Journal Mobile Options
Table of Contents
Vol. 32, No. 3, 2011
Issue release date: December 2011
Section title: Original Research Article
Free Access
Dement Geriatr Cogn Disord 2011;32:188–192
(DOI:10.1159/000333023)

Propositional Density and Apolipoprotein E Genotype among Persons at Risk for Familial Alzheimer’s Disease

Medina L.D.a · Rodriguez-Agudelo Y.b · Geschwind D.H.c · Gilbert P.E.a · Liang L.-J.d, e · Cummings J.L.c, e · Ringman J.M.c, e
aSDSU/UCSD Joint Doctoral Program in Clinical Psychology, San Diego, Calif., USA; bNational Institute of Neurology and Neurosurgery, Mexico City, Mexico; Departments of cNeurology and dMedicine, David Geffen School of Medicine at UCLA, and eMary S. Easton Center for Alzheimer’s Disease Research at UCLA, Los Angeles, Calif., USA
email Corresponding Author

Abstract

Background/Aims: A relationship between decreased propositional density (p-density) in young adulthood and future risk for Alzheimer’s disease (AD) has been postulated, but multiple interpretations of the nature of this relationship are possible. This study explored the relationship between familial AD (FAD) mutation status, apolipoprotein E (APOE) genotype, and p-density. Methods: Thirty-five non-demented persons at risk for FAD mutations were recruited. Subjects wrote brief biographical essays from which p-density, the ratio of the number of unique ideas to the number of words in the text, was calculated. Mixed-effects regression models were used to examine the relationship of p-density and FAD mutation status and APOE genotype. Results: FAD mutation status was not significantly associated with p-density. However, results from both models indicated that the presence of the APOE ε4 allele was significantly associated with p-density (p < 0.0001), with APOE ε4 carriers having lower p-density than non-carriers. Conclusions: Our results are consistent with an influence of APOE status on p-density in young adulthood that is independent of the AD risk per se and suggest the previous finding of increased risk for the development of AD in persons with decreased p-density may be related to APOE genotype.

© 2011 S. Karger AG, Basel


  

Key Words

  • Presenilin 1
  • Amyloid precursor protein
  • Early-onset Alzheimer’s disease
  • Preclinical dementia
  • Alzheimer’s disease
  • Linguistic ability

 Introduction

The Nun Study identified a connection between literacy in early life and memory decline in late life [1] and helped elaborate the idea of cognitive reserve in Alzheimer’s disease (AD). Cognitive reserve, a hypothesized protective factor against cognitive deficits later in life, posits that relevant abilities make the brain resistant to manifesting clinical symptoms in the face of developing AD or other neuropathology [2]. By relating archival essays written by nuns (mean age of 22 years) to cognitive function and neuropathological findings five to seven decades later, Snowdon et al. [1] found a link between decreased propositional density, or p-density, and neuropsychological deficits and AD neuropathology [3] later in life. P-density, first used by Kintsch and Keenan [4] as a measure of retention, is defined as the number of independent ideas embedded within a certain number of words in written text. Compared to other measures of linguistic ability (e.g. grammatical complexity), p-density has been shown to be relatively more resistant to normal aging processes, but sensitive to AD pathology, which leads to a rapid decline in p-density [5,6].

AD is the most common cause of dementia and affects nearly 5.4 million Americans [7]. In addition to early-life literacy and other factors related to cognitive reserve (e.g. educational and occupational attainment), risk factors include age, traumatic brain injury, cardiovascular risk factors, and the presence of the apolipoprotein ε4 allele (APOE ε4). Unlike these risk factors, which merely influence the likelihood that one might develop AD, autosomal dominant mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes are essentially determinant for the development of AD pathology at a relatively early age [8]. Persons at risk for inheriting this form of familial AD (FAD), in whom the genetic alteration has been present since conception, provide a unique opportunity to study the earliest changes related to the disease. Our prior studies have suggested a trend towards lower educational attainment in carriers of PSEN1 and APP mutations [9] and studies in Colombian persons at risk for the E280A PSEN1 mutation found diminished production of semantic units when describing a visual scene in preclinical mutation carriers (mean age, mid 40s) [10].

