Apoprotein E epsilon4 allele ассоциируется с лучшим языком выступления и визуальной памятью в спинномозговой атаксии типа 3.

INTRODUCTION

Spinocerebellar ataxia type 3 (SCA3), also known as Machado‐Joseph disease (MJD), is the most common subtype of SCA globally [ 1 ]. It is caused by unstable CAG repeat expansions in the ATXN3 gene, leading to misfolding and aggregation of the ataxin‐3 protein, which in turn results in neuronal dysfunction and degeneration [ 2 ]. The primary motor symptom of SCA3 is progressive cerebellar ataxia, while cognitive impairment is the main non‐motor symptom [ 3 ].

In Alzheimer's disease (AD), the apolipoprotein E ( APOE ) gene modulates tau protein production and is linked to neurodegeneration and cognitive decline [ 4 ]. Similarly, SCA3 is a neurodegenerative disorder associated with neurotoxic protein accumulation, with cognitive impairments as a prominent clinical feature. For instance, SCA3 patients exhibit impairments in executive function, visuospatial perception, and verbal memory [ 5 , 6 ]. However, the role of APOE as a genetic modifier in SCA3, particularly its influence on pathological protein production and related clinical symptoms, remains unclear.

The APOE gene (19q13.2) has three primary alleles (ε2, ε3, and ε4), encoding isoforms E2, E3, and E4 with distinct structures and functions [ 1 , 7 ]. APOE allele frequencies vary across populations and diseases. For example, the ε4 allele is more prevalent in AD patients across most racial groups [ 8 ]. In SCA3 patients from Portugal and China, APOE frequencies did not differ significantly from controls [ 9 , 10 , 11 ]. APOE ε4 is a known risk factor for motor and cognitive impairments in various neurodegenerative diseases. In Parkinson's disease (PD), APOE ε4 is linked to severe motor symptoms and rapid progression [ 12 , 13 ]. It also correlates with poorer cognitive outcomes in AD, PD, and multiple system atrophy (MSA) [ 14 , 15 , 16 , 17 ]. In SCA3, some studies have explored the role of APOE polymorphisms, particularly their influence on age at onset (AAO), but the findings are inconsistent [ 9 , 10 , 11 ]. While APOE ε4 is implicated in AD and PD, its effects on motor and cognitive function in SCA3 are still largely unexplored.

In this cross‐sectional study, we included 281 SCA3 patients. We examined the association between APOE ε4 and motor function and cognitive performance in SCA3 patients. Our results indicate that APOE ε4 correlates with better language and visual memory performance but more severe speech disturbance in SCA3 patients, suggesting its potential role as a disease modifier.

MATERIALS AND METHODS

Standard protocol approvals, registrations, and patient consent

This study received approval from the Ethics Committee for Medical Research of the Hospital of Fujian Medical University ([2019]195). The ClinicalTrials.gov ID number is NCT04010214 . All patients enrolled gave written informed consent for sharing personal data.

Study design and participants

In this study, we analyzed APOE genotype frequency retrospectively and investigated the association of the APOE ε4 allele with cognitive and motor functions prospectively in separate SCA3 patient cohorts.

To assess the frequency distribution of the APOE ε4 genotype in SCA3, we included 281 unrelated genetically confirmed SCA3 patients surveyed between July 2005 and August 2022 at the Neurology Department, First Affiliated Hospital of Fujian Medical University, Southeast China. Additionally, 182 unrelated individuals without neurodegenerative diseases (e.g., AD, PD, hereditary spastic paraplegia) were included as controls.

To investigate the relationship between the APOE ε4 genotype and cognitive and motor functions in SCA3 patients, we enrolled 96 SCA3 patients from a prospective cohort of 65 families [ 5 ], surveyed between March 2021 and August 2022, sourced from the Organization in South‐East China for Cerebellar Ataxia Research (OSCCAR), housed in the neurology department of Fujian Medical University. All patients had genetically confirmed SCA3 with CAG repeat expansion in ATXN3 alleles (56–84) [ 18 ]. Each patient underwent neuropsychological assessment and completed a comprehensive case report form (CRF). To ensure the accuracy and reliability of the study results, we excluded individuals who (1) taking drugs that might have effects on cognitive performance, such as antidepressants and antipsychotics, (2) previous or current addiction to substances, including alcohol, (3) a history of other neurologic or systemic diseases, and (4) other causes of structural lesions on MRIs.

