Behavior Genetics

, Volume 39, Issue 5, pp 496–503 | Cite as

Odor Identification Deficit as a Predictor of Five-Year Global Cognitive Change: Interactive Effects with Age and ApoE-ε4

  • Jonas K. Olofsson
  • Michael Rönnlund
  • Steven Nordin
  • Lars Nyberg
  • Lars-Göran Nilsson
  • Maria Larsson
Original Research


Olfactory impairments are present in common neurodegenerative disorders and predict conversion to dementia in non-demented individuals with cognitive impairment. In cognitively intact elderly, evidence is sparse regarding the role of olfactory deficits in predicting cognitive impairment. The present study investigated predictors of 5-year prospective decline in the Mini-Mental State Examination (MMSE) in a large (n = 501), population-based sample of elderly (65–90 years) individuals. All participants were genotyped for the ApoE gene, assessed for health factors, and were non-demented at the baseline assessment. After partialling out the influences of demographic and health-factors at baseline and dementia at follow-up, poor odor identification ability in combination with older age and the ApoE-ε4 allele predicted larger prospective global cognitive decline. This effect could not be produced by a vocabulary test. In sum, the findings suggest that an olfactory deficit can dissociate between benign and malign global cognitive development in non-demented, very old ε4-carriers, who are at high risk of developing dementia.


ApoE Odor identification Olfaction Aging Dementia 



The Betula Study is funded by the Bank of Sweden Tercentenary Foundation (1988-0082:17), Swedish Council for Planning and Coordination of Research (D1988-0092, D1989-0115, D1990-0074, D1991-0258, D1992-0143, D1997-0756, D1997-1841, D1999-0739, B1999-474), Swedish Council for Research in the Humanities and Social Sciences (F377/1988-2000), the Swedish Council for Social Research (1988-1990: 88-0082, and 311/1991-2000), and the Swedish Research Council (315-2004-6977). The authors acknowledge the contribution to this paper of the VIB—Department of Molecular Genetics at the University of Antwerp, Antwerpen, Belgium, and Rolf Adolfsson at the Department of Psychiatry, Umeå University, to the APOE genotyping of Betula individuals. The authors declare no conflict of interest.


