Neuropsychology 2015, Vol. 29, No. 3, 382–387
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Association of the Apolipoprotein E Genotype With Memory Performance and Executive Functioning in Cognitively Intact Elderly Tobias Luck, Francisca S. Then, and Melanie Luppa
Matthias L. Schroeter and Katrin Arélin
University of Leipzig
University of Leipzig and Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
Ralph Burkhardt and Joachim Thiery
Markus Löffler
University Hospital Leipzig, Leipzig, Germany
University of Leipzig
Arno Villringer
Steffi G. Riedel-Heller
Max Planck Institute for Human Cognitive and Brain Sciences and University of Leipzig
University of Leipzig
Objective: To test for a possible effect of the apolipoprotein E epsilon 4 (APOE ε4) allele on memory performance and executive functioning (EF) in cognitively intact elderly. Method: The authors studied 202 randomly selected and cognitively intact older adults (65⫹ years) of the Leipzig Research Center for Civilization Diseases Health Care Study. Intact global cognitive functioning was defined using a Mini-Mental Status Examination (MMSE) score ⱖ28. Performance in memory was assessed with the CERAD Word List and Constructional Praxis Recall, performance in EF with the Trail Making Test Part B (TMT-B). Multivariable linear regressions were used to evaluate the association between cognitive performance and APOE status, controlled for covariates. Results: Among the cognitively intact older adults, 21.3% (n ⫽ 43) were carriers of the APOE ε4 allele. Carriers did not differ significantly from noncarriers in terms of age, gender, intelligence level, or performance in memory but showed a significantly lower TMT-B performance as a measure of EF (TMT-B M time/SD ⫽ 105.6/36.2 vs. 91.9/32.7 s; Mann–Whitney U ⫽ 4,313.000; p ⫽ .009). The association between lower TMT-B performance and APOE ε4 genotype remained significant in multivariable linear regression analysis. Similar findings were found for the subsample of those 78 elderly, who reached a perfect MMSE-score of 30. Conclusions: A lower EF performance in cognitively intact older APOE ε4 allele carriers might be related to an early Alzheimer’s dementia (AD) prodrome. In this case, a stronger focus on first subtle changes in EF may help to improve early AD detection in those being at genetic risk. Keywords: apolipoprotein E, executive functioning, memory, cognitively normal elderly, Trail Making Test
Dementia—particularly of the Alzheimer’s type (AD) – is usually preceded by a transitional period of subclinical cognitive impairments. Such impairments are typically found in memory, but there is increasing evidence that preclinical AD is also char-
acterized by subtle deficits in a broader range of cognitive domains (Storandt, Grant, Miller, & Morris, 2006; Wierenga et al., 2010). Among those “nonamnestic” cognitive domains, executive functioning (EF) may be of particular interest, as findings suggest an
This article was published Online First November 3, 2014. Tobias Luck and Francisca S. Then, Institute of Social Medicine, Occupational Health and Public Health and LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig; Melanie Luppa, Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig; Matthias L. Schroeter and Katrin Arélin, University of Leipzig and Max Planck Institute for Human Cognitive and Brain Sciences & Day Clinic of Cognitive Neurology; Ralph Burkhardt and Joachim Thiery, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; Markus Löffler, Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig; Arno Villringer, Max Planck Institute for Human Cognitive and Brain Sciences and Day Clinic of Cognitive Neurology, University of Leipzig; Steffi G. Riedel-Heller,
Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig. This publication is supported by LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund and by means of the Free State of Saxony within the framework of the excellence initiative. Matthias L. Schroeter has further been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research, and by the Parkinson’s disease Foundation (Grant PDF-IRG-1307). Correspondence concerning this article should be addressed to Tobias Luck, University of Leipzig, Institute of Social Medicine, Occupational Health and Public Health, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany. E-mail: [email protected] 382
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APOE ε4 & COGNITION IN COGNITIVELY INTACT ELDERLY
early decline over time in this domain in subjects who would clinically manifest AD later (Chen et al., 2001). The risk of developing AD is influenced by multiple nonmodifiable factors like age or genetic susceptibility as well as modifiable factors like smoking or hypertension (Kidd, 2008). Among the genetic risk factors, the ε4 allele of the apolipoprotein E (APOE) gene is known as the most relevant one for late-onset AD (Paulson & Igo, 2011). Carrying the APOE ε4 allele is supposed to account for around 20 –50% of the attributable total risk for dementia (Slooter et al., 1998; Ashford, 2004). Expression of the allele has been shown to affect sterol homeostasis, cholesterol transport, membrane repair, and other cellular activities that are related to -amyloid accumulation and neurodegenerative processes in the human brain (Schipper, 2011a, 2011b). Findings from clinical studies, moreover, support the assumption that APOE ε4 allele carriers in general may have less effective neural protection and repair mechanisms: Ariza et al. (2006), for example, have shown that patients with moderate or severe traumatic brain injury who carried the APOE ε4 allele perform worse in neuropsychological tests and have more behavioral disturbances than corresponding traumatic brain injury patients without the allele. The effect of the APOE ε4 allele, thus, is not only limited to clinically manifest AD. There is also an increasing number of studies that provide evidence of an association between presence of the allele and poorer cognitive performance in cognitively healthy older adults (e.g., poorer performance in visuospatial attention, retention of memory for location, and attentional modulation of memory of target location, see Greenwood, Lambert, Sunderland, & Parasuraman, 2005; poorer performance in global cognitive functioning, episodic memory, and executive functioning, see Small, Rosnick, Fratiglioni, & Bäckman, 2004). In this study, we sought to provide further evidence on such an association. We particularly focused on possible effects of the APOE ε4 allele on memory and EF and thus on cognitive domains, whose declines are important indicators of a prodromal stage of AD.
Methods Participants Data were derived from the ongoing Health Care Study of the Leipzig Research Center for Civilization Diseases (LIFE) in Leipzig, Germany. The aim of the LIFE Health Care Study is to look at the causes and courses of common civilization diseases such as cardiovascular diseases, diabetes, depression, dementia, or allergies. To recruit adult participants (18 –79 years), Leipzig residents are randomly selected by the Leipzig registry office and invited. In this study, we studied a first sample of 280 older participants (ages: 65⫹ years) with available neuropsychological and genetic data. All participants provided written informed consent prior to their participation in the study. The study complies with the ethical standards of the Declaration of Helsinki and has been approved by the ethics committee of the University of Leipzig.
General Assessment Procedures All adult participants of the LIFE Health Care Study undergo an extensive assessment program, including different clinical exam-
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inations, standardized questionnaires, neuropsychological testing as well as collection of biological samples like blood and urine. A standardized interview provided information on sociodemographics, comorbidities, and other characteristics. Depressive symptoms are identified using the German version of the 20-item Center of Epidemiologic Studies Depression Scale with a cut-off ⱖ23 (CES-D; Radloff, 1977; Hautzinger, Bailer, Hofmeister, & Keller, 2012). Symptoms of anxiety are identified using the German version of the 7-item Generalized Anxiety Disorder Scale with a cut-off ⱖ10 (GAD-7; Spitzer, Kroenke, Williams, & Löwe, 2006). Participants aged over 65 years are asked to participate in further examinations, including a more extensive neuropsychological testing (see below) as well as a standardized interview on activities of daily living. All examinations are conducted by trained study personnel at the LIFE Research Center located on the premises of the University Hospital of Leipzig.