Neuropsychological tests

A detailed description of neuropsychological assessments can be found in our previous reports [ 5 ]. In summary, global cognitive function was evaluated using the Chinese versions of the Mini‐Mental State Examination (MMSE) [ 19 ] and the Montreal Cognitive Assessment (MoCA) [ 20 ]. Five specific cognitive domains were assessed using the modified Chinese version of Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) [ 5 , 21 ], including verbal memory (California Verbal Learning Test‐Second Edition [CVLT‐II]), visual memory (Brief Visuospatial Memory Test‐Revised [BVMT‐R]), visuospatial perception (Judgement of Line Orientation Test [JLO]), executive function (Controlled Oral Word Association Test [COWAT]), and information processing speed (Symbol Digit Modalities Test [SDMT] and Paced Auditory Serial Addition Task [PASAT], PASAT‐3 seconds and PASAT‐2 seconds). Our previous studies have validated the modified Chinese version of MACFIMS in SCA3 patients [ 5 ].

Additionally, depression and anxiety were assessed using the Hamilton Depression Rating Scale (HAMD) [ 22 ] and the Hamilton Anxiety Rating Scale (HAMA) [ 23 ], respectively. Fatigue, sleep quality, and daytime sleepiness were evaluated using the Fatigue Scale‐14 (FS‐14) [ 24 ], Pittsburgh Sleep Quality Index (PSQI), [ 25 ] and the Epworth Sleepiness Scale (ESS) [ 26 ], respectively.

To ensure data standardization and reliability, all neuropsychological tests were conducted by a trained team (LLQ, XYC, and CYH), with participants tested in the same manner, during the day, in a quiet room, and in a fixed order.

Due to the extensive time and complex process required for all components of the modified MACFIMS test, eight out of 96 SCA3 patients were unable to complete one or two component tests. Missing data were excluded from further analysis, with details provided in the table notes.

Clinical assessment

In this study, “age” refers to the age at neuropsychological examination. “Disease duration” refers to the time interval from the onset of initial symptoms to the date of the neuropsychological examination. Patient motor function was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS) [ 27 , 28 ]. SARA evaluates eight primary symptoms: gait, stance, sitting, speech disturbance, finger chase, nose‐finger test, fast alternating hand movements, and heel‐shin slide [ 28 ]. ICARS assesses four primary symptoms: postural and stance disturbances, limb movement disturbances, speech disorders, and oculomotor disorders [ 27 , 29 ]. These scales were used to analyze the impact of the APOE ε4 genotype and expanded ATXN3 CAG repeat length on motor function.

Patients with SARA scores <3 were categorized as presymptomatic SCA3, whereas those with SARA scores ≥3 were classified as symptomatic SCA3 [ 30 ]. To further explore motor scale score differences between APOE ε4 + and APOE ε4 − individuals at various disease durations, SCA3 patients were divided into two groups based on mean disease duration: an early‐stage group (46 patients, disease durations 1–7 years) and a late‐stage group (28 patients, disease durations >7 years) [ 31 ].

Genetic analysis of CAG repeats in the ATXN3 gene

Genomic DNA was isolated from peripheral blood using the QIAamp DNA Blood Mini kit (Qiagen, Hilden, Germany) following standard procedures. CAG repeat numbers were determined through PCR amplification and Sanger sequencing, as described previously [ 32 ].

Genotyping of APOE

“ APOE ε4 − ” refers to the absence of the APOE ε4 allele, whereas “ APOE ε4 + ” indicates the presence of one or two APOE ε4 alleles. See the supplementary file for details on APOE genotype testing.

Statistics

Continuous variables were presented as mean ( SD ), and categorical variables as number (%). Normality was assessed using the Shapiro–Wilk's test. The Mann–Whitney U test compared nonparametric continuous variables, whereas the independent samples t ‐test compared normally distributed continuous variables. Categorical variable differences were analyzed using the chi‐squared test (Fisher's exact test if expected values were <5). Spearman's rank correlation coefficient evaluated the correlation of nonnormally distributed continuous variables.