In the current study, we sought to replicate the finding of reduced p-density in persons destined to develop dementia in a preclinical Mexican and Mexican-American population at risk for inheriting FAD. We hypothesized that FAD mutation carriers (MCs) would exhibit lower p-density than non-carriers (NCs) when taking into account factors such as age, education, language of essay, acculturation, country of residence, and APOE status.

 Methods


 Study Population

Thirty-five participants were recruited. Of these, 30 were at risk for mutations in the PSEN1 gene, 1 for the PSEN2 gene, and 4 for the APP gene by virtue of being first-degree relatives of demented persons identified to have such a pathogenic mutation. All were at least 18 years of age and, at the time of the study, had Clinical Dementia Rating (CDR) scores of <1.0 (see below). All provided written informed consent, and all procedures were approved by the Institutional Review Boards at UCLA and the National Institute of Neurology and Neurosurgery in Mexico City.

 Procedures

Genetic testing was performed on all participants to determine whether they were FAD MCs or NCs. The presence of mutations in PSEN1 and PSEN2 was assessed using restriction fragment length polymorphism analyses. The presence of mutations in APP was assessed with direct sequencing. APOE genotyping was performed using standard techniques. The CDR [11] was performed with an unrelated informant and with the subject. This structured interview rates asymptomatic persons as 0, persons with questionable cognitive impairment as 0.5, and mild, moderate, and severe stages of dementia are rated as 1, 2, and 3 respectively. Subjects were also administered the Cognitive Abilities Screening Inventory (CASI) [12] and completed a questionnaire quantifying degree of acculturation to the United States [13]. Both the individuals and the investigators were blind to mutation status, except in the case of one presymptomatic MC who had undergone clinical testing. As in the original Nun Study [1], participants were given the following prompt in both English and Spanish:

Write a short sketch of your own life. This account should not contain more than two to three hundred words and should be written on a single sheet of paper. Include your place of birth, parentage, interesting and edifying events of your childhood, schools attended, religious life, and its outstanding events.

Participants wrote essays in the language with which they felt most comfortable (i.e. English or Spanish). Essays were then analyzed for p-density by 3 raters, fluent in both English and Spanish, who were blind to all clinical and genetic information in accordance with methods described by Snowdon et al. [1] using the last 10 sentences of each essay. Inter-rater reliability for all three raters had a Cronbach’s α value of 0.93. Mean p-density score was used in statistical analyses.

 Statistical Analysis

Although the age of onset in FAD tends to be consistent within families, it can vary between families [14]. Thus, an ‘adjusted age’ is calculated for each subject relative to the median age of disease diagnosis in their families. This allows for comparisons to be made between subjects with regard to proximity to the onset of FAD. Additional factors of interest included educational level, age at enrollment, gender, CDR score, country of residence, language of essay, and acculturation level. We compared each of these factors between FAD MCs and NCs as well as among APOE genotypes using ANOVA. Next, a mixed-effects regression model with family-level random effects was used to assess the association between genetic status (i.e. FAD mutation, APOE ε4 status) and p-density. The model included a family-level random intercept to account for dependence within families, which helps to avoid under-estimation of the fixed effect variance and increases efficiency in identifying important sources of variation [15]. Two mixed-effects regression analyses, unadjusted (Model 1) and adjusted (Model 2) for the predictors of interest, were performed. Values of p ≤ 0.05 were considered significant. All statistical analyses were performed using STATA, version 9.1.

 Results

MCs (n = 22) were significantly younger than NCs (n = 13) in both age at enrollment (MMC = 31.9, MNC = 40.1; p = 0.006) and age relative to expected disease onset (MMC = –13.4, MNC = –5.2; p = 0.028). There were no significant differences between MCs and NCs with regard to gender, years of education, country of residence, language of essay, acculturation score, or total CASI score. Distribution of APOE status among MCs and NCs was not statistically different. Mean p-density of the sample (M = 0.70, SD = 0.04) was comparable to means originally reported by Snowdon et al. [1] (M = 0.70, SD = 0.12).

Among the 35 subjects, 24 had the ε3/3, 6 the ε2/3 genotype, and 5 the ε4/3 APOE genotype. There were no differences between APOE genotype groups in age at enrollment, proximity to the onset of FAD, gender, years of education, language of essay, acculturation score, or total CASI score. However, those with the ε2/3 APOE genotype were more likely to reside in Mexico than those with the ε3/3 or ε4/3 genotypes (p = 0.008; table 1).