Neuropsychological Testing A broad range of tests are used in the LIFE Health Care Study to assess neuropsychological performance in the older participants. Results of the present study are based on the following tests. Global cognitive functioning. We used the Mini-Mental State Examination (MMSE; Folstein, Folstein, & McHugh, 1975) to assess global cognitive functioning. The MMSE includes items on several cognitive domains such as orientation, memory, language or calculation. The maximum score of the MMSE is 30 points. A higher score indicates a better global cognitive performance. We used an MMSE ⱖ28 to define intact global cognitive functioning, as this threshold score was found to discriminate best between cognitive normalcy and cognitive impairment compared to commonly used lower threshold scores (e.g., 25; Damian et al., 2011). Intelligence. We used the vocabulary test (Wortschatztest [WST]; Schmidt & Metzler, 1992) to briefly estimate general intelligence level. The WST consists of 42 lists including six words each: five pseudowords (distractors) and one meaningful word to be recognized among the distractors. The maximum WST score is 42 points. A higher score indicates a higher intelligence level. EF and cognitive processing speed. We used the Trail Making Test B (TMT-B; Reitan, 1992) to assess EF. The TMT consists of two parts. Part A requires participants to draw lines to connect consecutive numbers from 1 to 25 as quickly as possible. Part B requires drawing lines to connect numbers and letters in an alternating sequence (1-A-2-B-3-C, etc.) as quickly as possible. The time to complete each part is recorded (time limit of TMT-A ⫽ 180 s, of TMT-B ⫽ 300 s). Shorter time needed to complete the trails in Parts A and B indicates better cognitive performance. Performance on TMT-A is used as a measure of cognitive processing speed and performance on TMT-B, a test that involves switching between numbers and letters, is used to examine EF. Memory. We used the Word List subtests of the Consortium to Establish a Registry for Alzheimer’s Disease-Neuropsychological (CERAD) battery (CERAD Word List; Morris, Mohs, Rogers, Fillenbaum, & Heyman, 1988; Morris et al., 1989) to assess performance in verbal memory. The CERAD Word List consists of three subtests: The first subtest, Word List Memory, is used to assess the ability to learn new verbal information. Participants are
LUCK ET AL.
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asked to read 10 printed words presented at a rate of one every 2 s and then to recall as many as possible. Two further trials are administered in this fashion with a different word order each trial. The maximum total score of the subtest Word List Memory is 30 (10 correctly recalled words in each trial). The second subtest, Word List Recall, is used to assess delayed verbal memory in a free-recall task. The subtest is conducted approximately 10 min after the subtest Word List Memory. Participants are instructed to recall as many of the previously learned 10 words as they can (maximum of correct responses ⫽ 10). The last subtest, Word List Recognition, is used to assess delayed verbal memory in a recognition task. The subtest is conducted immediately after the subtest Word List Recall. The participant is asked to recognize the 10 previously learned words from a list of 20 words including the 10 target words and 10 distractor words. The maximum score of the subtest is 20 (10 words correctly recognized, 10 words correctly rejected; Andel et al., 2003). We additionally used the Constructional Praxis Recall subtest of the CERAD neuropsychological test battery to assess performance in nonverbal praxis memory. The subtest requires to recall and to draw four figures (circle, diamond, overlapping rectangles, Necker cube) which had to be copied earlier in the neuropsychological assessment session (CERAD subtest Constructional Praxis; Rosen, Mohs, & Davis, 1984). The maximum total score for the correct recall drawing of the four figures is 11 points.
APOE 4 Genotyping Genomic DNA was isolated from peripheral blood leukocytes using an automated protocol on the Qiagen Autopure LS (Qiagen, Hilden, Germany). DNA purity and yield was determined on a NanoDrop spectrophotometer. Genotyping of the APOE allele status (ε2, ε3, ε4) was performed on a Roche Lightcylcer 480 according to the method of Aslanidis and Schmitz (1999). For statistical analyses, participants were divided by APOE status into those with or without at least one ε4 allele. Participants were not informed whether they were carriers or noncarriers of the ε4 allele.
Statistical Analysis The statistical analyses were performed using Predictive Analytics Software (PASW), version 20.0 (IBM Corp., Armonk, NY). All analyses used an alpha level for statistical significance of .05 (two-tailed). Group differences were analyzed using t test, Mann– Whitney U test and 2 test as appropriate. We used multivariable linear regressions to evaluate the association between EF (performance in TMT-B) and APOE ε4 status in cognitively intact older adults, controlled for covariates. We included the covariates in the regression models based on their potential relationship with performance in TMT-B.
Results Among a randomly selected sample of 280 elderly participants (65⫹ years) of the LIFE Health Care Study, 202 were classified as cognitively intact (MMSE-score ⱖ28) and included in the analyses; 21.3% (n ⫽ 43) of these participants were carriers of an APOE ε4 allele (42 heterozygotes, one homozygote). As shown in Table 1, APOE ε4 allele carriers did not differ significantly from non-
carriers in terms of age, gender, or education. Carriers and noncarriers also showed a comparable picture of comorbidities. None of the participants reported an inability to perform activities of daily living as assessed by the Barthel-Index (Mahoney & Barthel, 1965; results not shown). With regard to neuropsychological test results, APOE ε4 allele carriers and noncarriers also showed a similar general intelligence level (Vocabulary Test WST: M/SD number of correct words ⫽ 33.0/3.3 vs. 33.0/3.9, Mann–Whitney U ⫽ 2,760.000, p ⫽ .523) and similar performances in verbal memory (CERAD Word List Memory subtest: M/SD number of correct words ⫽ 21.5/3.5 vs. 21.2/4.0, Mann–Whitney U ⫽ 3,485.500, p ⫽ .843; CERAD Word List Recall subtest: M/SD ⫽ 7.7/1.7 vs. 7.7/1.7, Mann–Whitney U ⫽ 3,470.500, p ⫽ .876; CERAD Word List Recognition subtest: M/SD ⫽ 19.7/0.7 vs. 19.6/0.8, Mann–Whitney U ⫽ 3,736.000, p ⫽ .135), nonverbal praxis memory (CERAD Constructional Praxis Recall subtest: M/SD points ⫽ 8.1/2.4 vs. 8.7/2.5, Mann– Whitney U ⫽ 3,593.000, p ⫽ .087) and in cognitive processing speed (M/SD time needed to complete the TMT-A ⫽ 43.5/12.4 vs. 40.7/13.5 s, Mann–Whitney U ⫽ 3,943.000, p ⫽ .123), but a significantly different performance in EF: Carriers needed significantly more time to complete the TMT-B than noncarriers (M/SD time ⫽ 105.6/36.2 vs. 91.9/32.7 s, Mann–Whitney U ⫽ 4,313.000, p ⫽ .009; see Table 1). Results of the multivariable linear regression analysis with adjustment for covariates confirmed the finding of a significant lower performance in EF (i.e., time needed to complete the TMT-B) in cognitively intact older adults with APOE ε4 allele compared to those without (see Table 2; Model 1). The regression model also showed male gender and lower intelligence level to be significantly associated with lower performance in EF (i.e., more time needed to complete the TMT-B). We additionally tested for an association between performance in EF and APOE ε4 status in a subgroup of those older adults, who reached a perfect score of 30 in the MMSE. Findings were similar to those for the group of participants with MMSE-score ⱖ28, as (a) APOE ε4 allele carriers needed significantly more time to complete the TMT-B than noncarriers (APOE ε4 allele carriers: M/SD ⫽ 106.85/32.73 s, n ⫽ 13; APOE ε4 allele noncarriers: M/SD ⫽ 83.55/24.44 s, n ⫽ 65; Mann–Whitney U ⫽ 623.000; p ⫽ .007) and (b) the association between performance in EF and APOE ε4 status remained significant in multivariable linear regression analysis with adjustment for covariates (see Table 2, Model 2).
