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Keywords:

  • age-associated memory problems;
  • apolipoprotein;
  • cognitive functioning;
  • genetics;
  • neuropsychology

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

Aim

The ε4 alelle of the apolipoprotein E gene is known to be a key genetic risk factor for Alzheimer's disease and possibly for other neurological disorders. Some evidence in the literature indicates that the ε4 allele interferes with human cognition independently of chronological age and diagnosis of Alzheimer's disease. The present study investigated the correlation of allelic variants of apolipoprotein E with the cognitive performance of elderly individuals without apparent cognitive impairment.

Methods

This was a cross-sectional analysis that included 213 non-demented elderly individuals (age ≥60 years) from the Brazilian Federal District. The analysis assessed the subjects for cognitive domains including short- and long-term episodic memory, processing speed, and attention and executive functions. Sociodemographic and other clinical characteristics were gathered and analyzed as covariates.

Results

Being sufficiently powered, the present study did not identify differential performance across apolipoprotein E genotypes. There was no influence of age, gender, marital status, schooling, depressive symptoms or use of central nervous system depressants when the analyses were controlled for such factors.

Conclusions

Our findings suggest that the ε4 allele does not contribute to detectable cognitive decline within the context of non-dementia.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

Population ageing results in an increased prevalence of neurodegenerative diseases, especially dementia. Among the different forms of dementia, Alzheimer's disease (AD) is the most common, and its prevalence has increased in recent decades.[1] AD causes a level of cognitive and behavioural impairment that interferes with everyday life activities and the quality of life. It is characterized by memory impairment associated with deficit in at least one other cognitive function, such as executive functions, language, or attention, with the exclusion of other causes of dementia.[2]

The markers and other features that allow for the early diagnosis of AD, especially genetic markers, are the subject of investigation.[3] The ε4 allele of the apolipoprotein E (ApoE) gene is the main genetic risk factor for AD,[4] and it is possibly involved in other neurological disorders.[5]

ApoE is the lipoprotein present in the greatest amount in the central nervous system (CNS), and the brain represents the second most important site for its synthesis in the entire human body. The allelic variants of ApoE in chromosome 19 exhibit three main isoforms (ε2, ε3 and ε4) and six different genotypic combinations: three homozygous (ε2/ε2, ε3/ε3 and ε4/ε4) and three heterozygous (ε2/ε3, ε3/ε4 and ε2/ε4).

Although there is evidence regarding the specific role that ApoE plays in the formation of amyloid plaque and neurofibrillary tangles as well as the association of these histopathological formations with the aetiology of AD, the underlying mechanisms are still poorly understood.[6] From the clinical perspective, there are doubts about when and how a given genotypic variant manifests phenotypically in human cognition. In this regard, some evidence indicates that allele ε4 interferes with human cognition independently of chronological age by determining signs and symptoms compatible with cognitive decline in a context devoid of dementia.[7, 8] Another line of research shows that the presence of this allele is a risk factor for AD and an accelerator of cognitive loss once the diagnosis is set, thus accounting for an allele-specific contribution to the appearance and progression of the disease.[9]

Studies conducted with non-demented elderly seek to identify impairment in cognitive ability that might be associated with the genotype. Therefore, the aim of the present study was to investigate the association between the allelic variants of ApoE and the cognitive performance of elderly individuals who lack apparent cognitive impairment.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

Study design and patients

This was a cross-sectional analytical study including non-demented elderly individuals (age ≥60 years) that was conducted from August 2009 to December 2010. The subjects were admitted to a health promotion programme for prevention of age-related chronic diseases at one of two general geriatric outpatient clinics in the metropolitan area of the Brazilian Federal District. Both institutions employ staff skilled at diagnosing and managing cognitive disorders. Diagnoses of dementia were made according to the DSM-IV criteria.[2] At admission, all patients were assessed with a validated Brazilian Portuguese version of the Mini-Mental State Examination (MMSE). Medical records were used only as source of preliminary information. Considering the heterogeneity of the Brazilian population, cut-off scores for the MMSE were set at 18 and 26 points for individuals with ≤7 years and ≥8 years of formal education, respectively.[10] Also, individuals exhibiting signs or symptoms of psychiatric disorders (e.g. schizophrenia, schizoaffective disorders, delusional or mood disorders, delirium or intense agitation), dementia (e.g. Alzheimer's, Parkinson's, vascular, frontotemporal or Lewy bodies) or important brain diseases/injuries (e.g. ischemic stroke, subdural haematoma, haemorrhage or trauma) were excluded. In addition, a patient was deemed cognitively preserved at the 1-year follow-up if none of these disorders were indicated and there was no decline in MMSE below the thresholds. All clinical assessments were executed by two experienced geriatricians.