TAB01
Table 1. Profile of the sample

No significant associations between p-density and proximity to the diagnosis of FAD (i.e., adjusted age), age at enrollment, CDR score, years of education, country of residence, language of essay, acculturation score, or mutation status were observed. Additionally, p-density did not differ significantly between the three FAD genes studied (i.e., PSEN1, PSEN2, and APP). However, results from both unadjusted and adjusted models indicated that the presence of the APOE ε4 allele was significantly associated with p-density (p < 0.0001) with the presence of the APOE ε4 allele being associated with lower p-density (fig. 1).

FIG01
Fig. 1. Mean p-density by APOE genotype.

 Discussion

Contrary to our expectations, no differences were observed in p-density between carriers and non-carriers of FAD mutations. However, individuals who were APOE ε4 positive had significantly lower p-density scores than those who were APOE ε4 negative, regardless of their FAD mutation status. These results held when accounting for educational level, CDR score, language of essay, acculturation score, and age relative to the typical age of the family-specific age of AD diagnosis.

In light of the findings in the Nun Study and the study by Cuetos et al. [10], we anticipated that preclinical FAD MCs would have a lower p-density than NCs. The population in the latter study, in which carriers of the E280A PSEN1 mutation produced fewer semantic categories during verbal description of the Cookie Theft Scenario, was slightly older (43 vs. 35 years) and had less variability in age (SD = 3.1 vs. 8.9 years) than our population. It is therefore possible therefore that the changes they found were evidence of incipient neurodegeneration and the lack of differences between FAD MCs and NCs in our study was related to the fact many carriers were quite young in relation to the age of disease onset. Alternatively, differences in the sensitivity of the specific language measures employed or levels of education between the two populations (5.1 vs. 12.6 years in our study) could account for the disparate findings.

APOE is a pleiotropic molecule and diverse mechanisms through which it contributes to AD risk have been proposed, including effects on development [16]. Although the original Nun Study paper did not examine literacy in relation to APOE, our finding of an association between the APOE ε4 genotype and p-density in subclinical persons is consistent with prior studies demonstrating subtle impairment of language abilities in APOE ε4 carriers. Such studies have found non-demented carriers of the APOE ε4 genotype to have poorer performance on object naming and semantic fluency than non-carriers [17] and persons with Down syndrome with the APOE ε4 allele had poorer language function than those without the APOE ε4 allele [18].

As none of the carriers of the APOE ε4 allele in our study were symptomatic (all had CDR scores of 0, CASI scores were non-significantly higher than the other groups), our results are not accountable for by the presence of the early stages of progressive dementia. However, the relatively small number of subjects in our study makes it susceptible to random effects and, therefore, interpretations should be made with caution. Nonetheless, our results are consistent with an effect of APOE status on p-density in early adulthood that is independent of AD risk per se and suggest that the previously reported association of reduced p-density and subsequent risk for AD may be related to APOE genotype.

 Acknowledgements

This study was supported by PHS K08 AG-22228, California DHS No. 04-35522, NIA U01 AG-032438, the Shirley and Jack Goldberg Trust, and the Easton Consortium for Biomarker and Drug Discovery in Alzheimer’s Disease. Further support for this study came from Alzheimer’s Disease Research Center Grants P50 AG-16570, PHS R01 AG-21055 from the National Institute on Aging, General Clinical Research Centers Program M01-RR00865, and the Sidell Kagan Foundation.

The authors are grateful to Alison Goate, DPhil, of the Dominantly Inherited Alzheimer Network’s Genetics Core at Washington University, St. Louis, Mo. for genotyping some of the participants.

