The ε4 allele of the apolipoprotein E gene (APOE-ε4) and a family history (+FH) of Alzheimer's disease (AD) are both risk factors for the development of AD. Although studies to identify a preclinical phase of AD have led to evidence of APOE-ε4- and +FH-related differences in brain and cognitive functioning in healthy adults, the relative influence of these factors in children is unknown.
To investigate this issue, school-age children (n = 109) received standardized achievement tests, the Rey-Osterrieth Complex Figure Test (Copy Condition; RCFT-CC), assessment of family medical history, and buccal swab testing to determine their APOE genotype.
Analyses revealed that, relative to children without these risk factors, children who possess both an APOE-ε4 allele and a +FH of AD and/or significant memory problems (MP) obtained lower scores on nearly every cognitive test administered.
Findings suggest that when both AD risk factors are present, cognition may be adversely affected as early as childhood. Thus, risk factors for a disorder of pathological aging (i.e., AD) may have implications for the etiology of certain types of learning difficulties in children.
The ε4 allele of the apolipoprotein E gene (APOE-ε4) and the presence of a first-degree relative with Alzheimer's disease (AD) are two known risk factors for the development of AD (
1). The discovery of these risk factors, coupled with interest in identifying and characterizing a preclinical phase of AD, has led to several studies that have found an adverse relationship between each risk factor and brain and cognitive function in healthy adult populations (
- Strittmatter W.J.
- Saunders A.M.
- Schmechel D.
- Pericak-Vance M.
- Enghild J.
- Salvesen G.S.
- et al.
Apolipoprotein E: High-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
Proc Nat Acad Sci U S A. 1993; 90: 1977-1981
2). Furthermore, subsequent studies of the combined influence of both risk factors in adults have suggested that, together, they may have a greater negative influence than either one alone (
- Small B.J.
- Rosnick C.B.
- Fratiglioni L.
- Backman L.
Apolipoprotein E and cognitive performance: A meta-analysis.
Psychol Aging. 2004; 19: 592-600
- Cupples L.A.
- Farrer L.A.
- Sadovnick A.D.
- Relkin N.
- Whitehouse P.
- Green R.C.(
Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: The REVEAL study.
Genet Med. 2004; 6: 192-196
4). There are, however, no studies of which we are aware that have assessed the combined effect of these AD risk factors on cognitive functioning in children.
- Johnson S.C.
- Schmitz T.W.
- Trivedi M.A.
- Ries M.L.
- Torgerson B.M.
- Carlsson C.M.
- et al.
The influence of Alzheimer disease family history and apolipoprotein E epsilon4 on mesial temporal lobe activation.
J Neurosci. 2006; 26: 6069-6076
Although studies in adolescents, thus far limited to examination of general cognitive ability, have generally failed to find APOE-related differences (
- Deary I.J.
- Whiteman M.C.
- Pattie A.
- Starr J.M.
- Hayward C.
- Wright A.F.
- et al.
Cognitive change and the APOE epsilon 4 allele.
Nature. 2002; 418: 932
- Plomin R.
- McClearn G.E.
- Smith D.L.
- Skuder P.
- Vignetti S.
- Chorney M.J.
- et al.
Allelic associations between 100 DNA markers and high versus low IQ.
Intelligence. 1995; 21: 31-48
7), investigations of the APOE-ε4 allele in human prenatal, perinatal, and infancy periods of life provide evidence of antagonistic pleiotropy. Antagonistic pleiotropy is a somewhat counterintuitive effect in which the ε4 allele appears to have protective effects early in development (e.g., on survival and cognition), but well-known detrimental effects during the post-reproductive years (
- Turic D.
- Fisher P.J.
- Plomin R.
- Owen M.J.(
No association between apolipoprotein E polymorphisms and general cognitive ability in children.
Neurosci Lett. 2001; 299: 97-100
- Wright R.O.
- Hu H.
- Silverman E.K.
