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| Reference | Study sample | Cognitive and neuropsychiatric assessment | Principal results |
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| Ramachandran et al. [39] | 46 AD patients; 135 controls, restricted to APOE ε3/3 and ε3/4 only | CDR, HAM-D, and SCID-DSM-III-R | Depression rating greater with APOE ε3/4 versus ε3/3 reference genotype. Psychosis greater with ε3/4 versus ε3/3 reference genotype |
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| Holmes et al. [53–55] | 164 AD patients
232 AD patients
210 AD patients | BDRS
CAMDEX and MOUSEPAD | APOE ε2 allele significantly associated with depressive symptoms. APOE ε2 allele significantly associated also with persecutory delusions |
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| Cacabelos et al. [40, 56] | 207 demented patients | MMSE, GDS, ADAS, BCRS, FAST, BEHAVE-AD, HAM-D, HAM-A, and SDASDS | Disorientation, agitation, and motor disorders were slightly more frequent in demented patients with APOE ε4/e4, while anxiety and sleep disorders appeared more frequently in APOE ε3/ ε4. However, these differences were not statistically significant |
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| Lehtovirta et al. [57] | 58 AD patients and 16 controls | MMSE, BCRS, and HAM-D; the presence of rigidity, hypokinesia, tremor at rest, orofacial dyskinesia, myoclonus, hallucinations, delusions, and different kinds of paresis was recorded in the neurologic examination. The occurrence of epileptic seizures, hallucinations, and delusions was also inquired from the caregivers | Cognitive and neuropsychiatric symptoms and signs were not related to the APOE genotype |
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| Murphy et al. [41] | 77 AD patients | MMSE, TBDQ, and ADAS non-cog | APOE ε4 allele associated with higher scores on TBDQ |
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| Cantillon et al. [58] | 162 AD patients | MMSE and CSDD | The APOE e4 allele frequency was not increased in the late-onset depression group among these AD patients |
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| Ballard et al. [80] | 51 AD patients | CAMCOG, CSDD, Burns symptom checklist, and SCID-DSM-III-R | Protective effect of APOE ε4 allele against depression. APOE ε4-carriers more likely to have future psychotic episode |
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| Forsell et al. [60, 61] | 806 participants aging 78 years and over | MMSE and CPRS | Depressed and nondepressed subjects had similar APOE genotype distributions among the demented, and among the nondemented, subjects. There was also no statistical significant difference in APOE genotype between subjects with and without psychotic symptoms, stratified by dementia diagnosis |
| 668 participants aging 75 years and over | Dementia was diagnosed using the DSM-III-R criteria Psychotic symptoms were defined according to DSM-IV criteria |
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| Lopez et al. [62] | 194 AD patients | MMSE. BRS-CERAD, and semi-structured psychiatric interview | No evidence for an association of NPS with any specific APOE genotype in probable AD patients |
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| Lyketsos et al. [63] | 120 AD patients | Diagnoses for major and minor depression according to DSM-IV, and assessment of delusions or hallucinations according to DSM-IV glossary definitions | There was no association between APOE genotype and the presence of NPS or the neuropsychiatric syndromes examined. There was an interesting suggestion that the e4 allele may be protective against the development of major depression; however, this association did not reach statistical significance |
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| Hirono et al. [64, 65] | 228 AD patients | MMSE, BEHAVE-AD, and NPI | The APOE ε4 allele had no effect on the manifestation of delusions, hallucinations, depression, or other NPS in AD |
| 175 AD patients | MMSE, CDR, and the Japanese version1of the NPI |
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| Levy et al. [25] | 605 AD patients | MMSE and NPI | Among patients with comparable disease severity, the APOE ε4 allele does not confer additional psychiatric morbidity |
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| Harwood et al. [66] | 501 AD patients | MMSE, HAM-D, and structured interview for specific delusions and hallucinations | Increased risk for psychosis with APOE ε4 allele |
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| Müller-Thomsen et al. [48] | 137 AD patients | MMSE and MADRS | Overrepresentation of the APOE ε4 allele in female AD patients |
| Liu et al. [67] | 149 AD patients | CASI, CDR, HAM-D, and SCID-DSM-III-R | No evidence of an association between depression in AD patients and presence or absence of the APOE ε4 or ε2 allele |
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| Scarmeas et al. [68] | 87 AD patients | MMSE, CUSPAD, BDRS, and SCID-DSM-III-R | APOE ε4 alleles associated with risk for incident delusions. APOE ε4/ε4 predicted protective effect against hallucinations |