Genetic analysis

The total genomic DNA of each participant was collected using routine laboratory procedures. The genotypes of ApoE common alleles (ε2, ε3 and ε4) were established according to a modified version of the method developed by Donohoe et al.[11, 12]

Procedures

Interviews

Individuals without psychiatric disorders, dementia or other neurological disorders were invited to participate in structured interviews to identify their sociodemographic and clinical characteristics. Data were collected on identity, gender, date of birth, level of schooling, marital status and medications used, among others. During the interviews, disorders that could interfere with a participant's overall state of health (e.g. cancer, epilepsy, immobility, and stroke), such as important sensory (visual and/or auditory) impairment and untreated sleep disorders, were identified by the clinical team and considered as further exclusion criteria. Users of medications that might interfere with cognition were also excluded from the study; for this purpose, a user was defined as any individual using a constant dose of prescribed CNS depressants (antipsychotics, tricyclic antidepressants, benzodiazepines, anticonvulsants, and/or sleep inducers) for at least 4 weeks prior to the initial interview. The present study was approved by the Research Ethics Committee of the School of Medicine of the University of Brasilia (#016/2009) (Brasilia, Brazil). This study was approved by the institutional ethics committee and conducted according to the Helsinki Declaration. Participation was voluntary, and written informed consent was obtained from each participant.

Neuropsychological tests

After the initial interview, the Geriatric Depression Scale and the MMSE were applied.[13, 14] The cognitive tests administered to participants encompassed several cognitive domains, including short- and long-term episodic memory, processing speed, and attention and executive functions. The cognitive tests included the Paired Associate Learning Test, forms I (PAL-I) and II (PAL-II) of the Wechsler Memory Scale,[15] Digit Span Forward and Backward of the Wechsler Adult Intelligence Scale-III,[16] simple reaction time tests (Visual Attention Variables Tests, reaction time, rate of false alarms, percentage of hits) and Tower of Hanoi.[17, 18] In the Digit Span test, the sum of each participant's time for Digit Span Forward and Digit Span Backward was also considered as an independent variable. For the Tower of Hanoi, two disks were used for training and three for testing;[19] these disks were used to assess the total time in seconds to perform the task, the number of errors and the number of correct movements. All neuropsychological tests were administered by the same examiner.

Data analyses

The average values of the quantitative variables collected in the cognitive tests were compared among the genotypic groups using anova when the distribution of variables was normal and the variance of each genotype was constant; otherwise, the Kruskal–Wallis non-parametric test was used. The χ2 test was used to analyze the qualitative variables. The sociodemographic variables (gender, age, schooling and marital status), depressive symptoms and the use of CNS depressants were considered covariables. For variables where the distribution of errors in anova did not exhibit a normal distribution and the variance was constant, Napierian logarithmic transformation was used. Tukey's adjustment was used to adjust multiple comparisons.

A multiple linear regression model was used to determine the influence of the sociodemographic variables, depressive symptoms and use of depressants on the cognitive tests. The model included 11 predictor variables for cognitive tests: age, schooling, gender, marital status, the presence or absence of depressive symptoms, the use of benzodiazepines, antipsychotics, antidepressants, tricyclic antidepressants, anticonvulsants or other drugs (such as anti-hypertensive, hypoglycaemic, hypolipidaemic drugs and bisphosphonates, which do not interfere with the CNS). For the sample comprising 213 individuals, with a 5% significance level and an effect size between 0.10 and 0.64, the test power exceeded 85%. The data were analyzed using the software SAS 9.2 for Windows (Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

From a pool of 398 eligible, cognitively preserved cases, we scheduled telephone and/or clinical interviews from July 2011 to December 2011. From this group of 398 subjects, 5 were excluded due to important auditory and/or visual impairment and 13 due to active disease that affected the participant's overall state of health (e.g. cancer, epilepsy or immobility). Furthermore, 13 patients had died before we contacted them, and 147 refused or were unable to participate in the study. Data from one patient were lost. With these exclusions, the following genotypic frequencies were obtained from 219 subjects: ε2/ε2 (n = 0; 0%), ε2/ε3 (n = 15; 6.8%), ε2/ε4 (n = 6; 2.7%), ε3/ε3 (n = 159; 72.6%), ε3/ε4 (n = 34; 15.5%), and ε4/ε4 (n = 5; 2.3%). As there is epidemiological and experimental evidence that the ApoE allele ε2 plays a role in preservation of cognitive function,[20] individuals with genotype ε2ε4 were excluded from the analysis because of the putative opposite effects of these alleles in cognition. Therefore, the final sample for comparison of genotypes comprised 213 individuals, including 187 women (87.8%). The mean age of the final sample was 72.9 ± 6.1 years, with 5.6 ± 4.6 years of schooling on average. Most of the patients were married (n = 86; 40.4%) or widowed (n = 82; 38.5%). The average values and percentages of sociodemographic variables found in the final sample did not differ significantly among the three genotype groups analyzed (Table 1).