Age at onset was adjusted for mean CAG repeats in the expanded ATXN3 allele using linear regression models. Multiple linear regression models analyzed the impact of the APOE ε4 genotype on cognitive function in SCA3 patients, with sex, age, education years, and expanded ATXN3 CAG repeat length as covariates. Similarly, the effect of expanded ATXN3 CAG repeat length on cognitive function was assessed, adjusting for sex, age, education years, and the presence of the APOE ε4 genotype.

Multiple linear regression models evaluated the impact of the APOE ε4 genotype on motor function in SCA3 patients, adjusting for sex, age, disease duration, and expanded ATXN3 CAG repeat length. Similarly, the effect of expanded ATXN3 CAG repeat length on motor function was assessed, with sex, age, disease duration, and the presence of the APOE ε4 genotype as covariates.

Statistical analyses utilized SPSS v26.0 (IBM, Armond, New York) and Prism v8.0 (GraphPad, San Diego, CA), with significance set at p < 0.05.

RESULTS

Frequency distributions of APOE genotypes in patients with SCA3

Table S1 presents the frequencies of APOE alleles and genotypes in 281 unrelated SCA3 patients. Compared to controls, SCA3 patients showed a lower frequency of the ε3 allele (76.1% vs. 84.3%, p = 0.003) and a higher frequency of the ε4 allele (15.7% vs. 9.9%, p = 0.012). Regarding APOE genotypes, SCA3 patients had a reduced frequency of the ε3/ε3 genotype (56.6% vs. 69.2%, p = 0.006) and an elevated frequency of the ε4/ε4 genotype (2.5% vs. 0%, p = 0.046). Furthermore, the proportion of APOE ε4 + carriers was significantly higher in SCA3 patients compared to controls ( p = 0.035) (Figure 1 ).

Demographic, clinical, and genetic characteristics of SCA3 patients

We further assessed the impact of the APOE ε4 + allele on cognition and motor function in patients with SCA3. A cohort of 96 SCA3 patients were included, with 25 patients identified as APOE ε4 + and 71 patients as APOE ε4 − .

Univariate analysis revealed that earlier AAO in APOE ε4 + patients compared to APOE ε4 − patients ( p = 0.033) (Table 1 ). An inverse correlation was found between expanded ATXN3 CAG repeats and AAO (Spearman's r = −0.646, p < 0.0001, N = 74) (Figure S1 ). After adjusting for expanded CAG repeats, the AAO had no difference between APOE ε4 + and APOE ε4 − patients. Additionally, APOE ε4 + and APOE ε4 − patients showed no differences in age, sex, education years, phenotype, disease duration, and expanded CAG repeat length (Table 1 ).

Comparison of cognitive function in SCA3 APOE ε4 + and APOE ε4 − individuals

In our previous prospective cohort study, we validated the modified Chinese version of the MACFIMS test for reliability and validity in SCA3 patients [ 5 ]. Here, we investigated cognitive differences between SCA3 patients with and without the APOE ε4 allele across global cognition and five specific cognitive domains (verbal memory, visual memory, visuospatial perception, executive function, and information processing speed).

Overall, APOE ε4 + individuals demonstrated higher MoCA scores than APOE ε4 − counterparts ( p = 0.047) (Table 2 ). In specific cognitive domains, APOE ε4 + subjects performed better in CVLT‐II and BVMT‐R compared to APOE ε4 − subjects (all p < 0.05), while no significant differences were observed in JLO, COWAT, SDMT, PASAT 3 s, and PASAT 2 s between SCA3 APOE ε4 + , and APOE ε4 − patients. Specifically, in CVLT‐II, APOE ε4 + individuals achieved higher scores in short‐term storages (II test, IV test, and total of five learning trials), long‐term delayed free recall (LDFR), short‐term and long‐term delayed cued recall (SDCR and LDCR), and total of delayed recall (DR), compared to APOE ε4 − individuals. Similarly, in BVMT‐R, APOE ε4 + individuals obtained higher scores in short‐term storages (I to III test and total of three learning trials) and total of DR compared to APOE ε4 − individuals (Table 2 ).