- Tsaih S.W.
- Schwartz J.
- Bellinger D.
- et al.
Apolipoprotein E genotype predicts 24-month Bayley scales infant development score.
Pediatr Res. 2003; 54: 819-825
- Becher J.C.
- Keeling J.W.
- McIntosh N.
- Wyatt B.
- Bell J.(
The distribution of apolipoprotein E alleles in Scottish perinatal deaths.
J Med Genet. 2006; 43: 414-418
10). In light of these findings, we predicted that in a sample of school-age children, the ε4 allele might be associated with better test performance in specific cognitive domains, rather than no association or the poorer performance that might be expected if its effects were constant across the life span. The lack of studies on the relationship between a positive family history (+FH) of AD and cognitive functions in children, however, made it difficult to predict what independent effect this risk factor may have on test performance or how it might interact with the presence of the APOE-ε4 allele during childhood.
- Zetterberg H.
- Palmer M.
- Ricksten A.
- Poirier J.
- Palmqvist L.
- Rymo L.
- et al.
Influence of the apolipoprotein E epsilon4 allele on human embryonic development.
Neurosci Lett. 2002; 324: 189-192
Methods and Materials
The study was approved by the Institutional Review Boards of the University of California, San Diego, and San Diego State University, and informed consent was obtained from a parent of each participant.
Children between 11 and 16 years of age were recruited from a group of public charter schools and genotyped for APOE. Subjects were screened, and DNA was collected using a buccal swab technique. Exclusion criteria consisted of the following: First language learned was not English, color blindness, uncorrected visual impairment, upper extremity motor disability, genetic disorder known to affect central nervous system functioning, history of head injury with loss of consciousness for greater than 10 minutes, and a diagnosed seizure disorder.
Each child's results from four verbal subtests of the California Achievement Test (CAT-6) (
11) were obtained, and each child was administered a test of visuospatial and constructional skills in their classroom setting (i.e., the Rey-Osterrieth Complex Figure Test Copy Condition; RCFT-CC) (
TerraNova, 2nd ed.
TerraNova, 2nd ed.
CTB/McGraw-Hill, Monterey, CA2001
- Osterrieth P.A.
Le test de copie d'une figure complexe Contribution a l'etude de la perception et de la memoire.
Arch Psychol. 1944; 30: 206-353.
13). The CAT-6 has been used in previous neurocognitive research (
- Fischer J.S.
- Loring D.W.
Lezak M.D. Howieson D.B. Loring D.W. Neuropsychological Assessment. 4th ed. Oxford University Press, New York2004: 531-568
14), and standardized normal curve equivalent (NCE) scores provided for each subtest are reported here. NCE scores have a mean of 50 and a standard deviation of 21. The RCFT-CC was scored using the Taylor Scoring Criteria and normative data (
- Tennison M.
- Kankirawatana P.
- Bowman M.R.
- Greenwood R.
- Lewis D.
- Burchinal M.(
Effect of chronic antiepileptic drug therapy on California achievement test scores.
J Epilepsy. 1998; 11: 208-214
- Waber D.P.
- Holmes J.M.
Assessing children's copy productions of the Rey-Osterrieth Complex Figure.
J Clin Exp Neuropsychol. 1985; 7: 264-280
16), and a Z score was calculated for each child, which was then transformed to a NCE score to facilitate direct comparisons with CAT-6 subtest scores.
- Kolb B.
- Whishaw I.
Fundamentals of Human Neuropsychology.
3rd ed. W.H. Freeman, New York1990
Parents of participants were asked to complete an online demographic questionnaire that included several questions pertaining to their child's family medical history (Supplement 1), including whether the child's biological family history (FH) was significant for AD or significant memory problems (MP). For each instance in which the parent endorsed a +FH, he or she was asked to indicate how the affected individual(s) is/was related to the child. Children were grouped on the basis of APOE genotype and the presence or absence of a +FH of AD and/or MP for our primary analyses.
