Many studies failed to detect any association between APOE
genotype and either delusions or psychosis in patients with AD.12,16,17,19-24,26
On the contrary, other studies11,15
have reported an increased frequency of psychosis in ε4 carriers. Similarly, it has been shown that ε4 was associated with psychosis (in particular, at the advanced stages of the disease),14
and an increased frequency of hallucinations and psychotic disturbances has been noted in patients with AD with the ε4 allele.13
Our key finding was a strong and dose-related association between the APOE genotype and the incidence of delusions. We also noted that the presence of two ε4 alleles was associated with a decreased risk for developing hallucinations (RR 0.2; 95% CI 0 to 0.9; p < 0.04) in the adjusted model only. This was not seen with one ε4 allele in the same model (RR 0.9; 95% CI 0.4 to 1.9; p < 0.71). In addition, this effect was not seen for one or two ε4 alleles in the unadjusted model. Given this weak association, the implications of this finding are unclear. One possible explanation is that treatment during follow-up with either antipsychotic or anticholinesterase medications in subjects with one or two ε4 alleles (who might have received these treatments because of more delusions) might have resulted in suppression of hallucinations and therefore artificially decreased incidence. To test this idea, we excluded subjects who received any of the above medications and repeated the analyses. The protective effect was no longer present (simple model—one ε4: RR 1.7, 95% CI 0.72 to 4.02, two ε4: RR 0.5, 95% CI 0.11 to 2.28; adjusted model–one ε4: RR 1.3, 95% CI 0.45 to 3.53, two ε4: RR 0.5, 95% CI 0.9 to 2.72), supporting this possibility. The results for delusions remained unchanged. Alternatively, there might be a real dissociation between the incidence of delusions and hallucinations. This would not be surprising given that we observe this dissociation in AD (where delusions are more common than hallucinations) and in diffuse Lewy body dementia (where hallucinations are more common than delusions). It may suggest differential pathophysiology or pathoanatomic localization underlying the development of these symptoms.
With regard to other psychiatric manifestations in AD, some studies did not detect any association between APOE
genotype and depressive symptoms in AD samples.18,19,23,25,26 APOE
genotype was not associated with any changes in depression scores in healthy elderly community residents.27
However, it has been reported that patients with AD with ε3/ε4 genotype were more likely to be depressed11
and that a positive correlation exists between the ε4 allele and mood disturbances.13
Unlike the previous studies, an increased risk for depression in carriers of the ε2 (rather than the ε4) allele12
and a protective role for the ε4 allele for depressive symptoms15
have been published. The current study failed to detect any association between APOE
genotype and depressive symptomatology.
Behavioral disturbances have also been investigated in relation to APOE
genotype. Although agitation was more common in ε4 carriers in one study,10
in a subsequent study, agitation and disorientation were more common in ε4/ε4 carriers, whereas anxiety and sleep disorders were more common in ε3/ε4 carriers.3
In another report, it was noted that the presence of the ε4 allele was associated with increased combativeness, agitation, wandering, and confusion.13
We detected no association between the APOE
genotype and incidence of behavioral disturbances in our cohort.
Explanations for the variable findings in previous studies include differences in patient populations (some of the studies included subjects with Lewy body disease), differences in the assessment of psychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies. In addition, many of the above studies did not control for potential confounding variables. Most important, all of the previous studies were cross-sectional, whereas the current study evaluated risk for incident symptoms in a prospectively followed cohort.
The current analyses are performed on a well-characterized sample of patients with probable AD who underwent a rigorous diagnostic process in AD research centers. Patients with a diagnosis of diffuse Lewy body disease or other dementias were not included. A widely used scale for psychopathology with well-documented reliability and validity was used. Additional strengths of the current cohort include enrollment of subjects who were at a relatively early stage of the disease and the long follow-up with semiannual recording of psychopathology. Thus, we have reliably recorded the progression of AD from its early stages, and we have accurately assessed the incidence of psychiatric symptoms.
We also tried to control for all potential confounders. Low educational attainment has been associated with high risk for developing AD43
and psychosis in AD.20
Similarly, female gender has been considered a risk factor in AD and has been related to APOE
We included both education and sex as covariates in our analyses. Because severity of AD might be associated with the risk for psychopathologic manifestations,2,20
we controlled for cognitive (mMMSE) and functional (BDRS) impairment as well as age and disease duration.
genotypes seem to confer different risks for developing AD (and therefore possible differential biologic effects) among different ethnic groups.42,44
Given the fact that the ethnic distribution of this AD population was heavily weighted for white persons, with few blacks or Hispanics, the results of the current study might not be generalizable to all ethnic groups. In addition, the population was derived from major university-based AD referral centers, and it might not be generalizable to the population of patients with AD in the community. Finally, it is plausible that the modest sample size of 87 subjects might have resulted in inadequate power to detect associations between the APOE
genotype and illusions, hallucinations, depression, and behavioral symptoms.
The clinical heterogeneity observed in AD45
could derive from underlying genetic variability. For example, the presence of the ε4 allele has been associated with earlier age at disease onset.41
The relation of APOE
genotype to extrapyramidal signs in AD has also been investigated. Psychotic manifestations and extrapyramidal signs are well-characterized predictors of rate of progression and outcomes in AD.7-9
The presence of the ε4 allele was associated with increased risk for psychosis in the current study but has been inversely associated with the development of extrapyramidal signs in previous reports.46
Finally, the association between the APOE
genotype and rate of cognitive decline or outcomes in AD has been controversial.7,41,46,47
In terms of neuropathologic correlates, patients with AD with the ε4 allele have increased β-amyloid burden.48,49
Psychiatric symptomatology has been associated with more severe neuropathologic changes.50,51
It is therefore plausible that the increased incidence of delusions in subjects with ε4 alleles could be a manifestation of more severe underlying pathology.
The ε4 allele has been associated with more profound deficits in cholinergic neurons, in particular in the frontal lobes,52,53
whereas the development of psychiatric symptoms in AD appears to be related to specific neurotransmitter imbalances, notably acetylcholine.54
Consequently, the presence of the ε4 allele could favor a preferential pathologic involvement of the cholinergic system, which in turn might result in more frequent psychiatric manifestations.
Psychotic manifestations in AD have been associated with pathology in the temporal lobe and hippocampus.50,55
SPECT evidence has suggested that delusions in AD may be associated with greater temporal lobe hypoperfusion.56
At the same time, SPECT and MRI studies have shown greater atrophy in medial temporal structures and more severe loss in hippocampal volumes in patients with AD carrying the ε4 allele.57,58
It is conceivable that the detected association between APOE
genotype and delusions might reflect neuropathology more heavily concentrated in the temporal lobe. Despite these speculations, the pathophysiologic explanation of the association between the APOE
genotype and development of delusions in AD is not clear.
The observed association between the APOE
geno-type and development of delusions is important, given the medical and social impact of psychiatric symptomatology in AD, its prognostic value for future outcomes, and the responsiveness of psychosis in AD to treatment.59-62