Discussion In this study, we sought to test for a possible effect of the APOE ε4 allele, the most important genetic risk factor for late-onset AD, on memory performance and EF in cognitively intact older adults. We found that carriers of at least one APOE ε4 allele did not differ significantly from noncarriers in their memory performance, but showed a significantly lower TMT-B performance as one measure of EF than the noncarriers - even after adjustment for age, gender, general intelligence level, and specific medical comorbidities. Previous studies suggest that, in addition to memory deficits, EF impairment is an important early indicator of early AD (e.g., Chen et al., 2001). These findings are also supported by imaging studies
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Table 1 Sociodemographics, Clinical, and Neuropsychological Characteristics of Cognitively Intact (MMSE ⱖ 28) APOE ε4 Allele Carriers and Noncarriers APOE ε4 allele noncarriers
APOE ε4 allele carriers
Characteristic
(n ⫽ 159)
(n ⫽ 43)
Age, years; M (SD) Gender, female; n (%) Education ⱕ 10 years; n (%) ⬎ 10 years; n (%) Comorbidity; n (%) Diabetes mellitusa Hypertensionb Strokec,d Myocardial infarctionc,d Symptoms of anxiety, GAD-7d Depressive symptoms, CES-Dd Intelligencee WST, correct words; M (SD) Verbal memory WL memory, correct words; M (SD) WL recall, correct words; M (SD) WL recognition,f correct words; M (SD) Nonverbal praxis memory CP Recall, points; M (SD) Cognitive processing speed TMT-A,g time in s; M (SD) Executive functioning TMT-B,g time in s; M (SD)
70.82 (3.64) 69 (43.40)
71.26 (3.66) 19 (44.19)
⫺0.702 0.009
.484 .926
70.91 (3.64) 88 (43.56)
89 (55.97) 70 (44.03)
26 (60.47) 17 (39.53)
0.278
.594
115 (56.93) 87 (43.07)
34 (21.79) 90 (60.40) 3 (1.91) 1 (0.64) 2 (1.26) 1 (0.63)
6 (14.63) 27 (65.85) 1 (2.38) 0 (0.00) 1 (2.33) 1 (2.33)
1.029 0.404 — — — —
.310 .525 — — — —
40 (20.30) 117 (61.58) 4 (2.01) 1 (0.50) 3 (1.49) 2 (0.99)
t, U, or 2 value
Total sample
p value (two-tailed)
(n ⫽ 202)
32.99 (3.86)
32.95 (3.34)
2,760.000
.523
32.98 (3.74)
21.21 (4.03) 7.69 (1.74) 19.60 (0.75)
21.47 (3.45) 7.74 (1.73) 19.74 (0.66)
3,485.500 3,470.500 3,736.000
.843 .876 .135
21.26 (3.91) 7.70 (1.74) 19.63 (0.73)
8.72 (2.47)
8.07 (2.44)
3,593.000
.087
8.59 (2.47)
40.69 (13.45)
43.49 (12.44)
3,943.000
.123
41.29 (13.26)
91.94 (32.71)
105.60 (36.16)
4,313.000
.009
94.85 (33.85)
Note. APOE ε4 ⫽ apolipoprotein E epsilon 4; CES-D⫽ Center of Epidemiologic Studies Depression Scale; CP ⫽ Constructional Praxis; GAD-7 ⫽ Generalized Anxiety Disorder Scale; MMSE ⫽ Mini-Mental State Examination; TMT-A ⫽ Trail Making Test Part A; TMT-B ⫽ Trail Making Test Part B; WL ⫽ Word List; WST ⫽ Wortschatztest (Vocabulary Test). a Data missing for 5 (2.5%) subjects. b Data missing for 12 (5.9%) subjects. c Data missing for 3 (1.5%) subjects. d No inferential statistics were calculated because of the small numbers of cases. e Data missing for 17 (8.4%) subjects. f Data missing for 3 (1.5%) subjects. g Participants made only few errors in the TMT (TMT-A: M/SD ⫽ 0.14/0.39, range ⫽ 0 –2; TMT-B ⫽ M/SD ⫽ 0.57/0.98, range ⫽ 0 – 6) and APOE ε4 allele noncarriers’ and carriers’ performance did not differ with regard to the number of errors (TMT-A: mean/SD ⫽ 0.15/0.40 vs. 0.12/0.32, Mann-Whitney U ⫽ 3,378.500, p ⫽ .837; TMT-B: mean/SD ⫽ 0.59/0.98 vs. 0.54/0.96, Mann-Whitney U ⫽ 3,264.000, p ⫽ .590).
showing that AD affects frontal neural networks related to executive functions, as well as the well-known hippocampal and parietal memory networks (Schroeter, Stein, Maslowski, Neumann, 2009; Schroeter et al., 2012). Recent findings of Carlson, Xue, Zhou, and Fried (2009) additionally suggest that a decline in EF
may actually precede a decline in memory. We found a pattern of lower EF performance in APOE4 allele carriers compared to noncarriers, but no significant differences in memory performance between the two groups. This may reflect a chronological sequence from EF decline to memory decline to frank clinical AD. That is,
Table 2 Multivariable Linear Regression to Evaluate the Association Between Performance in Executive Functioning (Time Needed to Complete the TMT-B; in seconds) and APOE ε4 Status in Cognitively Intact Older Adults, Controlled for Covariates Model 1
Model 2
MMSE-score ⱖ 28 (n ⫽ 175)a,b
MMSE-score ⫽ 30 (n ⫽ 69)c,d
Characteristics
Coefficient
SE
p value
Coefficient
SE
p value
APOE ε4 allele, carrier vs. noncarrier Age, every additional year Gender, female vs. male WST, every additional point Diabetes mellitus Hypertension Constant
12.260 0.635 ⫺10.417 ⫺2.937 2.516 ⫺0.733 146.507
5.574 0.646 4.754 0.630 5.745 4.838 49.101
.029 .072 .020 ⬍.001 .662 .880 .003
17.374 ⫺0.682 ⫺5.953 ⫺1.249 11.200 8.038 169.528
7.432 0.817 5.582 0.850 7.534 5.751 58.227
.023 .407 .290 .146 .142 .167 .005
Note. APOE ε4 ⫽ apolipoprotein E epsilon 4; TMT-B ⫽ Trail Making Test Part B; WST ⫽ Wortschatztest (Vocabulary Test). a Data missing for 27 (13.4%) of 202 subjects with Mini-Mental State Examination (MMSE)-score ⱖ 28 and age ⱖ 65 years. .120. c Data missing for nine (11.5%) of 78 subjects with MMSE-score ⫽ 30 and age ⱖ 65 years. d Adjusted R2 ⫽ .129.
b
Adjusted R2 ⫽
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cognitively intact APOE4 allele carriers may have been in an early prodromal stage of AD, during which subtle EF deficits become evident before memory deficits and before a global cognitive loss is noted. Because of the relatively young age of the APOE4 allele carriers in our study (M age ⫽ 71.3 years), this group could be expected to display prodromal AD symptoms rather than the clinical syndrome of AD. Studies have shown that the average onset of clinical manifest AD in ε4 heterozygotes is 75 years (compared with 78 – 84 years in noncarriers and to 68 –73 years in ε4 homozygotes; see Corder et al., 1993; Sando et al., 2008). Our study, however, is not without limitations. The generalizability of our results may be limited because of the low response rate of the ongoing LIFE Health Care Study so far (34.6%), as well as of the relatively small sample size our analyses were based on. Also, the MMSE is only a brief screening instrument for global cognitive functioning and the procedure of categorizing subjects as cognitively intact with the MMSE is associated with some inaccuracy. We aimed to minimize the inaccuracy by using the high cut-off of ⱖ28 MMSE points to discriminate between cognitive normalcy and cognitive impairment and also by repeating the analyses with the subgroup of those older adults, who reached a perfect score of 30 in the MMSE. However, even such a perfect MMSE score may lack some sensitivity when compared with more extensive clinical and neuropsychological examinations. This might be especially true for highly educated individuals. To exclude the possibility that the association between the APOE ε4 allele and the TMT-B performance may be mainly attributed to a sample including better educated individuals (who may be already cognitively impaired), we therefore also repeated the multivariable regression analysis with the subgroup of older adults, who reached the perfect MMSE-score of 30 and additionally controlled for education. We found that the association between lower TMT-B performance and APOE ε4 genotype still remained significant (coefficient ⫽ 17.856, standard error ⫽ 7.404, p ⫽ .019; results not shown). And finally, at this time, we were only able to provide cross-sectional findings and only findings of the TMT-B as one measure of EF. TMT-B performance, however, can be impaired not only by incipient AD but also by several further medical, psychiatric, and neuropsychological conditions. Longitudinal data of the present study as well as of others with additional EF measures will therefore help to investigate further whether lower EF performance in cognitively intact older APOE ε4 allele carriers might be related to an early AD prodrome. In this case, a stronger focus on first subtle changes in EF may help to improve early AD detection in those being at genetic risk.
