69)	6.27 (0.78)	11.5 (1.51)
AC group	101	26.8 (1.73)	5.92 (0.93)	10.4 (1.91)
t/z		2.405	3.663 ^a	4.709
p		0.018 ^*	0.000^***	0.000^***
rs886205 (AG/AA) patients
BC group	23	27.5 (1.27)	5.87 (0.57)	11.6 (1.53)
AC group	23	27.0 (1.74)	5.83 (0.73)	10.2 (2.37)
t/z		0.828	0.253	2.273
p		0.417	0.803	0.033 ^*

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^{^a}

Wilcoxon signed‐rank test.

p < 0.05.

^***

p < 0.001.

3.4. Cognitive abilities of ALDH2_rs4648328 patients before and after chemotherapy

The comparison results of cognitive function before and after chemotherapy for different SNPs in ALDH2_rs4648328 are shown in Figure 3 and Table 5. No significant difference was observed in cognitive function between the two groups. A statistically significant difference was noted in the VFT scores between the BC and AC groups in rs4648328 (CT/TT) patients. For rs4648328 (CC) patients, the DST and VFT scores after chemotherapy were significantly reduced, suggesting a decline in cognitive ability.

Comparison of cognitive abilities of patients before and after chemotherapy. (A) Score of MMSE of those with *ALDH2*_rs4648328_CC. (B) Score of DST of those with *ALDH2*_rs4648328_CC. (C) Score of VFT of those with *ALDH2*_rs4648328_CC. (D) Score of MMSE of those with *ALDH2*_rs4767944_TT. (E) Score of DST of those with *ALDH2*_rs4767944_TT. (F) Score of VFT of those with *ALDH2*_rs4767944_TT. BC means before chemotherapy, AC means after chemotherapy, *p < 0.05, **p < 0.01, ****p < 0.0001, and p < 0.05 were considered significant.

TABLE 5.

Comparison of cognitive abilities before and after chemotherapy based on rs4648328 type

rs4648328	N	MMSE	DST	VFT
Before chemotherapy
rs4648328 (CC) group	61	27.2 (1.68)	6.20 (0.78)	11.4 (1.46)
rs4648328 (CT/TT) group	63	27.6 (1.54)	6.19 (0.74)	11.6 (1.56)
t/z		−1.291	0.106	−0.594
p		0.199	0.916	0.554
rs4648328 (CC) patients
BC group	61	27.2 (1.68)	6.20 (0.78)	11.41 (1.46)
AC group	61	27.0 (1.81)	5.84 (0.86)	10.20 (1.91)
t/z		0.648	2.850 ^a	3.477
p		0.520	0.004^**	0.001^**
rs4648328 (CT/TT) patients
BC group	63	27.6 (1.54)	6.19 (0.74)	11.6 (1.56)
AC group	63	26.7 (1.64)	5.96 (0.93)	10.5 (2.08)
t/z		2.859 ^a	1.806	3.136
p		0.004^**	0.076	0.003^**

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^{^a}

Wilcoxon signed‐rank test.

^**

p < 0.01.

3.5. Cognitive abilities of ALDH2_rs4767944 patients before and after chemotherapy

The comparison results of cognitive function before and after chemotherapy for different SNPs in ALDH2_rs4767944 are shown in Figure 3 and Table 6. No significant difference was found in cognitive function between the two groups. A statistically significant difference was observed in the VFT scores between the BC and AC groups in rs4767944 (CT/CC) patients. For rs4767944 (TT) patients, the DST and VFT scores after chemotherapy were significantly reduced, suggesting a decline in cognitive ability.

TABLE 6.

Comparison of cognitive abilities before and after chemotherapy based on rs4767944 type

rs4767944	N	MMSE	DST	VFT
Before chemotherapy
rs4767944 (TT) group	48	27.2 (1.81)	6.31 (0.80)	11.4 (1.44)
rs4767944 (CT/CC) group	76	27.5 (1.48)	6.10 (0.72)	11.6 (1.56)
t/z		−1.109	1.418	−0.619
p		0.270	0.159	0.537
rs4767944 (TT) patients
BC group	48	27.2 (1.81)	6.31 (0.80)	11.4 (1.44)
AC group	48	27.0 (1.80)	5.89 (0.89)	10.3 (1.74)
t/z		0.669	2.967 ^a	2.776
p		0.507	0.003^**	0.008^**
rs4767944 (CT/CC) patients
BC group	76	27.5 (1.48)	6.10 (0.72)	11.6 (1.56)
AC group	76	26.8 (1.68)	5.90 (0.91)	10.3 (2.15)
t/z		2.560 ^a	1.878	3.757
p		0.010	0.064	0.000^***

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^{^a}

Wilcoxon signed‐rank test.

^**

p < 0.01.

^***

p < 0.001.

