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APOE-ε4 and APOE −491A polymorphisms in individuals with subjective memory loss

Molecular Psychiatry volume 7, pages 768–775 (2002)Cite this article

Abstract

The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of certainty in specialized centres. The identification of predictive or diagnostic genetic factors may improve accuracy of disease prediction or diagnosis. One major genetic risk factor, the ε4 allele of the apolipoprotein E gene, is universally recognised. We have recently shown that the A allele of the apolipoprotein E, −491A/T promoter polymorphism is also an important risk factor for Alzheimer's disease in an Australian population. We designed the present study to investigate the association between apolipoprotein E genotype, −491A/T polymorphism, plasma apoE levels and the subjective experience of memory decline among 98 subjects and 49 age, gender and education-matched normal controls. An increased frequency of the ε4 allele of apolipoprotein E was significantly associated with the ‘memory complainers’ group (OR = 2.35, P = 0.02) as was the A allele of the −491A/T polymorphism (OR = 2, P = 0.02). Among all subjects, only seven individuals were homozygous for both of these alleles, and six of these seven individuals belonged to the ‘memory complainers’ group. This sub-group also had relatively elevated plasma apolipoprotein E levels (P < 0.01) and tended to score lower on the Mini-Mental State Examination (MMSE) and Cambridge Cognition Test. These data suggest that the ε4 allele of apolipoprotein E and the −491A allele are over-represented among individuals who complain of memory difficulties. Follow-up studies should clarify whether these genotypes and phenotypes are useful in the prediction and/or diagnosis of Alzheimer's disease.

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References

  1. Miller BF, Keane CB (eds). Encyclopaedia and Dictionary of Medicine, Nursing and Allied Health, 2nd edn WB Saunders Co: Philadelphia 1978; 276 pp

    Google Scholar 

  2. Lishman WA (ed). Organic Psychiatry: the Psychological Consequences of Cerebral Disorder Blackwell Scientific: Oxford 1978

    Google Scholar 

  3. Lendon CL, Ashall F, Goate AM . Exploring the etiology of Alzheimer disease using molecular genetics JAMA 1997; 277: 825–831

    Article  CAS  Google Scholar 

  4. Folstein MF, Folstein SF, McHugh PR . Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician J Psychiatr Res 1975; 12: 189–198

    Article  CAS  Google Scholar 

  5. Bassett SS, Folstein MF . Memory complaint, memory performance and psychiatric diagnosis: a community study J Geriatr Psychiatry Neurol 1993; 6: 105–111

    Article  CAS  Google Scholar 

  6. Bolla KI, Lindgren KN, Bonaccorsy C, Bleecker ML . Memory complaints in older adults: fact or fiction Arch Neurol 1991; 48: 61–64

    Article  CAS  Google Scholar 

  7. Christensen H . The validity of memory complaints by elderly persons Int J Geriat Psychiat 1991; 6: 307–312

    Article  Google Scholar 

  8. Derouesne C, Alperovitch A, Arvay N, Migeon P, Moulin F, Vollant M et al. Memory complaints in the elderly: a study of 367 community dwelling individuals from 50 to 80 years old Arch Gerontol Geriatr 1989; 8 (suppl 1): 151–163

    Google Scholar 

  9. Flicker C, Ferris SH, Reisberg B . A longitudinal study of cognitive function in elderly persons with subjective memory complaints J Am Geriatr Soc 1993; 41: 1029–1032

    Article  CAS  Google Scholar 

  10. Gagnon M, Dartigues JF, Mazaux JM, Dequae L, Letenneur L, Giroire JM, Barberger-Gateau P . Self reported memory complaints and memory performance in elderly French community residents: results of the PAQUID research program Neuroepidemiology 1994; 13: 145–154

    Article  CAS  Google Scholar 

  11. Geerlings MI, Jonker C, Bouter LM, Ader HJ, Schmand B . Association between memory complaints incident Alzheimer's Disease in elderly people with normal baseline cognition Am J Psychiatry 1999; 156: 531–537

