Apolipoprotein ε4 is associated with more rapid decline in odor identification than in odor threshold or Dementia Rating Scale scores
Introduction
Alzheimer’s disease (AD) is a neurologic disorder accompanied by progressive memory and cognition loss and functional decline (American Psychiatric Association, 1994). Apolipoprotein E type ε4 (APOE4) allele has been associated with late onset familial and sporadic Alzheimer’s disease (Corder et al., 1993, Noguchi et al., 1993, Poirier et al., 1993, Saunders et al., 1993). Findings suggest that the APOE4 gene products may be directly involved in the mechanisms underlying AD pathogenesis (Namba et al., 1991, Poirier et al., 1993, Strittmatter et al., 1993, Strittmatter et al., 1994).
Changes in olfactory functioning occur with the onset of AD (Koss, 1986, Murphy et al., 1990, Serby, 1986). AD patients with moderate dementia show losses in olfactory threshold, odor identification, and odor recognition memory (Koss, 1986, Morgan et al., 1995, Murphy et al., 1990, Nordin and Murphy, 1996, Serby, 1986). Impaired olfaction has also been indicated as a marker for cognitive decline (Devanand et al., 2000, Graves et al., 1999, Murphy et al., 1990, Schiffman et al., 2002). This is not surprising because it has been shown that many areas of the brain involved in olfaction are affected by the onset of AD. Neurofibrillary tangles and neuritic plaques appear in the olfactory bulb, the anterior olfactory nucleus, and the prepiriform cortex (Esiri and Wilcock, 1984, Price et al., 1991, Wilcock, 1983). Braak and Braak, 1991, Braak and Braak, 1997 describe the initial lesions from neurofibrillary tangles occurring in the transentorhinal and entorhinal regions, areas critical for olfactory function. Therefore, olfactory testing may be an important component in the diagnostic battery, especially with regard to early diagnosis.
APOE4 status has also been associated with deficits in odor identification in nondemented older persons (Murphy, Bacon, Bondi, & Salmon, 1998). Odor identification is significantly compromised in APOE4 participants when no other preclinical evidence of AD is observed. What distinguishes the odor identification task from other purely cognitive tasks is that it relies on both olfactory sensory/perceptual functioning and semantic memory. Recent research indicates that semantic memory is affected early in AD (Heindel & Salmon, 2001). Therefore, one might expect to observe odor identification deficits early in the disease process. Murphy et al. (1998) observed cross-sectional differences in odor identification between genetically at-risk adults and normal controls. The present study assessed the performance of ε4+ and ε4− individuals on odor identification longitudinally, to investigate whether at-risk individuals display a larger decline in performance, thus reflecting the incipient processes associated with the disease.
Bacon, Bondi, Salmon, and Murphy (1998) demonstrated that odor threshold scores show a decline one year prior to diagnosis of AD. However, at-risk individuals may be experiencing neurological changes that occur several years before diagnosis. Therefore, although AD can affect both odor threshold and odor identification, it is plausible that odor identification would demonstrate a greater decline longitudinally because of the dual reliance of the odor identification task on intact olfactory detection, and semantic memory for odor. The goal of the present study is to compare longitudinal odor threshold and odor identification performance for genetically at-risk ε4+ with ε4− persons. It is hypothesized that ε4+ individuals will show greater longitudinal deficits in odor identification than odor threshold over time in comparison to ε4− individuals.
Section snippets
Participants
Fifty healthy normal elderly adults from the local San Diego community participated in this study. Participants were volunteers in longitudinal studies at San Diego State University, San Diego or at the University of California, San Diego. Twenty-eight participants were negative for the ε4 allele and twenty-two had one ε4 allele. Demographics for these groups are summarized in Table 1. There were no preexisting differences between ε4 allele positive and negative participants in age, education,
Data analysis
Data for each variable (odor identification, odor threshold, and DRS score) were analyzed using two-way, repeated measures ANOVA with allele status (ε4+, ε4−) as the between-subject variable and time of visit (Year 1, Year 4) as the within-subject factor.
Allele status and odor identification
As Fig. 1 illustrates, time and allele status interacted to affect performance on odor identification, (F (1, 48) = 8.0, p = .007). Follow-up simple effect analyses of allele status indicated that at baseline there was no significant difference
Discussion
The present study demonstrates that normal nondemented elderly adults who carry the ε4+ allele and are thus at risk for AD, showed a significant decline over a 4-year time period in performance on odor identification but not on odor threshold, picture identification or the DRS. The significant decline over time in odor identification performance cannot be explained by decline in global cognitive status, as evidenced by similar performance on the DRS at each time point. As noted above, odor
Acknowledgments
We gratefully acknowledge Drs. Robert Katzman, Leon Thal, and David Salmon of the UCSD Alzheimer’s Disease Research Center (P50 A605131) for DRS assessment and for genotyping. We also thank Jason Bailie, Vanessa Zizak, Tara Jaffe, Joe Dintino, and Mario Dulay for assistance. Supported by NIH grant Number AG04085 from the National Institute on Aging to C.M.
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