  1. Bäckman L, Laukka EJ, Wahlin A, Small BJ, Fratiglioni L (2002) Influences of preclinical dementia and impending death on the magnitude of age-related cognitive deficits. Psychol Aging 17(3):435–442PubMedCrossRefGoogle Scholar
  2. Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ (2004) Multiple cognitive deficits during the transition to Alzheimer’s disease. J Intern Med 256(3):195–204PubMedCrossRefGoogle Scholar
  3. Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ (2005) Cognitive impairment in preclinical Alzheimer’s disease: a meta-analysis. Neuropsychology 19(4):520–531PubMedCrossRefGoogle Scholar
  4. Bacon AW, Bondi MW, Salmon DP, Murphy C (1998) Very early changes in olfactory functioning due to Alzheimer’s disease and the role of apolipoprotein E in olfaction. Ann N Y Acad Sci 855:723–731PubMedCrossRefGoogle Scholar
  5. Bende M, Nordin S (1997) Perceptual learning in olfaction: professional wine tasters versus controls. Physiol Behav 62(5):1065–1070PubMedCrossRefGoogle Scholar
  6. Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE et al (2003) Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology 60(2):246–252PubMedGoogle Scholar
  7. Bennett DA, Schneider JA, Wilson RS, Bienias JL, Berry-Kravis E, Arnold SE (2005) Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. J Neurol Neurosurg Psychiatry 76(9):1194–1199PubMedCrossRefGoogle Scholar
  8. Bunce D, Fratiglioni L, Small BJ, Winblad B, Bäckman L (2004) APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology 63(5):816–821PubMedGoogle Scholar
  9. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923PubMedCrossRefGoogle Scholar
  10. Devanand DP, Michaels-Marston KS, Liu XH, Pelton GH, Padilla M, Marder K et al (2000) Olfactory deficits in patients with mild cognitive impairment predict Alzheimer’s disease at follow-up. Am J Psychiatry 157(9):1399–1405PubMedCrossRefGoogle Scholar
  11. Devanand DP, Pelton GH, Tabert M (2001) Olfactory deficit in Alzheimer’s disease? Dr. Devanand and colleagues reply. Am J Psychiatry 158(9):1534–1535CrossRefGoogle Scholar
  12. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (1994) American Psychiatric Association, Washington DCGoogle Scholar
  13. Dixon RA, Bäckman L, Nilsson LG (eds) (2004) New frontiers in cognitive aging. Oxford University Press, New YorkGoogle Scholar
  14. Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H (2007) Olfaction in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 29(5):693–706PubMedCrossRefGoogle Scholar
  15. Eggertsen G, Tegelman R, Ericsson S, Angelin B, Berglund L (1993) Apolipoprotein-E polymorphism in a healthy Swedish population—variation of allele frequency with age and relation to serum-lipid concentrations. Clin Chem 39(10):2125–2129PubMedGoogle Scholar
  16. Folstein MF, Folstein SE, Mchugh PR (1975) Mini-mental state—practical method for grading cognitive state of patients for clinician. J Psychiatr Res 12(3):189–198PubMedCrossRefGoogle Scholar
  17. Gilbert PE, Murphy C (2004) Differences between recognition memory and remote memory for olfactory and visual stimuli in nondemented elderly individuals genetically at risk for Alzheimer’s disease. Exp Gerontol 39(3):433–441PubMedCrossRefGoogle Scholar
  18. Graves AB, Bowen JD, Rajaram L, McCormick WC, McCurry SM, Schellenberg GD et al (1999) Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status. Neurology 53(7):1480–1487PubMedGoogle Scholar
  19. Handley OJ, Morrison CM, Miles C, Bayer AJ (2006) ApoE gene and familial risk of Alzheimer’s disease as predictors of odour identification in older adults. Neurobiol Aging 27(10):1425–1430PubMedCrossRefGoogle Scholar
  20. Hawkes C (2003) Olfaction in neurodegenerative disorder. Mov Disord 18(4):364–372PubMedCrossRefGoogle Scholar
  21. Larsson M, Nilsson LG, Olofsson JK, Nordin S (2004) Demographic and cognitive predictors of cued odor identification: evidence from a population-based study. Chem Senses 29(6):547–554PubMedCrossRefGoogle Scholar
  22. Li YJ, Scott WK, Hedges DJ, Zhang F, Gaskell PC, Nance MA et al (2002) Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 70(4):985–993PubMedCrossRefGoogle Scholar
  23. Mesholam RI, Moberg PJ, Mahr RN, Doty RL (1998) Olfaction in neurodegenerative disease—a meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases. Arch Neurol 55(1):84–90PubMedCrossRefGoogle Scholar
  24. Murphy C, Bacon AW, Bondi MW, Salmon DP (1998) Apolipoprotein E status is associated with odor identification deficits in nondemented older persons. Ann N Y Acad Sci 855:744–750PubMedCrossRefGoogle Scholar
  25. Nathan BP, Nisar R, Short J, Randall S, Grissom E, Griffin G et al (2005) Delayed olfactory nerve regeneration in ApoE-deficient mice. Brain Res 1041(1):87–94PubMedCrossRefGoogle Scholar