Sample Characteristics and Statistical Analyses
All ε2/4 heterozygotes (n = 4) were removed from the analysis. In total, there were 109 children for whom genotype, FH, and RCFT-CC data were available, and a subset of 102 children for whom CAT-6 subtest data were additionally available. There was one subject who had an RCFT-CC score that fell more than 3 standard deviations below the mean and was thus removed from all subsequent analyses of RCFT-CC scores. Statistical analyses (see Table 1 legend) were conducted using SPSS statistical software. An alpha level of .05 was used in the interpretation of all results.
Table 1Cognitive Test Performance by APOE-ε4 Status and Family History of AD and/or MP
|ε4−||ε4+||ε4||FH||Interaction||Simple Effect −FH vs. +FH Within ε4+|
|−FH (n = 52)||+FH (n = 28)||−FH (n = 12)||+FH (n = 10)||p|
|Reading||67.94 (19.32)||71.14 (15.69)||72.83 (10.95)||57.60 (16.91)||.310||.159||.032*||.027*|
|Language||69.79 (20.19)||71.21 (16.29)||74.17 (12.98)||56.50 (26.47)||.273||.086||.044*||.077|
|Spelling||64.69 (18.25)||66.21 (16.30)||69.58 (22.78)||62.00 (31.98)||.945||.535||.352||N/A|
|Math||62.77 (19.26)||68.39 (18.51)||64.83 (13.60)||56.30 (19.34)||.270||.748||.120||N/A|
Sample sizes for the Rey Complex Figure Test Copy Condition (RCFT-CC) analysis were slightly higher (i.e., ε4−/+FH, n = 31; ε4−/−FH, n = 53; ε4+/+FH, n = 11; ε4+/−FH, n = 13) than for the California Achievement Test (CAT-6) subtests; furthermore, the overall lower mean scores observed on the RCFT-CC relative to the achievement subtests likely reflect the fact that the two types of tests use different normative comparison groups. Data are standardized normal curve equivalent (NCE) scores, which have a mean of 50 and a standard deviation of 21. NCE scores are presented as mean (SD).
|50.67 (13.61)||55.48 (11.40)||57.51 (7.42)||48.32 (9.19)||.956||.439||.015*||.015*|
AD, Alzheimer's disease; APOE, apolipoprotein E gene; FH, family history; MP, memory problems.
Asterisks denote p < .05.
a Examined with univariate analysis of variance.
b Main effect of APOE-ε4 status.
c Main effects of AD/MP FH status.
d Effect of interaction between APOE-ε4 and FH status.
e Results of follow-up simple effects testing are also presented.
f Sample sizes for the Rey Complex Figure Test Copy Condition (RCFT-CC) analysis were slightly higher (i.e., ε4−/+FH, n = 31; ε4−/−FH, n = 53; ε4+/+FH, n = 11; ε4+/−FH, n = 13) than for the California Achievement Test (CAT-6) subtests; furthermore, the overall lower mean scores observed on the RCFT-CC relative to the achievement subtests likely reflect the fact that the two types of tests use different normative comparison groups. Data are standardized normal curve equivalent (NCE) scores, which have a mean of 50 and a standard deviation of 21. NCE scores are presented as mean (SD).
Demographic data are presented in Table 2. Twenty-two percent of subjects were ε4-positive, and 78.0% were ε4-negative. With respect to the sample as a whole, there were 32 children (29.1%) for whom a family history of AD was endorsed. The breakdown with regard to the relation of the reportedly affected relative(s) was as follows: grandparent, n = 18; great-grandparent, n = 10; great-aunt, n = 1; uncle, n = 1; and two or more relatives, n = 2. In addition, there were 22 children (20.0%) for whom a family history of significant MP was endorsed. The breakdown with regard to the relation of the reportedly affected relative(s) was as follows: grandparent, n = 15; great-grandparent, n = 4; and parent, n = 3. Furthermore, considering cases of overlap, there were 43 children (39.1%) for whom a +FH of AD, MP, or both were endorsed. When examining the combined effect of APOE genotype and FH status, analyses were initially completed with a +FH defined as the presence of a relative with AD and then again with a +FH defined as the presence of a relative with AD, MP, or both. The results of these two sets of analyses were similar; thus, because there was increased statistical power in the latter case (i.e., because of a slightly higher number of children in the +FH groups), those results are presented here.