    CAS  PubMed  Google Scholar 

  12. Grut M, Jorm AF, Fratiglioni L, Forsell Y, Viitanen M, Winblad B . Memory complaints of elderly people in a population survey: variation according to dementia stage and depression J Am Geriat Soc 1993; 41: 1295–1300

    Article  CAS  Google Scholar 

  13. Hanninen T, Hallikainen M, Koivisto K, Helkala EL, Reinikainen KJ, Soininen H et al. A follow-up study of age-associated memory impairment: neuropsychological predictors of dementia J Am Geriatr Soc 1995; 43: 1007–1015

    Article  CAS  Google Scholar 

  14. Hanninen T, Reinikainen KJ, Helkala EL, Koivisto K, Mykkanen L, Laakso M et al. Subjective memory complaints and personality traits in normal elderly subjects J Am Geriatr Soc 1994; 42: 1–4

    Article  CAS  Google Scholar 

  15. Helkala EL, Koivisto K, Hanninen T, Vanhanen M, Kuusisto J, Mykkanen L et al. Stability of age-associated memory impairment during a longitudinal population-based study J Am Geriatr Soc 1997; 45: 120–122

    Article  CAS  Google Scholar 

  16. Jonker C, Launer LJ, Hooijer C, Lindeboom J . Memory complaints and memory impairment in older individuals J Am Geriatr Soc 1996; 44: 44–49

    Article  CAS  Google Scholar 

  17. Jorm AF, Christensen H, Henderson AS, Korten AE, Mackinnon AJ, Scott R . Complaints of cognitive decline in the elderly: a comparison of reports by subjects and informants in a community survey Psychol Med 1994; 24: 365–374

    Article  CAS  Google Scholar 

  18. Jorm AF, Christensen H, Korten AE, Henderson AS, Jacomb PA, MacKinnon A . Do cognitive complaints either predict future cognitive decline or reflect past cognitive decline? A longitudinal study of an elderly community sample Psychol Med 1997; 27: 91–98

    Article  CAS  Google Scholar 

  19. Jorm AF, Christensen H, Korten AE, Jacomb PA, Henderson AS . Memory complaints as a precursor of memory impairment in older people: a longitudinal analysis over 7–8 years Psychol Med 2001; 31: 441–449

    CAS  PubMed  Google Scholar 

  20. O'Brien JT, Beats B, Hill K, Howard R, Sahakian B, Levy R . Do subjective memory complaints precede dementia? A three year follow up of patients with supposed ‘benign senescent forgetfulness’ Int J Geriatr Psychiatry 1992; 7: 481–486

    Article  Google Scholar 

  21. O'Connor DW, Pollitt PA, Roth M, Brook PB, Reiss BB . Memory complaints and impairment in normal, depressed and demented elderly persons identified in a community survey Arch Gen Psychiatry 1990; 47: 224–227

    Article  CAS  Google Scholar 

  22. Parnetti L, Lowenthal DT, Presciutti O, Pelliccioli GP, Palumbo R, Gobbi G et al. 1H-MRS, MRI-based hippocampal volumetry, and 99mTc-HMPAO-SPECT in normal aging, age-associated memory impairment, and probable Alzheimer's disease J Am Geriatr Soc 1996; 44: 133–138

    Article  CAS  Google Scholar 

  23. Schmand B, Jonker C, Hooijer C, Lindeboom J . Subjective memory complaints may announce dementia Neurology 1996; 46: 121–125

    Article  CAS  Google Scholar 

  24. Schmand B, Jonker C, Geerlings MI, Lindeboom J . Subjective memory complaints in the elderly: depressive symptoms and future dementia Br J Psychiatry 1997; 171: 373–376

    Article  CAS  Google Scholar 

  25. Schofield PW, Marder K, Dooneief G, Jacobs DM, Sano M, Stern Y . Association of subjective memory complaints with subsequent cognitive decline in community-dwelling elderly individuals with baseline cognitive impairment Am J Psychiatry 1997; 154: 609–615