  26. Nathan BP, Nannapaneni S, Gairhe S, Nwosu I, Struble RG (2007) The distribution of apolipoprotein E in mouse olfactory epithelium. Brain Res 1137(1):78–83PubMedCrossRefGoogle Scholar
  27. Nilsson LG, Bäckman L, Erngrund K, Nyberg L, Adolfsson R, Bucht G et al (1997) The Betula prospective cohort study: memory, health and aging. Aging Neuropsychol Cogn 4(1):1–32Google Scholar
  28. Nilsson LG, Adolfsson R, Bäckman L, de Frias CM, Molander B, Nyberg L (2004) Betula: a prospective cohort study on memory, health and aging. Aging Neuropsychol Cogn 11(2–3):134–148Google Scholar
  29. Nilsson LG, Adolfsson R, Bäckman L, Cruts M, Nyberg L, Small BJ et al (2006) The influence of APOE status on episodic and semantic memory: data from a population-based study. Neuropsychology 20(6):645–657PubMedCrossRefGoogle Scholar
  30. Nordin S, Murphy C (1996) Impaired sensory and cognitive olfactory function in questionable Alzheimer’s disease. Neuropsychology 10(1):113–119CrossRefGoogle Scholar
  31. Nordin S, Brämerson A, Liden E, Bende M (1998) The Scandinavian odor-identification test: development, reliability, validity and normative data. Acta Otolaryngol 118(2):226–234PubMedCrossRefGoogle Scholar
  32. Nyberg L, Maitland SB, Rönnlund M, Bäckman L, Dixon RA, Wahlin A et al (2003) Selective adult age differences in an age-invariant multifactor model of declarative memory. Psychol Aging 18(1):149–160PubMedCrossRefGoogle Scholar
  33. Olofsson JK, Nordin S, Wiens S, Hedner M, Nilsson L-G, Larsson M (in press) Odor identification impairment in carriers of ApoE-ε4 is independent of clinical dementia. Neurobiol AgingGoogle Scholar
  34. Royall DR, Chiodo LK, Polk MJ, Jaramillo CJ (2002) Severe dysosmia is specifically associated with Alzheimer-like memory deficits in nondemented elderly retirees. Neuroepidemiology 21(2):68–73PubMedCrossRefGoogle Scholar
  35. Serby M, Mohan C, Aryan M, Williams L, Mohs RC, Davis KL (1996) Olfactory identification deficits in relatives of Alzheimer’s disease patients. Biol Psychiatry 39(5):375–377PubMedCrossRefGoogle Scholar
  36. Small BJ, Rosnick CB, Fratiglioni L, Bäckman L (2004) Apolipoprotein E and cognitive performance: a meta-analysis. Psychol Aging 19(4):592–600PubMedCrossRefGoogle Scholar
  37. Smith JD (2002) Apolipoproteins and aging: emerging mechanisms. Ageing Res Rev 1(3):345–365PubMedCrossRefGoogle Scholar
  38. Struble RG, Short J, Ghobrial M, Nathan BP (1999) Apolipoprotein E immunoreactivity in human and mouse olfactory bulb. Neurosci Lett 267(2):137–140PubMedCrossRefGoogle Scholar
  39. Swan GE, Carmelli D (2002) Impaired olfaction predicts cognitive decline in nondemented older adults. Neuroepidemiology 21(2):58–67PubMedCrossRefGoogle Scholar
  40. Tabert MH, Liu XH, Doty RL, Serby M, Zamora D, Pelton GH et al (2005) A 10-item smell identification scale related to risk for Alzheimer’s disease. Ann Neurol 58(1):155–160PubMedCrossRefGoogle Scholar
  41. Tulving E (1972) Episodic and semantic memory. In: Tulving E, Donaldson W (eds) Organization of memory. Academic Press, New York, pp 382–403Google Scholar
  42. van Rensburg SJ, Potocnik FC, De Villiers JN, Kotze MJ, Taljaard JJ (2000) Earlier age of onset of Alzheimer’s disease in patients with both the transferrin C2 and apolipoprotein E-epsilon 4 alleles. Ann N Y Acad Sci 903:200–203PubMedCrossRefGoogle Scholar
  43. Wang QS, Tian L, Huang YL, Qin S, He LQ, Zhou JN (2002) Olfactory identification and apolipoprotein E epsilon 4 allele in mild cognitive impairment. Brain Res 951(1):77–81PubMedCrossRefGoogle Scholar
  44. Wenham PR, Price WH, Blundell G (1991) Apolipoprotein-E genotyping by one-stage PCR. Lancet 337(8750):1158–1159PubMedCrossRefGoogle Scholar
  45. Wilson RS, Arnold SE, Tang YX, Bennett DA (2006) Odor identification and decline in different cognitive domains in old age. Neuroepidemiology 26(2):61–67PubMedCrossRefGoogle Scholar
  46. Wilson RS, Arnold SE, Schneider JA, Tang Y, Bennett DA (2007) The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry 78(1):30–35PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jonas K. Olofsson
    • 1
    • 2
    • 3
  • Michael Rönnlund
    • 1
    • 4
  • Steven Nordin
    • 1
    • 5
  • Lars Nyberg
    • 6
  • Lars-Göran Nilsson
    • 2
    • 3
  • Maria Larsson
    • 2
    • 3
  1. 1.Department of PsychologyUmeå UniversityUmeåSweden
  2. 2.Department of PsychologyStockholm UniversityStockholmSweden
  3. 3.Stockholm Brain InstituteStockholmSweden
  4. 4.Centre for Population StudiesUmeå UniversityUmeåSweden
  5. 5.Department of PsychologySan Diego State UniversitySan DiegoUSA
  6. 6.Department of Radiation SciencesUmeå UniversityUmeåSweden

Personalised recommendations