 Disclosure Statement

No authors have relevant conflicts of interest. L.D.M. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


References

  1. Snowdon DA, Kemper SJ, Mortimer JA, et al: Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life. Findings from the Nun Study. JAMA 1996;275:528–532.
  2. Snowdon DA: Healthy aging and dementia: findings from the Nun Study. Ann Intern Med 2003;139(part 2):450–454.
  3. Riley KP, Snowdon DA, Desrosiers MF, Markesbery WR: Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study. Neurobiol Aging 2005;26:341–347.
  4. Kintsch W, Keenan J: Reading rate and retention as a function of the number of propositions in the base structure of sentences. Cogn Psychol 1973;5:257–274.
  5. Kemper S, Greiner LH, Marquis JG, Prenovost K, Mitzner TL: Language decline across the life span: findings from the Nun Study. Psychol Aging 2001;16:227–239.
  6. Kemper S, Marquis J, Thompson M: Longitudinal change in language production: effects of aging and dementia on grammatical complexity and propositional content. Psychol Aging 2001;16:600–614.
  7. Alzheimer’s Association, Thies W, Bleiler L: 2011 Alzheimer’s disease facts and figures. Alzheimers Dement 2011;7:208–244.
  8. Ringman JM: What the study of persons at risk for familial Alzheimer’s disease can tell us about the earliest stages of the disorder: a review. J Geriatr Psychiatry Neurol 2005;18:228–233.
  9. Ringman JM, Rodriguez Y, Diaz-Olavarrieta C, et al: Performance on MMSE sub-items and education level in presenilin-1 mutation carriers without dementia. Int Psychogeriatr 2007;19:323–332.
  10. Cuetos F, Arango-Lasprilla JC, Uribe C, Valencia C, Lopera F: Linguistic changes in verbal expression: a preclinical marker of Alzheimer’s disease. J Int Neuropsychol Soc 2007;13:433–439.
  11. Morris JC: Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9(suppl 1):173–176, discussion 177–178.
  12. Teng EL, Hasegawa K, Homma A, et al: The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr 1994;6:45–58, discussion 62.
  13. Cuéllar I, Arnold B, Maldonado R: Acculturation Rating Scale for Mexican Americans-II: a revision of the original ARSMA scale. Hisp J Behavi Sci 1995;17:275–304.
  14. Murrell J, Ghetti B, Cochran E, et al: The A431E mutation in PSEN1 causing familial Alzheimer’s disease originating in Jalisco State, Mexico: an additional fifteen families. Neurogenetics 2006;7:277–279.
  15. Snijders TAB, Bosker RJ: Multilevel analysis: An introduction to basic and advanced multilevel modeling. Thousand Oaks, Sage, 1999.
  16. Kim J, Basak JM, Holtzman DM: The role of apolipoprotein E in Alzheimer’s disease. Neuron 2009;63:287–303.
  17. Miller KJ, Rogers SA, Siddarth P, Small GW: Object naming and semantic fluency among individuals with genetic risk for Alzheimer’s disease. Int J Geriatr Psychiatry 2005;20:128–136.
  18. Alexander GE, Saunders AM, Szczepanik J, et al: Relation of age and apolipoprotein E to cognitive function in Down syndrome adults. Neuroreport 1997;8:1835–1840.

  

Author Contacts

Luis D. Medina, BA
SDSU/UCSD Joint Doctoral Program in Clinical Psychology
6363 Alvarado Court, Suite 103
San Diego, CA 92120 (USA)
Tel. +1 619 594 8374, E-Mail MedinaL@rohan.sdsu.edu

  

Article Information

Accepted: August 30, 2011
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 1, Number of References : 18

  

Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 32, No. 3, Year 2011 (Cover Date: December 2011)

Journal Editor: Chan-Palay V. (Boston, Mass.)
ISSN: 1420-8008 (Print), eISSN: 1421-9824 (Online)

For additional information: http://www.karger.com/DEM


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background/Aims: A relationship between decreased propositional density (p-density) in young adulthood and future risk for Alzheimer’s disease (AD) has been postulated, but multiple interpretations of the nature of this relationship are possible. This study explored the relationship between familial AD (FAD) mutation status, apolipoprotein E (APOE) genotype, and p-density. Methods: Thirty-five non-demented persons at risk for FAD mutations were recruited. Subjects wrote brief biographical essays from which p-density, the ratio of the number of unique ideas to the number of words in the text, was calculated. Mixed-effects regression models were used to examine the relationship of p-density and FAD mutation status and APOE genotype. Results: FAD mutation status was not significantly associated with p-density. However, results from both models indicated that the presence of the APOE ε4 allele was significantly associated with p-density (p < 0.0001), with APOE ε4 carriers having lower p-density than non-carriers. Conclusions: Our results are consistent with an influence of APOE status on p-density in young adulthood that is independent of the AD risk per se and suggest the previous finding of increased risk for the development of AD in persons with decreased p-density may be related to APOE genotype.