Table 2Basic Demographic Information by APOE–ε4 Status
|ε4− (n = 85)||ε4+ (n = 24)||p|
|Percentage in Allele Category||78.0||22.0||n/a|
|Age at Exam|
|13.42 (1.22)||13.42 (1.40)||.979|
|Parent Education in Years|
|Mother||16.35 (2.09)||16.46 (2.17)||.829|
|16.26 (2.41)||16.21 (2.60)||.925|
|AD/MP Family History (Yes/No)||32/53||11/13||.469|
AD, Alzheimer's disease; APOE, apolipoprotein E gene; L, left; MP, memory problems; R, right.
a Data are presented as mean (standard deviation).
b One-way analysis of variance used to test group differences.
c Chi-square used to test group differences.
d Based on n = 108.
There were no significant main effects of APOE-ε4 status or FH status for any of the CAT-6 subtests or the RCFT-CC (Table 1). There were, however, significant interaction effects between APOE-ε4 status and FH status with respect to the Reading subtest [F(1,98) = 4.726, p = .032; ηp2 = .046], Language subtest [F(1,98) = 4.151, p = .044; ηp2 = .041], and the RCFT-CC [F(1,104) = 6.181, p = .015; ηp2 = .056]. Table 1 depicts the mean scores for each group, and, as shown, children with both an APOE-ε4 allele and a +FH of AD/MP obtained lower scores on each measure relative to children in the other three groups. To explore this finding further, follow-up simple effects testing was performed, and among APOE-ε4 allele carriers, results revealed significantly lower reading and RCFT-CC scores among +FH children relative to −FH children (Table 1); among children without an APOE-ε4 allele, there were no significant differences in scores as a function of FH status. Analyses were also completed with a subset of the other FH conditions assessed (Supplement 1), and no other FH condition (e.g., stroke) showed a significant interaction with APOE-ε4 status for any of the cognitive measures.
Here we present the first evidence of which we are aware that the combined presence of two risk factors for AD, the APOE-ε4 allele and a +FH of AD/MP, may be associated with lower cognitive test performance in school-age children. Although children with both risk factors obtained mean test scores within the average range, their lowered performance relative to the other groups suggests that there may be a subtle synergistic effect of these AD risk factors that could lead to the development of less cognitive reserve early in life. These results also invite the hypothesis that factors still unknown at this time (e.g., other genetic factors, environmental factors) that are embodied in a +FH of AD/MP may interact with APOE during early development to adversely affect cognition in childhood. Thus risk factors for a disorder of pathologic aging (i.e., AD) may have implications for the etiology of certain types of learning difficulties in children, which is consistent with retrospective work in this area (
17). Furthermore, our results are generally consistent with neuroimaging findings of APOE-ε4-related differences in young adults (
- Snowdon D.A.
- Greiner L.H.
- Markesbery W.R.(
Linguistic ability in early life and the neuropathology of Alzheimer's disease and cerebrovascular disease Findings from the Nun Study.
Ann N Y Acad Sci. 2000; 903: 34-38
- Reiman E.M.
- Chen K.
- Alexander G.E.
- Caselli R.J.
- Bandy D.
- Osborne D.
- et al.
Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia.