Furthermore, there were no significant differences in psychological scales assessed between patients with APOE ε4 + and APOE ε4 − , including HAMD, HAMA, FS‐14, PSQI, and ESS (Table S2 ).

Impact of APOE ε4 allele and expanded ATXN3 CAG repeat length on cognitive function in SCA3 patients

To determine the impact of the APOE ε4 allele on cognitive function in SCA3, we conducted multiple regression analysis, considering sex, age, education years, and expanded ATXN3 CAG repeat length as covariates. Results showed significant associations between the APOE ε4 allele and higher scores in CVLT‐II II test ( B = 1.007, 95% CI = 0.078–1.936, p = 0.034), BVMT‐R II test ( B = 1.569, 95% CI = −0.332 to 2.807, p = 0.014), BVMT‐R TL ( B = 3.327, 95% CI = 0.069–6.585, p = 0.045), and BVMT‐R DR ( B = 1.236, 95% CI = 0.001–2.471, p = 0.0498) (Table 3 ).

Correlation analyses initially revealed positive associations between expanded ATXN3 CAG repeat length and cognitive test scores, encompassing MMSE, MoCA, CVLT‐II (I test, LDCR, DR, and LDR correct), and BVMT‐R (I test, II test, and TL). Detailed data are provided in Table S3 . However, after adjusting for sex, age, education years, and APOE ε4 allele, these correlations did not remain significant. Interestingly, negative associations were found between expanded ATXN3 CAG repeat length and CVLT‐II III test ( B = −0.248, 95% CI = −0.377 to −0.119, p = 0.0002), CVLT‐II IV test ( B = −0.165, 95% CI = −0.309 to −0.021, p = 0.025), CVLT‐II TL ( B = −0.686, 95% CI = −1.230 to −0.142, p = 0.014), CVLT‐II SDFR ( B = −0.186, 95% CI = −0.371 to −0.001, p = 0.049), and SDMT ( B = −1.243, 95% CI = −2.031 to −0.454, p = 0.002) scores (Table 3 ).

Comparison of motor function in SCA3 APOE ε4 + and APOE ε4 − individuals

Among individuals with SCA3, those with and without the APOE ε4 allele showed no significant differences in total scores or individual item scores on the SARA and ICARS assessments (Tables 1 and S4 ). However, when stratified by disease stage, early‐stage SCA3 individuals carrying the APOE ε4 allele exhibited higher scores on the SARA gait ( p = 0.041) and speech disturbance ( p = 0.024), as well as ICARS speech disorders ( p = 0.027) compared to those without the allele (Table 4 ). These differences were not observed in later disease stages.

Impact of APOE ε4 allele and expanded ATXN3 CAG repeat length on motor function in SCA3 patients

We conducted multiple regression analysis to assess the impact of the APOE ε4 allele on motor function in SCA3. After adjusting for sex, age, disease duration, and expanded ATXN3 CAG repeat length, the APOE ε4 allele was associated with speech disturbance on both the SARA ( B = 0.494, 95% CI = 0.024–0.964, p = 0.040) and ICARS scales ( B = 0.742, 95% CI = 0.133–1.351, p = 0.017) (Table 5 ). SCA3 APOE ε4 + individuals exhibited higher scores for gait impairment on both scales.

Additionally, we investigated the association between expanded ATXN3 CAG repeat length and motor function in SCA3. Correlation analysis did not reveal statistically significant differences between SCA3 APOE ε4 + and APOE ε4 − individuals (Table S5 ). However, after adjusting for covariates (sex, age, disease duration, and APOE ε4), we found that in SCA3 APOE ε4 + patients, expanded ATXN3 CAG repeat length was positively associated with gait impairment ( B = 0.094, 95% CI = 0.009–0.179, p = 0.031) and fast alternating hand movements ( B = 0.049, 95% CI = 0.007–0.091, p = 0.023) on the SARA scale, as well as speech impairment ( B = 0.085, 95% CI = 0.002 to 0.168, p = 0.045) and oculomotor disorders ( B = 0.134, 95% CI = 0.043 to 0.226, p = 0.004) on the ICARS scale (Table 5 ).