References Andel, R., McCleary, C. A., Murdock, G. A., Fiske, A., Wilcox, R. R., & Gatz, M. (2003). Performance on the CERAD Word List Memory task: A comparison of university-based and community-based groups. International Journal of Geriatric Psychiatry, 18, 733–739. http://dx.doi.org/ 10.1002/gps.913 Ariza, M., Pueyo, R., Matarín, M. M., Junqué, C., Mataró, M., Clemente, I., . . . Sahuquillo, J. (2006). Influence of APOE polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury. Journal of Neurology, Neurosurgery, & Psychiatry, 77, 1191–1193. http://dx.doi.org/10.1136/jnnp.2005.085167
Ashford, J. W. (2004). APOE genotype effects on Alzheimer’s disease onset and epidemiology. Journal of Molecular Neuroscience, 23, 157– 166. http://dx.doi.org/10.1385/JMN:23:3:157 Aslanidis, C., & Schmitz, G. (1999). High-speed apolipoprotein E genotyping and apolipoprotein B3500 mutation detection using real-time fluorescence PCR and melting curves. Clinical Chemistry, 45, 1094 – 1097. Carlson, M. C., Xue, Q. L., Zhou, J., & Fried, L. P. (2009). Executive decline and dysfunction precedes declines in memory: The Women’s Health and Aging Study II. The Journals of Gerontology: Series A: Biological Sciences and Medical Sciences, 64A, 110 –117. http://dx.doi .org/10.1093/gerona/gln008 Chen, P., Ratcliff, G., Belle, S. H., Cauley, J. A., DeKosky, S. T., & Ganguli, M. (2001). Patterns of cognitive decline in presymptomatic Alzheimer disease: A prospective community study. Archives of General Psychiatry, 58, 853– 858. http://dx.doi.org/10.1001/archpsyc.58.9.853 Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., . . . Pericak-Vance, M. A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261, 921–923. http://dx.doi.org/10.1126/ science.8346443 Damian, A. M., Jacobson, S. A., Hentz, J. G., Belden, C. M., Shill, H. A., Sabbagh, M. N., . . . Adler, C. H. (2011). The Montreal Cognitive Assessment and the Mini-Mental State Examination as screening instruments for cognitive impairment: Item analyses and threshold scores. Dementia and Geriatric Cognitive Disorders, 31, 126 –131. http://dx.doi .org/10.1159/000323867 Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189 –198. http://dx .doi.org/10.1016/0022-3956(75)90026-6 Greenwood, P. M., Lambert, C., Sunderland, T., & Parasuraman, R. (2005). Effects of apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle-aged adults: Results from the National Institute of Mental Health’s BIOCARD study. Neuropsychology, 19, 199 –211. http://dx.doi.org/10.1037/0894-4105.19.2 .199 Hautzinger, M., Bailer, M., Hofmeister, D., & Keller, F. (2012). Allgemeine Depressionsskala: Manual [article in German]. Göttingen, Germany: Hogrefe Verlag. Kidd, P. M. (2008). Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: Current understanding and progress toward integrative prevention. Alternative Medicine Review, 13, 85–115. Mahoney, F. I., & Barthel, D. W. (1965). Functional evaluation: The Barthel Index. Maryland State Medical Journal, 14, 61– 65. Morris, J. C., Heyman, A., Mohs, R. C., Hughes, J. P., van Belle, G., Fillenbaum, G., . . . Clark, C. (1989). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD): Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology, 39, 1159 – 1165. http://dx.doi.org/10.1212/WNL.39.9.1159 Morris, J. C., Mohs, R. C., Rogers, H., Fillenbaum, G., & Heyman, A. (1988). Consortium to establish a registry for Alzheimer’s disease (CERAD) clinical and neuropsychological assessment of Alzheimer’s disease. Psychopharmacology Bulletin, 24, 641– 652. Paulson, H. L., & Igo, I. (2011). Genetics of dementia. Seminars in Neurology, 31, 449 – 460. http://dx.doi.org/10.1055/s-0031-1299784 Radloff, L. S. (1977). The CES-D scale: A self-report depression scale for research in the general population. Applied Psychological Measurement, 1, 385– 401. http://dx.doi.org/10.1177/014662167700100306 Reitan, R. M. (1992). Trail Making Test: Manual for administration and scoring. Tucson, AZ: Reitan Neuropsychology Laboratory.
This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
APOE ε4 & COGNITION IN COGNITIVELY INTACT ELDERLY Rosen, W. G., Mohs, R. C., & Davis, K. L. (1984). A new rating scale for Alzheimer’s disease. The American Journal of Psychiatry, 141, 1356 – 1364. Sando, S. B., Melquist, S., Cannon, A., Hutton, M. L., Sletvold, O., Saltvedt, I., . . . Aasly, J. O. (2008). APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurology, 8, 9. http://dx.doi.org/10.1186/ 1471-2377-8-9 Schipper, H. M. (2011a). Apolipoprotein E: Implications for AD neurobiology, epidemiology and risk assessment. Neurobiology of Aging, 32, 778 –790. http://dx.doi.org/10.1016/j.neurobiolaging.2009.04.021 Schipper, H. M. (2011b). Presymptomatic apolipoprotein E genotyping for Alzheimer’s disease risk assessment and prevention. Alzheimer’s & Dementia, 7, e118 – e123. http://dx.doi.org/10.1016/j.jalz.2010.06.003 Schmidt, K. H., & Metzler, P. (1992). Wortschatztest (WST). Weinheim, Germany: Beltz Test. Schroeter, M. L., Stein, T., Maslowski, N., & Neumann, J. (2009). Neural correlates of Alzheimer’s disease and mild cognitive impairment: A systematic and quantitative meta-analysis involving 1351 patients. NeuroImage, 47, 1196 –1206. http://dx.doi.org/10.1016/j.neuroimage.2009 .05.037 Schroeter, M. L., Vogt, B., Frisch, S., Becker, G., Barthel, H., Mueller, K., . . . Sabri, O. (2012). Executive deficits are related to the inferior frontal junction in early dementia. Brain: A Journal of Neurology, 135, 201– 215. http://dx.doi.org/10.1093/brain/awr311
387
Slooter, A. J., Cruts, M., Kalmijn, S., Hofman, A., Breteler, M. M., Van Broeckhoven, C., & van Duijn, C. M. (1998). Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: The Rotterdam Study. Archives of Neurology, 55, 964 –968. http://dx .doi.org/10.1001/archneur.55.7.964 Small, B. J., Rosnick, C. B., Fratiglioni, L., & Bäckman, L. (2004). Apolipoprotein E and cognitive performance: A meta-analysis. Psychology and Aging, 19, 592– 600. http://dx.doi.org/10.1037/0882-7974.19.4 .592 Spitzer, R. L., Kroenke, K., Williams, J. B., & Löwe, B. (2006). A brief measure for assessing generalized anxiety disorder: The GAD-7. Archives of Internal Medicine, 166, 1092–1097. http://dx.doi.org/10.1001/ archinte.166.10.1092 Storandt, M., Grant, E. A., Miller, J. P., & Morris, J. C. (2006). Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI. Neurology, 67, 467– 473. http://dx.doi.org/10.1212/01 .wnl.0000228231.26111.6e Wierenga, C. E., Stricker, N. H., McCauley, A., Simmons, A., Jak, A. J., Chang, Y. L., . . . Bondi, M. W. (2010). Increased functional brain response during word retrieval in cognitively intact older adults at genetic risk for Alzheimer’s disease. NeuroImage, 51, 1222–1233. http://dx.doi.org/10.1016/j.neuroimage.2010.03.021
Received February 21, 2014 Revision received September 8, 2014 Accepted September 8, 2014 䡲
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Association of the Apolipoprotein E Genotype With Memory Performance and Executive Functioning in Cognitively Intact Elderly Tobias Luck, Francisca S. Then, and Melanie Luppa
Matthias L. Schroeter and Katrin Arélin
University of Leipzig
University of Leipzig and Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
Ralph Burkhardt and Joachim Thiery
Markus Löffler
University Hospital Leipzig, Leipzig, Germany
University of Leipzig
Arno Villringer
Steffi G. Riedel-Heller
Max Planck Institute for Human Cognitive and Brain Sciences and University of Leipzig
University of Leipzig