    Article  CAS  Google Scholar 

  26. Sunderland A, Watts K, Baddeley AD, Harris JE . Subjective memory assessment and test performance in elderly adults J Gerontol 1986; 41: 376–384

    Article  CAS  Google Scholar 

  27. Taylor JL, Miller TP, Tinklenberg JR . Correlates of memory decline: a 4 year longitudinal study of older adults with memory complaints Psychol Aging 1992; 7: 185–193

    Article  CAS  Google Scholar 

  28. Clarnette RM, Almeida OP, Forstl H, Paton A, Martins RN . Clinical characteristics of individuals with subjective memory loss in Western Australia: results from a cross-sectional survey Int J Geriat Psychiat 2001; 16: 168–174

    Article  CAS  Google Scholar 

  29. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease Neurology 1984; 34: 939–944

    Article  CAS  Google Scholar 

  30. Martins RN, Clarnette R, Fisher C, Broe GA, Brooks WS, Montgomery P, Gandy SE . ApoE genotypes in Australia: roles in early and late onset Alzheimer's disease and Down's syndrome Neuroreport 1995; 6: 1513–1516

    Article  CAS  Google Scholar 

  31. Taddei K, Clarnette R, Gandy SE, Martins RN . Increased plasma apolipoprotein E (apoE) levels in Alzheimer's disease Neurosci Lett 1997; 223: 29–33

    Article  Google Scholar 

  32. Artiga MJ, Bullido MJ, Sastre I, Recuero M, Garcia MA, Aldudo J et al. Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene FEBS Lett 1998; 421: 105–108

    Article  CAS  Google Scholar 

  33. Bullido MJ, Artiga MJ, Recuero M, Sastre I, Garcia MA, Aldudo J et al. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia Nature Genet 1998; 18: 69–71

    Article  CAS  Google Scholar 

  34. Lambert JC, Berr C, Pasquier F, Delacourte A, Frigard B, Cottel D et al. Pronounced impact of Th1/E47cs mutation compared with −491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease Hum Mol Gen 1998; 7: 1511–1516

    Article  CAS  Google Scholar 

  35. Lambert JC, Pasquier F, Cottel D, Frigard B, Amouyel P, Chartier-Harlin MC . A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease Hum Mol Gen 1998; 7: 533–540

    Article  CAS  Google Scholar 

  36. Laws SM, Taddei K, Martins G, Paton A, Fisher C, Clarnette R et al. The −491AA polymorphism in the APOE gene is associated with increased plasma apoE levels in Alzheimer's disease Neuroreport 1999; 10: 879–882

    Article  CAS  Google Scholar 

  37. De Ronchi D, Fratiglioni L, Rucci P, Paternico A, Graziani S, Dalmonte E . The effect of education on dementia occurrence in an Italian population with middle to high socioeconomic status Neurology 1998; 50: 1231–1238

    Article  CAS  Google Scholar 

  38. Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R . Influence of education and occupation on the incidence of Alzheimer's disease JAMA 1994; 271: 1004–1010

    Article  CAS  Google Scholar 

  39. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, Goddard R . CAMDEX: A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia Brit J Psychiat 1986; 149: 698–709

    Article  CAS  Google Scholar 

  40. Hodkinson HM . Evaluation of a mental test score for the assessment of mental impairment in the elderly Age Ageing 1972; 1: 233–238

    Article  CAS  Google Scholar 

  41. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. DSM-IV APA: Washington DC 1994

  42. Hixson JE, Vernier DT . Restriction of human apolipoprotein E by gene amplification and cleavage with Hla1 J Lipid Res 1990; 31: 545–548

    CAS  Google Scholar 

  43. Wenham PR, Price WH, Blundell G . Apolipoprotein E genotyping by one-stage PCR Lancet 1991; 337: 1158–1159

    Article  CAS  Google Scholar 

  44. Dik MG, Jonker C, Bouter LM, Geerlings MI, van Kamp GJ, Deeg DJ . APOE-epsilon4 is associated with memory decline in cognitively impaired elderly Neurology 2000; 54: 1492–1497