Table 1. Comparison of continuous and categorical variables across the three groups of ApoE genotypes
VariableGroupsP-value
ε2/ε3 (n = 15)ε3/ε3 (n = 159)ε4/ε4 + ε3/ε4 (n = 39)
  1. Percentages are expressed within genotype. P-values for categorical analyses were obtained using the χ2 test and those for continuous data with ANOVA. †Significance verified with the Kruskal–Wallis test. ApoE, apolipoprotein E.

Age, years (mean ± SD)74.5 ± 6.772.7 ± 6.173.5 ± 6.10.780
Schooling, years (mean ± SD)5.0 ± 5.16.0 ± 4.75.1 ± 4.40.343
Women, n (%)14 (93.3)142 (89.3)31 (79.5)0.194
Marital status, n (%)    
Married7 (46.7)62 (39.0)17 (43.6)0.858
Widowed4 (26.7)62 (39.0)16 (41.0)
Presence of depressive symptoms, n (%)4 (26.7)40 (25.2)13 (33.3)0.896
Use of benzodiazepines, n (%)2 (13.3)12 (7.5)5 (12.8)0.482
Use of antipsychotics, n (%)0 (0.0)01 (0.6)0 (0.0)0.843
Use of antidepressants, n (%)1 (6.7)22 (13.8)9 (23.1)0.226
Use of tricyclic antidepressants, n (%)1 (6.7)7 (4.4)1 (2.6)0.779
Use of anticonvulsants, n (%)0 (0.0)6 (3.8)1 (2.6)0.707
Use of other drugs, n (%)14 (93.3)142 (89.3)32 (82.0)0.369

For inferential analysis, the genotypes were clustered to clarify the differences between carriers of different alleles as follows: carriers of ε2 (ε2ε3), homozygous ε3 (ε3ε3), and carriers of ε4 (ε4/ε4 + ε3/ε4). The average performance in the cognitive tests did not indicate significant differences in skills related to episodic memory, processing speed, and attention and executive capabilities among the three investigated genotype groups (Table 2). Also, the covariables of age, gender, marital status, level of schooling, depressive symptoms, and the different classes of CNS depressants in use did not have a significant influence on the model when the analyses were controlled for such factors.

Table 2. Comparison of cognitive variables across the three groups of ApoE genotypes
TestsGroups (mean ± SD)P-value
ε3/ε3 (n = 159)ε4/ε4 + ε3/ε4 (n = 39)ε2/ε3 (n = 15)ε3/ε3 vs ε4/ε4 vs ε3/ε4ε3/ε3 vs ε4/ε4 + ε3/ε4ε3/ε3 vs ε2/ε3ε4/ε4 + ε3/ε4 vs ε2/ε3
  1. P-values were calculated using ancova adjusted for sociodemographic data, depressive symptoms and use of depressant drugs. Multiple comparisons were adjusted using Tukey's test. ‡Napierian logarithmic transformation was used. % hits, percentage of correct hits in TEVA; ApoE, apolipoprotein E; DSB, Digit Span Test Backward; DSF, Digit Span Test Forward; DSTotal, sum of DSF and DSB; HanoiE, number of errors in Tower of Hanoi; HanoiM, number of correct movements in Tower of Hanoi; HanoiT, total time to perform Tower of Hanoi; MMSE, Mini-Mental State Examination; PAL-I, Paired Associate Learning Test, form I; PAL-II, Paired Associate Learning Test, form II; RT, reaction time in TEVA; TEVA, Visual Attention Variables Test; xpFA, rate of false alarms in TEVA.

MMSE25.9 ± 2.725.5 ± 3.124.5 ± 2.70.2730.9990.2470.331
PAL-I11.6 ± 4.111.3 ± 3.611.1 ± 3.00.8660.9480.9170.855
PAL-II4.6 ± 1.74.5 ± 1.44.5 ± 1.20.9910.9990.9930.991
DSF6.0 ± 1.85.5 ± 1.45.3 ± 1.60.1460.2530.3670.966
DSB3.7 ± 1.83.4 ± 1.63.1 ± 1.60.7360.9810.7160.834
DSTotal9.7 ± 3.18.9 ± 2.68.5 ± 2.70.2840.5260.4010.873
HanoiT104.9 ± 68.595.8 ± 65.6118.9 ± 53.10.2000.4050.5200.198
HanoiM13.7 ± 6.113.1 ± 5.616.4 ± 5.10.0970.5980.1690.079
HanoiE1.5 ± 1.21.2 ± 1.01.7 ± 1.30.0820.0670.9980.372
RT482.7 ± 85.7470.1 ± 56.7460.1 ± 65.50.2170.4690.3210.835
% hits93.5 ± 12.796.3 ± 8.091.7 ± 11.20.2790.2570.9980.577
xpFA0.0 ± 0.00.0 ± 0.00.0 ± 0.10.1670.9910.1540.163