Objective: To test for a possible effect of the apolipoprotein E epsilon 4 (APOE ε4) allele on memory performance and executive functioning (EF) in cognitively intact elderly. Method: The authors studied 202 randomly selected and cognitively intact older adults (65⫹ years) of the Leipzig Research Center for Civilization Diseases Health Care Study. Intact global cognitive functioning was defined using a Mini-Mental Status Examination (MMSE) score ⱖ28. Performance in memory was assessed with the CERAD Word List and Constructional Praxis Recall, performance in EF with the Trail Making Test Part B (TMT-B). Multivariable linear regressions were used to evaluate the association between cognitive performance and APOE status, controlled for covariates. Results: Among the cognitively intact older adults, 21.3% (n ⫽ 43) were carriers of the APOE ε4 allele. Carriers did not differ significantly from noncarriers in terms of age, gender, intelligence level, or performance in memory but showed a significantly lower TMT-B performance as a measure of EF (TMT-B M time/SD ⫽ 105.6/36.2 vs. 91.9/32.7 s; Mann–Whitney U ⫽ 4,313.000; p ⫽ .009). The association between lower TMT-B performance and APOE ε4 genotype remained significant in multivariable linear regression analysis. Similar findings were found for the subsample of those 78 elderly, who reached a perfect MMSE-score of 30. Conclusions: A lower EF performance in cognitively intact older APOE ε4 allele carriers might be related to an early Alzheimer’s dementia (AD) prodrome. In this case, a stronger focus on first subtle changes in EF may help to improve early AD detection in those being at genetic risk. Keywords: apolipoprotein E, executive functioning, memory, cognitively normal elderly, Trail Making Test
Dementia—particularly of the Alzheimer’s type (AD) – is usually preceded by a transitional period of subclinical cognitive impairments. Such impairments are typically found in memory, but there is increasing evidence that preclinical AD is also char-
acterized by subtle deficits in a broader range of cognitive domains (Storandt, Grant, Miller, & Morris, 2006; Wierenga et al., 2010). Among those “nonamnestic” cognitive domains, executive functioning (EF) may be of particular interest, as findings suggest an
This article was published Online First November 3, 2014. Tobias Luck and Francisca S. Then, Institute of Social Medicine, Occupational Health and Public Health and LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig; Melanie Luppa, Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig; Matthias L. Schroeter and Katrin Arélin, University of Leipzig and Max Planck Institute for Human Cognitive and Brain Sciences & Day Clinic of Cognitive Neurology; Ralph Burkhardt and Joachim Thiery, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; Markus Löffler, Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig; Arno Villringer, Max Planck Institute for Human Cognitive and Brain Sciences and Day Clinic of Cognitive Neurology, University of Leipzig; Steffi G. Riedel-Heller,
Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig. This publication is supported by LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund and by means of the Free State of Saxony within the framework of the excellence initiative. Matthias L. Schroeter has further been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research, and by the Parkinson’s disease Foundation (Grant PDF-IRG-1307). Correspondence concerning this article should be addressed to Tobias Luck, University of Leipzig, Institute of Social Medicine, Occupational Health and Public Health, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany. E-mail: [email protected] 382
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APOE ε4 & COGNITION IN COGNITIVELY INTACT ELDERLY
early decline over time in this domain in subjects who would clinically manifest AD later (Chen et al., 2001). The risk of developing AD is influenced by multiple nonmodifiable factors like age or genetic susceptibility as well as modifiable factors like smoking or hypertension (Kidd, 2008). Among the genetic risk factors, the ε4 allele of the apolipoprotein E (APOE) gene is known as the most relevant one for late-onset AD (Paulson & Igo, 2011). Carrying the APOE ε4 allele is supposed to account for around 20 –50% of the attributable total risk for dementia (Slooter et al., 1998; Ashford, 2004). Expression of the allele has been shown to affect sterol homeostasis, cholesterol transport, membrane repair, and other cellular activities that are related to -amyloid accumulation and neurodegenerative processes in the human brain (Schipper, 2011a, 2011b). Findings from clinical studies, moreover, support the assumption that APOE ε4 allele carriers in general may have less effective neural protection and repair mechanisms: Ariza et al. (2006), for example, have shown that patients with moderate or severe traumatic brain injury who carried the APOE ε4 allele perform worse in neuropsychological tests and have more behavioral disturbances than corresponding traumatic brain injury patients without the allele. The effect of the APOE ε4 allele, thus, is not only limited to clinically manifest AD. There is also an increasing number of studies that provide evidence of an association between presence of the allele and poorer cognitive performance in cognitively healthy older adults (e.g., poorer performance in visuospatial attention, retention of memory for location, and attentional modulation of memory of target location, see Greenwood, Lambert, Sunderland, & Parasuraman, 2005; poorer performance in global cognitive functioning, episodic memory, and executive functioning, see Small, Rosnick, Fratiglioni, & Bäckman, 2004). In this study, we sought to provide further evidence on such an association. We particularly focused on possible effects of the APOE ε4 allele on memory and EF and thus on cognitive domains, whose declines are important indicators of a prodromal stage of AD.
Methods Participants Data were derived from the ongoing Health Care Study of the Leipzig Research Center for Civilization Diseases (LIFE) in Leipzig, Germany. The aim of the LIFE Health Care Study is to look at the causes and courses of common civilization diseases such as cardiovascular diseases, diabetes, depression, dementia, or allergies. To recruit adult participants (18 –79 years), Leipzig residents are randomly selected by the Leipzig registry office and invited. In this study, we studied a first sample of 280 older participants (ages: 65⫹ years) with available neuropsychological and genetic data. All participants provided written informed consent prior to their participation in the study. The study complies with the ethical standards of the Declaration of Helsinki and has been approved by the ethics committee of the University of Leipzig.
General Assessment Procedures All adult participants of the LIFE Health Care Study undergo an extensive assessment program, including different clinical exam-
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inations, standardized questionnaires, neuropsychological testing as well as collection of biological samples like blood and urine. A standardized interview provided information on sociodemographics, comorbidities, and other characteristics. Depressive symptoms are identified using the German version of the 20-item Center of Epidemiologic Studies Depression Scale with a cut-off ⱖ23 (CES-D; Radloff, 1977; Hautzinger, Bailer, Hofmeister, & Keller, 2012). Symptoms of anxiety are identified using the German version of the 7-item Generalized Anxiety Disorder Scale with a cut-off ⱖ10 (GAD-7; Spitzer, Kroenke, Williams, & Löwe, 2006). Participants aged over 65 years are asked to participate in further examinations, including a more extensive neuropsychological testing (see below) as well as a standardized interview on activities of daily living. All examinations are conducted by trained study personnel at the LIFE Research Center located on the premises of the University Hospital of Leipzig.