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| Gabryelewicz et al. [69] | 139 AD patients | MMSE, GDS, and BEHAVE-AD | The APOE e4 allele had no effect on the behavioural changes in AD |
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| Sweet et al. [70] | 316 AD patients | MMSE, BRS-CERAD, and SCID-DSM-III-R | There was no significant association of APOE genotype with time to psychosis onset and no significant interaction of this genotypes with time to psychosis onset |
|
| Craig et al. [26, 71] | 400 AD patients
404 AD patients | NPI with caregiver distress
MMSE and NPI with caregiver distress | Increase in agitation/aggression in patients with the APOE ε4 allele, while APOE genotype created no additional risk for depressive symptoms in AD |
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| Chang et al. [72] | 135 AD patients | CASI, CDR, and SCID-DSM-III-R | APOE ε4 significantly associated with hallucinations and delusions |
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| Robertson et al. [73] | 125 AD patients | CSDD and NPI | Greater level of anxiety in APOE ε4/ε4 versus ε3ε/3 bearers in both genders and versus ε3/ε4 in males only |
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| Borroni et al. [28] | 232 AD patients | By Principal Component Analysis of NPI symptoms, four endophenotypes were identified, these were termed “psychosis,” “moods,” “apathy,” and “frontal” | APOE genotype did not correlate with any neuropsychiatric endophenotype |
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| Hollingworth et al. [29] | 1,120 AD patients | By Principal Component Analysis of NPI symptoms, four interpretable components were identified: behavioral dyscontrol (euphoria, disinhibition, aberrant motor behavior, and sleep and appetite disturbances), psychosis (delusions and hallucinations), mood (depression, anxiety, and apathy), and agitation (aggression and irritability) | None of the neuropsychiatric endophenotypes identified were associated with age at assessment, years of education, or number of APOE ε4 alleles |
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| Monastero et al. [74] | 197 AD patients | MMSE and NPI | The presence of apathy was significantly associated with the APOE ε4 allele independently from age, education, sex, and duration of disease |
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| Spalletta et al. [59] | 171 AD patients | MMSE and NPI | The association between NEUROPSYCHIATRIC SYMPTOMS and APOE ε4 allele in AD was confirmed for delusions only |
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| Pritchard et al. [27] | 388 AD patients | MMSE and NPI | Protective effect of the APOE ε3/ε4 genotype that was significantly associated with hallucinations symptoms. APOE ε3/ε4 genotype is significantly associated with anxiety |
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| van der Flier et al. [75] | 110 AD patients | MMSE and NPI | Delusions and agitation/aggression were more common and severer among homozygous APOE ε4 carriers than among heterozygous or APOE-ε4-negative patients |
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| Zdanys et al. [76] | 266 AD patients | MMSE, ADL, IADL, and NPI | APOE ε4 was significantly associated with psychotic symptoms, adjusting for age, sex, education, and MMSE score |
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| Delano-Wood et al. [49] | 323 AD patients | MMSE and SCID-DSM-III-R | Higher prevalence rate of the APOE ε4 genotype in the depressed group compared to the nondepressed AD patients. This effect was primarily accounted for by women |
| Chopra et al. [77] | 175 cognitively impaired subjects, of which 92 AD and 80 MCI patients | MMSE, GDS-15, and NPI | The difference in the proportion of participant reporting “low energy” at GDS-15 between the three APOE ε4 allele frequency groups approached statistical significance |
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| Del Prete et al. [78] | 53 AD patients | MMSE and NPI | Patients with APOE 4 allele showed a wider range of NEUROPSYCHIATRIC SYMPTOMS when compared to noncarriers and higher scores for hallucinations and aberrant motor behaviors. Over time, ε4 carriers showed an increase/delayed onset in some symptoms and a parallel decrease in others, while noncarriers presented an undifferentiated worsening of symptomatology |
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| Woods et al. [79] | 36 demented patients | MMSE and mABRS | Patients with an APOE ε4 allele had a significant increase in their observed NEUROPSYCHIATRIC SYMPTOMS, including restlessness and vocalizations, compared to those who did not have an APOE ε4 allele present |
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| D’Onofrio et al. [30] | 201 AD patients and 121 controls | MMSE, ADL, IADL, CIRS, and NPI. Furthermore, AD patients with NEUROPSYCHIATRIC SYMPTOMS were further subdivided in four groups according to the EADC classification of neuropsychiatric syndromes in AD: hyperactive, psychotic, affective, and apathetic | No difference in the distribution of APOE genotypes was found between AD patients with and without NEUROPSYCHIATRIC SYMPTOMS. In AD patients APOE ε4-carriers, there was an increased risk of affective and apathetic syndromes |
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