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

The present study did not identify a correlation between classic genotypes of ApoE and differential performances in a battery of neuropsychological tests (MMSE, PAL-I, PAL-II, Digit Span Forward, Digit Span Backward, the sum of the Digit Span tests, Tower of Hanoi, and simple reaction time) in elderly individuals clinically identified as having preserved cognitive functions. Investigating the performance of elderly subjects on cognitive tests requires judicious procedures that are able to establish their cognitive integrity in order to exclude those with mild cognitive impairment and preclinical stages of AD. In this regard, our study represents a contribution to the scientific literature because it was performed with a sample enrolled in a prospective research project where clinical follow-up was performed on a regular basis, thus ensuring the exclusion of diseases and other variables that might interfere with cognition, such as subclinical and early cases of AD. Despite the exclusion criteria used, the methodological rigour in the application of tests and the control of confounding variables, such as schooling, age, comorbidities, and use of medications, the observed differences between carriers and non-carriers of a given ApoE allelic form were not significant. The multiple linear regression model indicated that the lack of significant differences could not be attributed to the limited power of the test, which varied between 0.86 and 1.00 for all investigated variables.

There is no consensus in the literature on the possible correlation between ApoE genotypes and cognitive performance in non-demented individuals. From the histopathological point of view, the current notions on the role of ApoE in the human brain assert that it favours the deposition of beta-amyloid plaques,[21] increases the phosphorylation of protein tau,[22] and impairs neuronal repair among ε4 carriers compared to non-carriers.[23] However, these histopathological changes do not necessarily imply established dementia, and there is a discussion as to whether there is a definite phenotype associated with allele ε4,[24] or rather a particular trigger event that underlies the pathological processes with which it is related.[23] Despite the differences between both theoretical points of view, they share a common feature: the significant contribution of the allele ε4 once repair/compensation mechanisms have become deficient and the impairment of human cognition has become apparent. Some studies have investigated the contribution of the ε4 allele to the clinical progression of mild cognitive disorders;[25] they found that conversion to AD was more frequent among carriers compared to non-carriers.[26, 27] However, the ε4 genotype does not seem necessary for the onset of the mild cognitive impairment itself.[28] Although some research groups work on the assumption of an association between ApoE genotypes and cognitive performance under the antagonistic pleiotropy hypothesis (better performance in youth, worse status in old age),[29] our findings corroborate results in which differences in cognitive performance are attributed to different stages of life rather than to the ε4 allele.[9, 30] The mere presence of the allele does not determine subclinical phenotypes within a non-demented context. Accordingly, mild cognitive impairment might be understood as a symptom of subclinical stages inherent to the heterogeneity of a condition as complex as Alzheimer's dementia, to which the phenotypic expression of the ε4 allele contributes.

With regard to the sensitivity of the selected tests, they are widely used to assess specific cognitive functions (episodic memory, working memory, mental speed, reaction time) and due compensation mechanisms in the ageing process, thus differing from wider-scoped batteries of tests that aim to assess overall cognitive performance.[31] Moreover, these instruments also considered the ability of participants to understand and execute the tasks regardless of their age and level of schooling. Despite our attempt to exclude subclinical dementia by following up with each subject for at least 1 year, the neuropsychological protocol employed herein does not rule out the possibility of unnoticed mild cognitive disorders and future decline or conversion to dementia, which may be considered a limitation of this study. Another consideration with regard to the present study is that the cross-sectional design used is unable to make direct causal relationships evident. Future studies must consider using longitudinal designs to ensure a systematic cognitive assessment of groups of non-demented elderly individuals who are or are not carriers of ε4.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

To summarize, our study did not find a relationship between ApoE genotypes and cognitive performance in non-demented elderly individuals. Our findings indicate that the ε4 allele does not promote detectable cognitive disorder within the context of non-dementia.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

This work was supported by Fundação de Apoio à Pesquisa do Distrito Federal (grant number 193.000.449-2008), Fundação de Empreendimentos Científicos e Tecnológicos (grant number 5563/2009) and Universidade de Brasília (UnBDoc 121696/2011). A fellowship for productivity in research from Conselho Nacional de Desenvolvimento Científico e Tecnológico was granted to O.T. Nóbrega. The authors have no conflict of interest to report.

References

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
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