Neuropsychological Testing A broad range of tests are used in the LIFE Health Care Study to assess neuropsychological performance in the older participants. Results of the present study are based on the following tests. Global cognitive functioning. We used the Mini-Mental State Examination (MMSE; Folstein, Folstein, & McHugh, 1975) to assess global cognitive functioning. The MMSE includes items on several cognitive domains such as orientation, memory, language or calculation. The maximum score of the MMSE is 30 points. A higher score indicates a better global cognitive performance. We used an MMSE ⱖ28 to define intact global cognitive functioning, as this threshold score was found to discriminate best between cognitive normalcy and cognitive impairment compared to commonly used lower threshold scores (e.g., 25; Damian et al., 2011). Intelligence. We used the vocabulary test (Wortschatztest [WST]; Schmidt & Metzler, 1992) to briefly estimate general intelligence level. The WST consists of 42 lists including six words each: five pseudowords (distractors) and one meaningful word to be recognized among the distractors. The maximum WST score is 42 points. A higher score indicates a higher intelligence level. EF and cognitive processing speed. We used the Trail Making Test B (TMT-B; Reitan, 1992) to assess EF. The TMT consists of two parts. Part A requires participants to draw lines to connect consecutive numbers from 1 to 25 as quickly as possible. Part B requires drawing lines to connect numbers and letters in an alternating sequence (1-A-2-B-3-C, etc.) as quickly as possible. The time to complete each part is recorded (time limit of TMT-A ⫽ 180 s, of TMT-B ⫽ 300 s). Shorter time needed to complete the trails in Parts A and B indicates better cognitive performance. Performance on TMT-A is used as a measure of cognitive processing speed and performance on TMT-B, a test that involves switching between numbers and letters, is used to examine EF. Memory. We used the Word List subtests of the Consortium to Establish a Registry for Alzheimer’s Disease-Neuropsychological (CERAD) battery (CERAD Word List; Morris, Mohs, Rogers, Fillenbaum, & Heyman, 1988; Morris et al., 1989) to assess performance in verbal memory. The CERAD Word List consists of three subtests: The first subtest, Word List Memory, is used to assess the ability to learn new verbal information. Participants are
LUCK ET AL.
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asked to read 10 printed words presented at a rate of one every 2 s and then to recall as many as possible. Two further trials are administered in this fashion with a different word order each trial. The maximum total score of the subtest Word List Memory is 30 (10 correctly recalled words in each trial). The second subtest, Word List Recall, is used to assess delayed verbal memory in a free-recall task. The subtest is conducted approximately 10 min after the subtest Word List Memory. Participants are instructed to recall as many of the previously learned 10 words as they can (maximum of correct responses ⫽ 10). The last subtest, Word List Recognition, is used to assess delayed verbal memory in a recognition task. The subtest is conducted immediately after the subtest Word List Recall. The participant is asked to recognize the 10 previously learned words from a list of 20 words including the 10 target words and 10 distractor words. The maximum score of the subtest is 20 (10 words correctly recognized, 10 words correctly rejected; Andel et al., 2003). We additionally used the Constructional Praxis Recall subtest of the CERAD neuropsychological test battery to assess performance in nonverbal praxis memory. The subtest requires to recall and to draw four figures (circle, diamond, overlapping rectangles, Necker cube) which had to be copied earlier in the neuropsychological assessment session (CERAD subtest Constructional Praxis; Rosen, Mohs, & Davis, 1984). The maximum total score for the correct recall drawing of the four figures is 11 points.
APOE 4 Genotyping Genomic DNA was isolated from peripheral blood leukocytes using an automated protocol on the Qiagen Autopure LS (Qiagen, Hilden, Germany). DNA purity and yield was determined on a NanoDrop spectrophotometer. Genotyping of the APOE allele status (ε2, ε3, ε4) was performed on a Roche Lightcylcer 480 according to the method of Aslanidis and Schmitz (1999). For statistical analyses, participants were divided by APOE status into those with or without at least one ε4 allele. Participants were not informed whether they were carriers or noncarriers of the ε4 allele.
Statistical Analysis The statistical analyses were performed using Predictive Analytics Software (PASW), version 20.0 (IBM Corp., Armonk, NY). All analyses used an alpha level for statistical significance of .05 (two-tailed). Group differences were analyzed using t test, Mann– Whitney U test and 2 test as appropriate. We used multivariable linear regressions to evaluate the association between EF (performance in TMT-B) and APOE ε4 status in cognitively intact older adults, controlled for covariates. We included the covariates in the regression models based on their potential relationship with performance in TMT-B.
Results Among a randomly selected sample of 280 elderly participants (65⫹ years) of the LIFE Health Care Study, 202 were classified as cognitively intact (MMSE-score ⱖ28) and included in the analyses; 21.3% (n ⫽ 43) of these participants were carriers of an APOE ε4 allele (42 heterozygotes, one homozygote). As shown in Table 1, APOE ε4 allele carriers did not differ significantly from non-
carriers in terms of age, gender, or education. Carriers and noncarriers also showed a comparable picture of comorbidities. None of the participants reported an inability to perform activities of daily living as assessed by the Barthel-Index (Mahoney & Barthel, 1965; results not shown). With regard to neuropsychological test results, APOE ε4 allele carriers and noncarriers also showed a similar general intelligence level (Vocabulary Test WST: M/SD number of correct words ⫽ 33.0/3.3 vs. 33.0/3.9, Mann–Whitney U ⫽ 2,760.000, p ⫽ .523) and similar performances in verbal memory (CERAD Word List Memory subtest: M/SD number of correct words ⫽ 21.5/3.5 vs. 21.2/4.0, Mann–Whitney U ⫽ 3,485.500, p ⫽ .843; CERAD Word List Recall subtest: M/SD ⫽ 7.7/1.7 vs. 7.7/1.7, Mann–Whitney U ⫽ 3,470.500, p ⫽ .876; CERAD Word List Recognition subtest: M/SD ⫽ 19.7/0.7 vs. 19.6/0.8, Mann–Whitney U ⫽ 3,736.000, p ⫽ .135), nonverbal praxis memory (CERAD Constructional Praxis Recall subtest: M/SD points ⫽ 8.1/2.4 vs. 8.7/2.5, Mann– Whitney U ⫽ 3,593.000, p ⫽ .087) and in cognitive processing speed (M/SD time needed to complete the TMT-A ⫽ 43.5/12.4 vs. 40.7/13.5 s, Mann–Whitney U ⫽ 3,943.000, p ⫽ .123), but a significantly different performance in EF: Carriers needed significantly more time to complete the TMT-B than noncarriers (M/SD time ⫽ 105.6/36.2 vs. 91.9/32.7 s, Mann–Whitney U ⫽ 4,313.000, p ⫽ .009; see Table 1). Results of the multivariable linear regression analysis with adjustment for covariates confirmed the finding of a significant lower performance in EF (i.e., time needed to complete the TMT-B) in cognitively intact older adults with APOE ε4 allele compared to those without (see Table 2; Model 1). The regression model also showed male gender and lower intelligence level to be significantly associated with lower performance in EF (i.e., more time needed to complete the TMT-B). We additionally tested for an association between performance in EF and APOE ε4 status in a subgroup of those older adults, who reached a perfect score of 30 in the MMSE. Findings were similar to those for the group of participants with MMSE-score ⱖ28, as (a) APOE ε4 allele carriers needed significantly more time to complete the TMT-B than noncarriers (APOE ε4 allele carriers: M/SD ⫽ 106.85/32.73 s, n ⫽ 13; APOE ε4 allele noncarriers: M/SD ⫽ 83.55/24.44 s, n ⫽ 65; Mann–Whitney U ⫽ 623.000; p ⫽ .007) and (b) the association between performance in EF and APOE ε4 status remained significant in multivariable linear regression analysis with adjustment for covariates (see Table 2, Model 2).