Proc Nat Acad Sci U S A. 2004; 101: 284-289
Because this is a preliminary study, findings should be viewed with some caution in light of the relatively small sample sizes studied, as well as the fact that FH status was based primarily on second-degree relatives and assessed through parent report. Results also suggest a number of areas for further study. Most notably, future studies that examine additional cognitive domains—in particular, memory—would be critical given that most studies that have found differences between individuals with and without a family history of AD have primarily observed these differences with respect to learning and memory (
- Bondi M.W.
- Monsch A.U.
- Galasko D.
- Butters N.
- Salmon D.P.
- Delis D.C.(
Preclinical cognitive markers of dementia of the Alzheimer type.
Neuropsychology. 1994; 8: 374-384
20). In addition, more detailed assessment of family history status (e.g., confirmed by medical records), as well as assessment of additional early-life variables (e.g., perinatal complications) and genetic factors that have been implicated in AD pathogenesis may help elucidate the complex relationship between environmental and genetic risk factors for AD and their impact on cognitive functioning in early life.
- La Rue A.
- O'Hara R.
- Matsuyama S.S.
- Jarvik L.F.(
Cognitive changes in young-old adults: Effect of family history of dementia.
J Clin Exp Neuropsychol. 1995; 17: 65-70
We thank the children, families, and teachers who gave of their time to participate in this study. This work was supported in part by the National Institutes of Health (Grant Nos. K24 AG026431, RO1 AG12674, and P50 AG05131) and by a Merit Review Research Program from the Department of Veterans Affairs.
The authors report no biomedical financial interests or potential conflicts of interest.
- Supplement 1
- Apolipoprotein E: High-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.Proc Nat Acad Sci U S A. 1993; 90: 1977-1981
- Apolipoprotein E and cognitive performance: A meta-analysis.Psychol Aging. 2004; 19: 592-600
- Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: The REVEAL study.Genet Med. 2004; 6: 192-196
- The influence of Alzheimer disease family history and apolipoprotein E epsilon4 on mesial temporal lobe activation.J Neurosci. 2006; 26: 6069-6076
- Cognitive change and the APOE epsilon 4 allele.Nature. 2002; 418: 932
- Allelic associations between 100 DNA markers and high versus low IQ.Intelligence. 1995; 21: 31-48
- No association between apolipoprotein E polymorphisms and general cognitive ability in children.Neurosci Lett. 2001; 299: 97-100
- Apolipoprotein E genotype predicts 24-month Bayley scales infant development score.Pediatr Res. 2003; 54: 819-825
- The distribution of apolipoprotein E alleles in Scottish perinatal deaths.J Med Genet. 2006; 43: 414-418
- Influence of the apolipoprotein E epsilon4 allele on human embryonic development.Neurosci Lett. 2002; 324: 189-192
- TerraNova, 2nd ed.CTB/McGraw-Hill, Monterey, CA2001
- Le test de copie d'une figure complexe.Arch Psychol. 1944; 30: 206-353.
- Lezak M.D. Howieson D.B. Loring D.W. Neuropsychological Assessment. 4th ed. Oxford University Press, New York2004: 531-568
- Effect of chronic antiepileptic drug therapy on California achievement test scores.J Epilepsy. 1998; 11: 208-214
- Assessing children's copy productions of the Rey-Osterrieth Complex Figure.J Clin Exp Neuropsychol. 1985; 7: 264-280
- Fundamentals of Human Neuropsychology.3rd ed. W.H. Freeman, New York1990
- Linguistic ability in early life and the neuropathology of Alzheimer's disease and cerebrovascular disease.Ann N Y Acad Sci. 2000; 903: 34-38
- Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia.Proc Nat Acad Sci U S A. 2004; 101: 284-289
- Preclinical cognitive markers of dementia of the Alzheimer type.Neuropsychology. 1994; 8: 374-384
- Cognitive changes in young-old adults: Effect of family history of dementia.J Clin Exp Neuropsychol. 1995; 17: 65-70
Published online: August 26, 2008
Accepted: July 8, 2008
Received in revised form: May 15, 2008
Received: March 14, 2008
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.