Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status

Neurology. 1999 Oct 22;53(7):1480-7. doi: 10.1212/wnl.53.7.1480.


Objective: To determine whether olfactory status predicts cognitive decline (CD) over a 2-year follow-up period.

Methods: The authors enrolled individuals in a community-based longitudinal study of memory and aging in the Japanese-American community in King County, WA, between 1992 and 1994. At baseline they screened 1,985 persons using the Cognitive Abilities Screening Instrument (CASI) and the 12-item Cross-Cultural Smell Identification Test (CC-SIT). Of these 1,985 people, 1,836 were found not to be demented. Two years later the authors rescreened 1,604 participants with the CASI. They defined CD as a 2-year loss of > or =5.15 points/100 on the CASI. They genotyped 69% of the 1,604 people completing both examinations for apolipoprotein E (apoE).

Results: After adjusting for age, CASI score at baseline, education, smoking, sex, and follow-up time, the authors determined an odds ratio (OR) for CD of 0.90 (95% CI, 0.84 to 0.97) for an increase in each correct point on the CC-SIT (range, 0 to 12). Compared with normosmics, the OR for persons with impaired olfaction (microsmics) was 1.25 (95% CI, 0.83 to 1.89) and for anosmics the OR was 1.92 (95% CI, 1.06 to 3.47). Persons who were anosmic at baseline and who had at least one APOE-epsilon4 allele had 4.9 times the risk of CD (95% CI, 1.6 to 14.9) compared with normosmics without the epsilon4 allele. The estimated relative risk among women was 9.7 (95% CI, 1.3 to 70.4), and for men the risk was 3.2 (95% CI, 0.8 to 12.6). Receiver operating characteristic (ROC) curves showed that although the area under the curve (AUC) for baseline CASI was only 0.51, the AUC for CC-SIT alone was 0.62. Adding CC-SIT to the ROC model with CASI improved the AUC curve from 0.51 to 0.62.

Conclusions: Unexplained olfactory dysfunction in the presence of one or more APOE-epsilon4 alleles is associated with a high risk of cognitive decline. Cross-Cultural Smell Identification Test classifies people with cognitive decline correctly to a greater degree than a global cognitive test.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alleles
  • Apolipoprotein E4
  • Apolipoproteins E / genetics*
  • Cognition Disorders / genetics*
  • Cognition Disorders / physiopathology*
  • Cohort Studies
  • Female
  • Forecasting
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Odds Ratio
  • ROC Curve
  • Smell / physiology*


  • Apolipoprotein E4
  • Apolipoproteins E