Discussion In this study, we sought to test for a possible effect of the APOE ε4 allele, the most important genetic risk factor for late-onset AD, on memory performance and EF in cognitively intact older adults. We found that carriers of at least one APOE ε4 allele did not differ significantly from noncarriers in their memory performance, but showed a significantly lower TMT-B performance as one measure of EF than the noncarriers - even after adjustment for age, gender, general intelligence level, and specific medical comorbidities. Previous studies suggest that, in addition to memory deficits, EF impairment is an important early indicator of early AD (e.g., Chen et al., 2001). These findings are also supported by imaging studies
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Table 1 Sociodemographics, Clinical, and Neuropsychological Characteristics of Cognitively Intact (MMSE ⱖ 28) APOE ε4 Allele Carriers and Noncarriers APOE ε4 allele noncarriers
APOE ε4 allele carriers
Characteristic
(n ⫽ 159)
(n ⫽ 43)
Age, years; M (SD) Gender, female; n (%) Education ⱕ 10 years; n (%) ⬎ 10 years; n (%) Comorbidity; n (%) Diabetes mellitusa Hypertensionb Strokec,d Myocardial infarctionc,d Symptoms of anxiety, GAD-7d Depressive symptoms, CES-Dd Intelligencee WST, correct words; M (SD) Verbal memory WL memory, correct words; M (SD) WL recall, correct words; M (SD) WL recognition,f correct words; M (SD) Nonverbal praxis memory CP Recall, points; M (SD) Cognitive processing speed TMT-A,g time in s; M (SD) Executive functioning TMT-B,g time in s; M (SD)
70.82 (3.64) 69 (43.40)
71.26 (3.66) 19 (44.19)
⫺0.702 0.009
.484 .926
70.91 (3.64) 88 (43.56)
89 (55.97) 70 (44.03)
26 (60.47) 17 (39.53)
0.278
.594
115 (56.93) 87 (43.07)
34 (21.79) 90 (60.40) 3 (1.91) 1 (0.64) 2 (1.26) 1 (0.63)
6 (14.63) 27 (65.85) 1 (2.38) 0 (0.00) 1 (2.33) 1 (2.33)
1.029 0.404 — — — —
.310 .525 — — — —
40 (20.30) 117 (61.58) 4 (2.01) 1 (0.50) 3 (1.49) 2 (0.99)
t, U, or 2 value
Total sample
p value (two-tailed)
(n ⫽ 202)
32.99 (3.86)
32.95 (3.34)
2,760.000
.523
32.98 (3.74)
21.21 (4.03) 7.69 (1.74) 19.60 (0.75)
21.47 (3.45) 7.74 (1.73) 19.74 (0.66)
3,485.500 3,470.500 3,736.000
.843 .876 .135
21.26 (3.91) 7.70 (1.74) 19.63 (0.73)
8.72 (2.47)
8.07 (2.44)
3,593.000
.087
8.59 (2.47)
40.69 (13.45)
43.49 (12.44)
3,943.000
.123
41.29 (13.26)
91.94 (32.71)
105.60 (36.16)
4,313.000
.009
94.85 (33.85)
Note. APOE ε4 ⫽ apolipoprotein E epsilon 4; CES-D⫽ Center of Epidemiologic Studies Depression Scale; CP ⫽ Constructional Praxis; GAD-7 ⫽ Generalized Anxiety Disorder Scale; MMSE ⫽ Mini-Mental State Examination; TMT-A ⫽ Trail Making Test Part A; TMT-B ⫽ Trail Making Test Part B; WL ⫽ Word List; WST ⫽ Wortschatztest (Vocabulary Test). a Data missing for 5 (2.5%) subjects. b Data missing for 12 (5.9%) subjects. c Data missing for 3 (1.5%) subjects. d No inferential statistics were calculated because of the small numbers of cases. e Data missing for 17 (8.4%) subjects. f Data missing for 3 (1.5%) subjects. g Participants made only few errors in the TMT (TMT-A: M/SD ⫽ 0.14/0.39, range ⫽ 0 –2; TMT-B ⫽ M/SD ⫽ 0.57/0.98, range ⫽ 0 – 6) and APOE ε4 allele noncarriers’ and carriers’ performance did not differ with regard to the number of errors (TMT-A: mean/SD ⫽ 0.15/0.40 vs. 0.12/0.32, Mann-Whitney U ⫽ 3,378.500, p ⫽ .837; TMT-B: mean/SD ⫽ 0.59/0.98 vs. 0.54/0.96, Mann-Whitney U ⫽ 3,264.000, p ⫽ .590).
showing that AD affects frontal neural networks related to executive functions, as well as the well-known hippocampal and parietal memory networks (Schroeter, Stein, Maslowski, Neumann, 2009; Schroeter et al., 2012). Recent findings of Carlson, Xue, Zhou, and Fried (2009) additionally suggest that a decline in EF
may actually precede a decline in memory. We found a pattern of lower EF performance in APOE4 allele carriers compared to noncarriers, but no significant differences in memory performance between the two groups. This may reflect a chronological sequence from EF decline to memory decline to frank clinical AD. That is,
Table 2 Multivariable Linear Regression to Evaluate the Association Between Performance in Executive Functioning (Time Needed to Complete the TMT-B; in seconds) and APOE ε4 Status in Cognitively Intact Older Adults, Controlled for Covariates Model 1
Model 2
MMSE-score ⱖ 28 (n ⫽ 175)a,b
MMSE-score ⫽ 30 (n ⫽ 69)c,d
Characteristics
Coefficient
SE
p value
Coefficient
SE
p value
APOE ε4 allele, carrier vs. noncarrier Age, every additional year Gender, female vs. male WST, every additional point Diabetes mellitus Hypertension Constant
12.260 0.635 ⫺10.417 ⫺2.937 2.516 ⫺0.733 146.507
5.574 0.646 4.754 0.630 5.745 4.838 49.101
.029 .072 .020 ⬍.001 .662 .880 .003
17.374 ⫺0.682 ⫺5.953 ⫺1.249 11.200 8.038 169.528
7.432 0.817 5.582 0.850 7.534 5.751 58.227
.023 .407 .290 .146 .142 .167 .005
Note. APOE ε4 ⫽ apolipoprotein E epsilon 4; TMT-B ⫽ Trail Making Test Part B; WST ⫽ Wortschatztest (Vocabulary Test). a Data missing for 27 (13.4%) of 202 subjects with Mini-Mental State Examination (MMSE)-score ⱖ 28 and age ⱖ 65 years. .120. c Data missing for nine (11.5%) of 78 subjects with MMSE-score ⫽ 30 and age ⱖ 65 years. d Adjusted R2 ⫽ .129.
b
Adjusted R2 ⫽
LUCK ET AL.
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cognitively intact APOE4 allele carriers may have been in an early prodromal stage of AD, during which subtle EF deficits become evident before memory deficits and before a global cognitive loss is noted. Because of the relatively young age of the APOE4 allele carriers in our study (M age ⫽ 71.3 years), this group could be expected to display prodromal AD symptoms rather than the clinical syndrome of AD. Studies have shown that the average onset of clinical manifest AD in ε4 heterozygotes is 75 years (compared with 78 – 84 years in noncarriers and to 68 –73 years in ε4 homozygotes; see Corder et al., 1993; Sando et al., 2008). Our study, however, is not without limitations. The generalizability of our results may be limited because of the low response rate of the ongoing LIFE Health Care Study so far (34.6%), as well as of the relatively small sample size our analyses were based on. Also, the MMSE is only a brief screening instrument for global cognitive functioning and the procedure of categorizing subjects as cognitively intact with the MMSE is associated with some inaccuracy. We aimed to minimize the inaccuracy by using the high cut-off of ⱖ28 MMSE points to discriminate between cognitive normalcy and cognitive impairment and also by repeating the analyses with the subgroup of those older adults, who reached a perfect score of 30 in the MMSE. However, even such a perfect MMSE score may lack some sensitivity when compared with more extensive clinical and neuropsychological examinations. This might be especially true for highly educated individuals. To exclude the possibility that the association between the APOE ε4 allele and the TMT-B performance may be mainly attributed to a sample including better educated individuals (who may be already cognitively impaired), we therefore also repeated the multivariable regression analysis with the subgroup of older adults, who reached the perfect MMSE-score of 30 and additionally controlled for education. We found that the association between lower TMT-B performance and APOE ε4 genotype still remained significant (coefficient ⫽ 17.856, standard error ⫽ 7.404, p ⫽ .019; results not shown). And finally, at this time, we were only able to provide cross-sectional findings and only findings of the TMT-B as one measure of EF. TMT-B performance, however, can be impaired not only by incipient AD but also by several further medical, psychiatric, and neuropsychological conditions. Longitudinal data of the present study as well as of others with additional EF measures will therefore help to investigate further whether lower EF performance in cognitively intact older APOE ε4 allele carriers might be related to an early AD prodrome. In this case, a stronger focus on first subtle changes in EF may help to improve early AD detection in those being at genetic risk.