© 2011 S. Karger AG, Basel


  

Author Contacts

Luis D. Medina, BA
SDSU/UCSD Joint Doctoral Program in Clinical Psychology
6363 Alvarado Court, Suite 103
San Diego, CA 92120 (USA)
Tel. +1 619 594 8374, E-Mail MedinaL@rohan.sdsu.edu

  

Article Information

Accepted: August 30, 2011
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 1, Number of References : 18

  

Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 32, No. 3, Year 2011 (Cover Date: December 2011)

Journal Editor: Chan-Palay V. (Boston, Mass.)
ISSN: 1420-8008 (Print), eISSN: 1421-9824 (Online)

For additional information: http://www.karger.com/DEM


Article / Publication Details

First-Page Preview
Abstract of Original Research Article

Published online: 8/30/2011
Issue release date: December 2011

Number of Print Pages: 5
Number of Figures: 1
Number of Tables: 1

ISSN: 1420-8008 (Print)
eISSN: 1421-9824 (Online)

For additional information: http://www.karger.com/DEM


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Snowdon DA, Kemper SJ, Mortimer JA, et al: Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life. Findings from the Nun Study. JAMA 1996;275:528–532.
  2. Snowdon DA: Healthy aging and dementia: findings from the Nun Study. Ann Intern Med 2003;139(part 2):450–454.
  3. Riley KP, Snowdon DA, Desrosiers MF, Markesbery WR: Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study. Neurobiol Aging 2005;26:341–347.
  4. Kintsch W, Keenan J: Reading rate and retention as a function of the number of propositions in the base structure of sentences. Cogn Psychol 1973;5:257–274.
  5. Kemper S, Greiner LH, Marquis JG, Prenovost K, Mitzner TL: Language decline across the life span: findings from the Nun Study. Psychol Aging 2001;16:227–239.
  6. Kemper S, Marquis J, Thompson M: Longitudinal change in language production: effects of aging and dementia on grammatical complexity and propositional content. Psychol Aging 2001;16:600–614.
  7. Alzheimer’s Association, Thies W, Bleiler L: 2011 Alzheimer’s disease facts and figures. Alzheimers Dement 2011;7:208–244.
  8. Ringman JM: What the study of persons at risk for familial Alzheimer’s disease can tell us about the earliest stages of the disorder: a review. J Geriatr Psychiatry Neurol 2005;18:228–233.
  9. Ringman JM, Rodriguez Y, Diaz-Olavarrieta C, et al: Performance on MMSE sub-items and education level in presenilin-1 mutation carriers without dementia. Int Psychogeriatr 2007;19:323–332.
  10. Cuetos F, Arango-Lasprilla JC, Uribe C, Valencia C, Lopera F: Linguistic changes in verbal expression: a preclinical marker of Alzheimer’s disease. J Int Neuropsychol Soc 2007;13:433–439.
  11. Morris JC: Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9(suppl 1):173–176, discussion 177–178.
  12. Teng EL, Hasegawa K, Homma A, et al: The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr 1994;6:45–58, discussion 62.
  13. Cuéllar I, Arnold B, Maldonado R: Acculturation Rating Scale for Mexican Americans-II: a revision of the original ARSMA scale. Hisp J Behavi Sci 1995;17:275–304.
  14. Murrell J, Ghetti B, Cochran E, et al: The A431E mutation in PSEN1 causing familial Alzheimer’s disease originating in Jalisco State, Mexico: an additional fifteen families. Neurogenetics 2006;7:277–279.
  15. Snijders TAB, Bosker RJ: Multilevel analysis: An introduction to basic and advanced multilevel modeling. Thousand Oaks, Sage, 1999.
  16. Kim J, Basak JM, Holtzman DM: The role of apolipoprotein E in Alzheimer’s disease. Neuron 2009;63:287–303.
  17. Miller KJ, Rogers SA, Siddarth P, Small GW: Object naming and semantic fluency among individuals with genetic risk for Alzheimer’s disease. Int J Geriatr Psychiatry 2005;20:128–136.
  18. Alexander GE, Saunders AM, Szczepanik J, et al: Relation of age and apolipoprotein E to cognitive function in Down syndrome adults. Neuroreport 1997;8:1835–1840.