3.6. Correlation analysis of cognitive outcomes in patients with SNPs characteristic of cognitive decline after chemotherapy

A significant positive correlation exists between MMSE and VFT scores in patients with ALDH2_rs671_GG after chemotherapy (Figure 4A). A significant positive correlation was found between the MMSE and DST scores in patients with ALDH2_rs886205_GG after chemotherapy (Figure 4B). A significant positive correlation was observed between DST and VFT in patients with ALDH2_rs4648328_CC after chemotherapy (Figure 4C). A significant positive correlation was observed between DST and VFT in patients with ALDH2_rs4767944_TT after chemotherapy (Figure 4D).

Correlation analysis of cognitive outcomes in patients with single‐nucleotide polymorphisms characteristic of cognitive decline after chemotherapy. (A) Correlation between MMSE and VFT in *ALDH2*_rs671_GG patients after chemotherapy. (B) Correlation between MMSE and DST in *ALDH2*_rs886205_GG patients after chemotherapy. (C) Correlation between DST and VFT in *ALDH2*_rs4648328_CC patients after chemotherapy. (D) Correlation between DST and VFT in *ALDH2*_rs4767944_TT patients after chemotherapy

3.7. The expression of ALDH2 in the brain

ALDH2 expression differs in different parts of the brain. The highest expression was observed in the cerebral cortex and the lowest in the olfactory bulb. We further analysed the expression of ALDH2 in hippocampal formation and amygdala, and the results are shown in Figure 5.

Expression of *ALDH2* in the brain. (A) Expression of *ALDH2* in different parts of the brain. (B) Expression of *ALDH2* in different parts of the hippocampal formation. (C) Expression of *ALDH2* in different parts of the amygdala

4. DISCUSSION

This study explored the decline in cognitive function in patients with different molecular types of ALDH2 after chemotherapy and found that patients with rs671_GG, rs886205_GG, rs4648328_CC, and rs4767944_TT were more likely to have cognitive decline after chemotherapy. This method can help identify the population susceptible to cognitive decline in chemotherapy and help these patients by providing early intervention to improve their QoL, which is meaningful.

As we know, the ALDH2 gene is a key gene for aldehyde metabolism. ⁴² In addition, aldehydes can damage the nerve cells in the brain. ⁴³ , ⁴⁴ , ⁴⁵ Therefore, one of the possible reasons for cognitive impairment in patients undergoing chemotherapy is the accumulation of aldehydes in the body and nervous system. There are common polymorphisms of ALDH2 in Asians: ALDH2_rs671 (AG/AA) and wild‐type ALDH2_rs671 (GG). These two genotypes are almost halved in the Asian population. ¹⁹ Studies have found that patients with an inactivating point gene polymorphism coding for ALDH2_rs671 (AG/AA) are markedly protected against alcoholism. Cognitive impairment caused due to alcohol is similar to that caused by chemotherapy. ⁴⁶ , ⁴⁷ Interestingly, our results indicated that patients with ALDH2_rs671 (AG/AA) had no significant changes in cognitive function after chemotherapy, while those with ALDH2_rs671 (GG) showed a significant cognitive decline (Table 2). Therefore, we propose that patients with ALDH2_rs671 (GG) may be more susceptible to CRCI. Such patients should receive early cognitive interventions to help improve their QoL.

To improve the sensitivity of CRCI‐susceptible population discrimination, we analysed three other common ALDH2 alleles: rs886205, rs4648328, and rs4767944. These polymorphism sites also correlate with cognitive function and can be used to identify Alzheimer's disease, ⁴⁸ , ⁴⁹ alcohol‐related cognitive impairment, and other diseases. ⁵⁰ , ⁵¹ We found that patients with breast cancer with ALDH2_rs886205_GG, ALDH2_rs4648328_CC, and ALDH2_rs4767944_TT also showed a significant cognitive decline after chemotherapy (TABLE 3‐5). A possible reason is that patients with different ALDH2 genotypes have different abilities to metabolise aldehydes. ⁵² Therefore, there are differences in the degree of cognitive impairment caused by aldehyde accumulation during chemotherapy. ⁵³ , ⁵⁴

Recent studies have confirmed that ALDH2 in astrocytes is involved in the regulation of behavioural and cognitive functions related to ethanol metabolism in the brain. ⁵⁵ Both chemotherapy‐ and ethanol metabolism‐induced cognitive impairment can be caused by aldehydes ⁴² , ⁵⁶ ; thus, ALDH2 in the brain may also affect CRCI by participating in aldehyde regulation. In this study, we analysed the expression of ALDH2 in the brain, hippocampal formation, and amygdala based on the HPA database. In future studies, it may be possible to improve and prevent CRCI by regulating the function of ALDH2 in the brain, which will greatly enhance the QoL of patients with cancer undergoing chemotherapy.

The limitations of this study include the following aspects that need to be addressed in future studies. Patients with both primary and metastatic breast cancer were enrolled in this study. This heterogeneity of the sample will affect the persuasiveness of the results. This was a cross‐sectional study, and future studies should include a control group and conduct long‐term follow‐ups. Our study focused on Asian populations. Although Asians have a higher mutation rate of ALDH2, aldehyde detoxification of ALDH2 is also worthy of investigation in other ethnic groups with CRCI. The MMSE lacks sensitivity for CRCI, and more effective cognitive testing methods should be used in future research. Repeated measurements will increase the results' accuracy. It would be meaningful to measure cognitive function at different time points after chemotherapy to explore the correlation between CRCI symptoms and the time after chemotherapy.