References Andel, R., McCleary, C. A., Murdock, G. A., Fiske, A., Wilcox, R. R., & Gatz, M. (2003). Performance on the CERAD Word List Memory task: A comparison of university-based and community-based groups. International Journal of Geriatric Psychiatry, 18, 733–739. http://dx.doi.org/ 10.1002/gps.913 Ariza, M., Pueyo, R., Matarín, M. M., Junqué, C., Mataró, M., Clemente, I., . . . Sahuquillo, J. (2006). Influence of APOE polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury. Journal of Neurology, Neurosurgery, & Psychiatry, 77, 1191–1193. http://dx.doi.org/10.1136/jnnp.2005.085167
Ashford, J. W. (2004). APOE genotype effects on Alzheimer’s disease onset and epidemiology. Journal of Molecular Neuroscience, 23, 157– 166. http://dx.doi.org/10.1385/JMN:23:3:157 Aslanidis, C., & Schmitz, G. (1999). High-speed apolipoprotein E genotyping and apolipoprotein B3500 mutation detection using real-time fluorescence PCR and melting curves. Clinical Chemistry, 45, 1094 – 1097. Carlson, M. C., Xue, Q. L., Zhou, J., & Fried, L. P. (2009). Executive decline and dysfunction precedes declines in memory: The Women’s Health and Aging Study II. The Journals of Gerontology: Series A: Biological Sciences and Medical Sciences, 64A, 110 –117. http://dx.doi .org/10.1093/gerona/gln008 Chen, P., Ratcliff, G., Belle, S. H., Cauley, J. A., DeKosky, S. T., & Ganguli, M. (2001). Patterns of cognitive decline in presymptomatic Alzheimer disease: A prospective community study. Archives of General Psychiatry, 58, 853– 858. http://dx.doi.org/10.1001/archpsyc.58.9.853 Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., . . . Pericak-Vance, M. A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261, 921–923. http://dx.doi.org/10.1126/ science.8346443 Damian, A. M., Jacobson, S. A., Hentz, J. G., Belden, C. M., Shill, H. A., Sabbagh, M. N., . . . Adler, C. H. (2011). The Montreal Cognitive Assessment and the Mini-Mental State Examination as screening instruments for cognitive impairment: Item analyses and threshold scores. Dementia and Geriatric Cognitive Disorders, 31, 126 –131. http://dx.doi .org/10.1159/000323867 Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189 –198. http://dx .doi.org/10.1016/0022-3956(75)90026-6 Greenwood, P. M., Lambert, C., Sunderland, T., & Parasuraman, R. (2005). Effects of apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle-aged adults: Results from the National Institute of Mental Health’s BIOCARD study. Neuropsychology, 19, 199 –211. http://dx.doi.org/10.1037/0894-4105.19.2 .199 Hautzinger, M., Bailer, M., Hofmeister, D., & Keller, F. (2012). Allgemeine Depressionsskala: Manual [article in German]. Göttingen, Germany: Hogrefe Verlag. Kidd, P. M. (2008). Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: Current understanding and progress toward integrative prevention. Alternative Medicine Review, 13, 85–115. Mahoney, F. I., & Barthel, D. W. (1965). Functional evaluation: The Barthel Index. Maryland State Medical Journal, 14, 61– 65. Morris, J. C., Heyman, A., Mohs, R. C., Hughes, J. P., van Belle, G., Fillenbaum, G., . . . Clark, C. (1989). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD): Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology, 39, 1159 – 1165. http://dx.doi.org/10.1212/WNL.39.9.1159 Morris, J. C., Mohs, R. C., Rogers, H., Fillenbaum, G., & Heyman, A. (1988). Consortium to establish a registry for Alzheimer’s disease (CERAD) clinical and neuropsychological assessment of Alzheimer’s disease. Psychopharmacology Bulletin, 24, 641– 652. Paulson, H. L., & Igo, I. (2011). Genetics of dementia. Seminars in Neurology, 31, 449 – 460. http://dx.doi.org/10.1055/s-0031-1299784 Radloff, L. S. (1977). The CES-D scale: A self-report depression scale for research in the general population. Applied Psychological Measurement, 1, 385– 401. http://dx.doi.org/10.1177/014662167700100306 Reitan, R. M. (1992). Trail Making Test: Manual for administration and scoring. Tucson, AZ: Reitan Neuropsychology Laboratory.
This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
APOE ε4 & COGNITION IN COGNITIVELY INTACT ELDERLY Rosen, W. G., Mohs, R. C., & Davis, K. L. (1984). A new rating scale for Alzheimer’s disease. The American Journal of Psychiatry, 141, 1356 – 1364. Sando, S. B., Melquist, S., Cannon, A., Hutton, M. L., Sletvold, O., Saltvedt, I., . . . Aasly, J. O. (2008). APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurology, 8, 9. http://dx.doi.org/10.1186/ 1471-2377-8-9 Schipper, H. M. (2011a). Apolipoprotein E: Implications for AD neurobiology, epidemiology and risk assessment. Neurobiology of Aging, 32, 778 –790. http://dx.doi.org/10.1016/j.neurobiolaging.2009.04.021 Schipper, H. M. (2011b). Presymptomatic apolipoprotein E genotyping for Alzheimer’s disease risk assessment and prevention. Alzheimer’s & Dementia, 7, e118 – e123. http://dx.doi.org/10.1016/j.jalz.2010.06.003 Schmidt, K. H., & Metzler, P. (1992). Wortschatztest (WST). Weinheim, Germany: Beltz Test. Schroeter, M. L., Stein, T., Maslowski, N., & Neumann, J. (2009). Neural correlates of Alzheimer’s disease and mild cognitive impairment: A systematic and quantitative meta-analysis involving 1351 patients. NeuroImage, 47, 1196 –1206. http://dx.doi.org/10.1016/j.neuroimage.2009 .05.037 Schroeter, M. L., Vogt, B., Frisch, S., Becker, G., Barthel, H., Mueller, K., . . . Sabri, O. (2012). Executive deficits are related to the inferior frontal junction in early dementia. Brain: A Journal of Neurology, 135, 201– 215. http://dx.doi.org/10.1093/brain/awr311
387
Slooter, A. J., Cruts, M., Kalmijn, S., Hofman, A., Breteler, M. M., Van Broeckhoven, C., & van Duijn, C. M. (1998). Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: The Rotterdam Study. Archives of Neurology, 55, 964 –968. http://dx .doi.org/10.1001/archneur.55.7.964 Small, B. J., Rosnick, C. B., Fratiglioni, L., & Bäckman, L. (2004). Apolipoprotein E and cognitive performance: A meta-analysis. Psychology and Aging, 19, 592– 600. http://dx.doi.org/10.1037/0882-7974.19.4 .592 Spitzer, R. L., Kroenke, K., Williams, J. B., & Löwe, B. (2006). A brief measure for assessing generalized anxiety disorder: The GAD-7. Archives of Internal Medicine, 166, 1092–1097. http://dx.doi.org/10.1001/ archinte.166.10.1092 Storandt, M., Grant, E. A., Miller, J. P., & Morris, J. C. (2006). Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI. Neurology, 67, 467– 473. http://dx.doi.org/10.1212/01 .wnl.0000228231.26111.6e Wierenga, C. E., Stricker, N. H., McCauley, A., Simmons, A., Jak, A. J., Chang, Y. L., . . . Bondi, M. W. (2010). Increased functional brain response during word retrieval in cognitively intact older adults at genetic risk for Alzheimer’s disease. NeuroImage, 51, 1222–1233. http://dx.doi.org/10.1016/j.neuroimage.2010.03.021
Received February 21, 2014 Revision received September 8, 2014 Accepted September 8, 2014 䡲