DISCUSSION

In this study, we retrospectively analyzed the APOE genotype frequency in SCA3 patients from southeastern China and prospectively evaluated the impact of the APOE ε4 allele on neuropsychological and motor phenotypes in these patients. Our findings indicate that in a prospective cohort of SCA3 patients, the APOE ε4 allele is associated with better performance in verbal memory (short‐term storage) and visual memory (short‐term storage and delayed recall), along with more severe speech disturbance. Conversely, the expanded ATXN3 CAG repeat length are associated with poorer performance in verbal memory (short‐term storage) and information processing speed, as well as more severe gait disturbances, fast alternating hand movements, speech disturbance, and oculomotor disorders.

Previous studies have reported APOE allele and/or genotype frequencies in SCA3. Research from the Azores ( n = 59), mainland Portugal ( n = 73), Brazil ( n = 60), and central China ( n = 155) found no significant differences compared to the corresponding populations of origin [ 9 , 10 ]. Our earlier study examined APOE allele and genotype frequencies in SCA3 patients from eastern and southeastern China [ 11 ] but did not include comparisons with the populations of origin. In this study, we analyzed APOE allele frequencies in 281 SCA3 patients from southeastern China. The ε3 allele frequency was decreased (76.1%), and the ε4 allele frequency was increased (15.7%) compared to the corresponding populations. Notably, the ε4 allele frequency varied across different SCA3 populations: 9.3% in the Azores, 8.2% in mainland Portugal, 14.2% in Brazil [ 9 ], 11.3% in central China [ 10 ], and 11.17% in eastern and southeastern China [ 11 ]. The reasons for the observed increase in the ε4 allele frequency in our cohort remain unclear. However, regional genetic factors and demographic influences, such as the high prevalence of consanguineous marriages in southeastern China, where our cohort is located, may have contributed to the formation of a founder effect with regional characteristics [ 33 ].

The impact of the APOE ε4 allele on cognitive function in SCA3 remains unclear. This study evaluated five cognitive domains in SCA3 patients: verbal memory, visual memory, visuospatial perception, executive function, and information processing speed. We found that the APOE ε4 allele was associated with better performance in verbal memory (short‐term storage) and visual memory (short‐term storage and delayed recall). A previous study involving 398 cognitively normal subjects (aged ≤70 years) reported that APOE ε4 carriers excelled in visual working memory and had advantages in verbal memory tests requiring high attention and working memory [ 34 ]. Similarly, several studies on healthy subjects of various ages (ranging from 20 to 82 years) have reported a short‐term memory advantage in APOE ε4 carriers [ 35 , 36 , 37 ]. These studies suggest a cognitive advantage associated with the APOE ε4 allele. However, the mechanisms underlying this beneficial effect remain unclear. Some researchers have proposed a compensatory mechanism recruitment hypothesis based on functional neuroimaging studies in healthy populations [ 38 , 39 ]. This hypothesis suggests that ε4 carriers can maintain cognitive function by recruiting additional brain regions to compensate for disease‐related decline. In SCA3 patients, the primary neuropathological changes are concentrated in the cerebellum, brainstem, thalamus, and basal ganglia, with relatively minor cortical involvement [ 40 ]. Therefore, we speculate that this compensatory recruitment hypothesis may partially explain the superior cognitive performance observed in our cohort of APOE ε4 + SCA3 patients.

Although the impact of the APOE ε4 allele on the motor phenotype of SCA3 remains unreported, studies in other neurodegenerative diseases have documented its effects. In PD, the APOE ε4 allele increases the risk of gait freezing in early‐stage PD [ 41 ] and exacerbates impairments in speech, hand movements, rapid alternating movements, and postural stability in late‐onset PD [ 12 ]. Furthermore, the APOE ε4 allele accelerates the rate of motor progression in PD patients [ 13 ]. In our SCA3 cohort, the APOE ε4 allele was associated with more severe speech disturbances. The cerebellum and brainstem, which are crucial for motor coordination and language function, are significantly impacted in SCA3. The speech deficits in SCA3 primarily stem from cerebellar ataxia and dysfunction in associated motor pathways. However, the specific role of the APOE ε4 allele in these deficits remains unclear, warranting further study.