    Article  CAS  Google Scholar 

  45. Wang JC, Kwon JM, Shah P, Morris JC, Goate A . Effect of APOE genotype and promoter polymorphism on risk of Alzheimer's disease Neurology 2000; 55: 1644–1649

    Article  CAS  Google Scholar 

  46. Lambert JC, Mann D, Goumidi L et al. Effect of the APOE promoter polymorphisms on cerebral amyloid peptide deposition in Alzheimer's disease Lancet 2001; 357: 608–609

    Article  CAS  Google Scholar 

  47. Fukuyama R, Mizuno T, Mori S, Yanagisawa K, Nakajima K, Fushiki S . Age-dependent decline in the apolipoprotein E level in cerebrospinal fluid from control subjects and its increase in cerebrospinal fluid from patients with Alzheimer's disease Eur Neurol 2000; 43: 161–169

    Article  CAS  Google Scholar 

  48. Landen M, Hesse C, Fredman P, Regland B, Wallin A, Blennow K . Apolipoprotein E in cerebrospinal fluid from patients with Alzheimer's disease and other forms of dementia is reduced but without any correlation to the apoE4 isoform Dementia 1996; 7: 273–278

    CAS  PubMed  Google Scholar 

  49. Lehtimaki T, Pirttila T, Mehta PD, Wisniewski HM, Frey H, Nikkari T . Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer's disease Hum Genet 1995; 95: 39–42

    Article  CAS  Google Scholar 

  50. Pirttila T, Soininen H, Heinonen O, Lehtimaki T, Bogdanovic N, Paljarvi L et al. Apolipoprotein E (apoE) levels in brains from Alzheimer disease patients and controls Brain Res 1996; 722: 71–77

    Article  CAS  Google Scholar 

  51. Pirttila T, Mehta PD, Soininen H, Kim KS, Heinonen O, Paljarvi L et al. Cerebrospinal fluid concentrations of soluble amyloid beta-protein and apolipoprotein E in patients with Alzheimer's disease: correlations with amyloid load in the brain Arch Neurol 1996; 53: 189–193

    Article  CAS  Google Scholar 

  52. Bales KR, Verina T, Dodel RC et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition Nat Genet 1997; 17: 263–264

    Article  CAS  Google Scholar 

  53. Bales KR, Verina T, Cummins DJ et al. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease Proc Natl Acad Sci USA 1999; 96: 15233–15238

    Article  CAS  Google Scholar 

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Acknowledgements

This project was supported by the Department of Veteran Affairs, NHMRC (Australia), the McCusker Foundation for Alzheimer's Disease Research, and US NIH Program AG10491. SM Laws is a recipient of a Dora Lush (Biomedical) postgraduate research scholarship from the NHMRC (Australia).

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Authors and Affiliations

  1. Department of Surgery, Sir James McCusker Alzheimer's Disease Research Unit, University of Western Australia, Hollywood Private Hospital, Perth, Western Australia

    S M Laws, R M Clarnette, K Taddei, G Martins, A Paton & R N Martins

  2. Department of Psychiatry and Behavioural Science, Stamford University, Palo Alto, CA, USA

    J Hallmayer

  3. Department of Psychiatry and Behavioural Science, University of Western Australia, QEII Medical Centre, Perth, Western Australia

    O P Almeida

  4. School of Biomedical Science, Curtin University of Technology, Bentley, Western Australia

    D M Groth

  5. Alzheimer Research Program, New York University, NS Kline Institute, Orangeburg, New York, USA

    S E Gandy

  6. Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany

    H Förstl

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  1. S M Laws
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Correspondence to R N Martins.

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Laws, S., Clarnette, R., Taddei, K. et al. APOE-ε4 and APOE −491A polymorphisms in individuals with subjective memory loss. Mol Psychiatry 7, 768–775 (2002). https://doi.org/10.1038/sj.mp.4001083

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