5. CONCLUSION

Since breast cancer CRCI is very common and markedly affects patients' QoL, it is clinically meaningful to identify which patients are more likely to develop CRCI. ³⁷ , ⁵⁷ This study indicated that patients with ALDH2 rs671_GG, rs886205_GG, rs4648328_CC, and rs4767944_TT polymorphisms were more likely to suffer from cognitive impairment during chemotherapy. For these patients, their cognitive status should be monitored while paying attention to somatic side effects to improve QoL (Figure 6). More importantly, as ALDH2 rs671 is a common polymorphism site in Asians, this study has important implications for Asian women with breast cancer. Broadly, this study highlighted the direction for the study of ALDH2 in CRCI; however, the specific mechanism can be explored through animal experiments in the future.

AUTHOR CONTRIBUTIONS

Senbang Yao: Conceptualization (lead); formal analysis (lead); investigation (lead); resources (lead); software (lead); writing – original draft (lead). Wen Li: Conceptualization (equal); data curation (equal); investigation (equal); resources (equal). Shaochun Liu: Formal analysis (equal); investigation (equal); supervision (equal); writing – original draft (equal). Yinlian Cai: Data curation (supporting); supervision (supporting). Qianqian Zhang: Formal analysis (supporting); methodology (supporting); resources (supporting). Lingxue Tang: Data curation (supporting); investigation (supporting); visualization (supporting). Sheng Yu: Data curation (supporting); supervision (supporting); writing – review and editing (supporting). Yanyan Jing: Data curation (supporting); methodology (supporting); project administration (supporting). Xiangxiang Yin: Data curation (supporting); funding acquisition (supporting); validation (supporting). Huaidong Cheng: Conceptualization (lead); funding acquisition (lead); writing – review and editing (lead).

FUNDING INFORMATION

This study was supported by The National Natural Science Foundation of China (Nos. 81872504 and 81372487).

CONFLICT OF INTEREST

The authors declare there are no competing interests.

ETHICS APPROVAL

All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Research Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (approval number:2012088), and all patients provided written informed consent.

Supporting information

Figures S1‐S2

Click here for additional data file.^{(878.7KB, pdf)}

Data S1

Click here for additional data file.^{(5.3MB, rar)}

Data S2

Click here for additional data file.^{(6.3MB, zip)}

ACKNOWLEDGMENTS

We thank all the patients for participating in this research as well as our collaborators for their contributions. We appreciate the valuable suggestions from the reviewer for this study. We also thank Yu Zhu, PhD (School of Public Health, Anhui Medical University), for his help with statistics during the revision process. We thank the Pinclipart web site and relevant author for providing publicly available picture material.

Yao S, Li W, Liu S, et al. Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy‐related cognitive impairment in patients with breast cancer who receive chemotherapy. Cancer Med. 2023;12:5209‐5221. doi: 10.1002/cam4.5319

Senbang Yao, Wen Li, and Shaochun Liu are contributed equally to this research.

DATA AVAILABILITY STATEMENT

The data of this study will be available from the correspondent on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figures S1‐S2

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Data S1

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Data S2

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Data Availability Statement

The data of this study will be available from the correspondent on reasonable request.

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PERMALINK

Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy‐related cognitive impairment in patients with breast cancer who receive chemotherapy

Senbang Yao

Wen Li

Shaochun Liu

Yinlian Cai

Qianqian Zhang

Lingxue Tang

Sheng Yu

Yanyan Jing

Xiangxiang Yin

Huaidong Cheng

Abstract

Background

Methods

Results

Conclusion

1. INTRODUCTION

2. MATERIALS AND METHODS

2.1. Patients

TABLE 1.

2.2. Genotyping

2.3. Cognitive screening test

2.4. Neuropsychological tests

2.5. The expression of ALDH2 in brain

2.6. Statistical analysis

3. RESULTS

3.1. Process and enrolled patient profiles of the research

FIGURE 1.

TABLE 2.

3.2. Cognitive abilities of ALDH2_rs671 patients before and after chemotherapy

FIGURE 2.

TABLE 3.

3.3. Cognitive abilities of ALDH2_rs886205 patients before and after chemotherapy

TABLE 4.

3.4. Cognitive abilities of ALDH2_rs4648328 patients before and after chemotherapy

FIGURE 3.

TABLE 5.

3.5. Cognitive abilities of ALDH2_rs4767944 patients before and after chemotherapy

TABLE 6.

3.6. Correlation analysis of cognitive outcomes in patients with SNPs characteristic of cognitive decline after chemotherapy

FIGURE 4.

3.7. The expression of ALDH2 in the brain

FIGURE 5.

4. DISCUSSION

5. CONCLUSION

FIGURE 6.

AUTHOR CONTRIBUTIONS

FUNDING INFORMATION

CONFLICT OF INTEREST

ETHICS APPROVAL

Supporting information

ACKNOWLEDGMENTS

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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