Previous studies have reported a negative correlation between expanded ATXN3 CAG repeat length and visuoconstructive and planning abilities (the Bender‐Gestalt Test) in 22 SCA3 patients, while finding no significant association with verbal memory (the Chinese Rey Auditory Verbal Learning Test [C‐RAVLT]) [ 29 ]. In our current investigation, employing a larger prospective cohort of SCA3 patients, linear regression analyses revealed a negative relationship between expanded ATXN3 CAG repeat length and short‐term verbal memory (CVLT‐II) as well as information processing speed (SDMT), but no observed significant correlation with visuospatial perception (JLO). Both studies suggest that expanded ATXN3 CAG repeat length affects cognitive function in SCA3 patients, though the affected domains differ. These discrepancies may arise from differences in sample size, statistical methods, and cognitive assessment tools. Our study's fourfold larger sample may reduce statistical biases compared to prior studies of 22 patients. Further research is needed to validate the effects of expanded ATXN3 CAG repeat length on cognitive domains in SCA3.

This study has several limitations. First, the prospective analysis relies on cross‐sectional data, limiting the ability to track changes over time. Longitudinal studies are needed to clarify the trajectories of cognitive and motor functions and the long‐term impact of APOE genotypes in SCA3. Additionally, future research using structural MRI and postmortem tissue pathology is necessary to confirm our findings.

In conclusion, our findings reveal a correlation between the APOE ε4 allele and improved cognitive performance, alongside worsened motor phenotypes in SCA3. This supports the hypothesis that the ε4 allele may act as a disease modifier in SCA3, although the biological mechanisms that explain these observations are unclear.

AUTHOR CONTRIBUTIONS

Xuanyu Chen: Conceptualization; investigation; methodology; writing – review and editing; software; formal analysis; data curation; writing – original draft; visualization. Kunxin Lin: Conceptualization; investigation; methodology; writing – review and editing; data curation; supervision; validation; visualization. Zhixian Ye: Conceptualization; investigation; methodology; writing – review and editing; data curation; supervision; validation; visualization. Liangliang Qiu: Data curation; resources. Yusen Qiu: Data curation; resources. Ruying Yuan: Data curation; resources. Xintong Yu: Data curation; resources. Chunyu Huang: Data curation; resources. Bi Cheng: Data curation; resources. Wei Lin: Data curation; resources. Tianmin Lai: Data curation; resources. Wanjin Chen: Data curation; resources. Ning Wang: Data curation; resources; funding acquisition. Shirui Gan: Conceptualization; investigation; data curation; resources; funding acquisition. Qiuni Su: Conceptualization; investigation; data curation; resources. Ying Fu: Conceptualization; investigation; methodology; writing – review and editing; formal analysis; supervision; funding acquisition; project administration.

FUNDING INFORMATION

This work was supported by the grants U21A20360 (Y.F.), 82371349 (Y.F.), 82230039 (N.W.), and 82371879 (S.R.G.) from the National Natural Science Foundation of China and the grant 2022ZQNZD005 (Y.F.) from the Major Scientific Research Program for Young and Middle‐aged Health Professionals of Fujian Province.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no competing interests.

Supporting information

Data S1.

ACKNOWLEDGMENTS

Special thanks to all participants and caregivers for their contribution to this work.

Chen X, Lin K, Ye Z, et al. Apolipoprotein E epsilon4 allele is associated with better performance language and visual memory in spinocerebellar ataxia type 3. Eur J Neurol. 2025;32:e70017. doi: 10.1111/ene.70017

Xuanyu Chen, Kunxin Lin, and Zhixian Ye contributed equally to this work.

Contributor Information

Shirui Gan, Email: ganshirui@fjmu.edu.cn.

Qiuni Su, Email: nizi727@hotmail.com.

Ying Fu, Email: fuying@fjmu.edu.cn.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

Supplementary Materials

Data S1.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.