To examine the relationship between apolipoprotein E ε4 (ApoE ε4) and psychiatric symptoms, we compared ε4/ε4, ε3/ε3, and ε3/ε4 subjects. 659 outpatients with memory complaints underwent comprehensive neuropsychiatric assessment interview and neurological examination and ApoE genotyping: 98 were ε4/ε4. 18.4% (n = 18) ε4/ε4, 19.3% (n = 45) ε3/ε4, and 5.4% (n = 14) ε3/ε3 presented with symptoms of anxiety (p = 0.00001). ε4/ε4 patients with mild cognitive impairment (MCI; p < 0.0001) and those with Alzheimer's disease with late onset (p = 0.0175) were the most frequently affected. For anxiety, there were no gender dependent differences in the two homozygous groups, however, in the ε3/ε4 group, anxiety symptoms were evident in 7.3% (n = 8) of the male versus 30.1% (n = 37) of the female ε3/ε4 heterozygotes (p < 0.0001). Depression was found in 20.4% (n = 20) ε4/ε4 and 21.0% (n = 49) ε3/ε4 compared to 17.1% (n = 44) ε3/ε3 (p = 0.5181). Visual hallucinations were reported in 5.1% (n = 5) ε4/ε4 as opposed to 3.8% (n = 9) ε3/ε4 and 2.3% (n = 6) ε3/ε3 (p = 0.5278). We have seen a higher association of anxiety with the ApoE ε4 allele across all stages of disease and what may be a dosing effect in the early stage (MCI) for this ostensible risk, since we see a significantly higher frequency in the ApoE ε4 homozygotes when compared to the heterozygotes.

To investigate the correlation between cognitive impairment, Parkinson's disease (PD) symptoms and ApoE ε4/ε4 homozygosity an ApoE ε4/ε4 homozygous cohort was compared with an ApoE ε3/ε3 homozygous comparison group. A total of 696 outpatients with memory complaints had undergone comprehensive neuropsychiatric assessment including interview and examination by clinical psychiatrists and neurologists as well as laboratory blood testing (including ApoE genotyping). Patients also underwent the Consortium to Establish a Registry on Alzheimer's Disease (CERAD) test battery and the Clock-Drawing Test (Shulman scoring). Of the 623 selected individuals 258 were homozygous for ApoE ε3 and 133 were homozygous for ApoE ε4, while 232 were heterozygous for ApoE ε3/ε4. Thirty patients in the entire sample were diagnosed with PD (4.8 %). In the ApoE ε4/ε4 group seven persons had PD (5.3 %), while in the ApoE ε3/ε3 comparison group nine persons were diagnosed with PD (3.5 %). In the ApoE ε3/ε4 heterozygous group we found 14 (6.03 %) subjects meeting criteria for PD, P = 0.406. This is to our knowledge the largest retrospective cohort study to date of ApoE ε4 homozygous carriers. In comparison with the ApoE ε3 homozygous carriers in our study, subjects who were homozygous for ApoE ε4 demonstrated a slightly but statistically insignificant higher prevalence of PD, while in the ApoE ε3/ε4 heterozygous group we detected the highest rate of probands diagnosed with PD. We conclude that there is no correlation between allele combinations of ApoE ε3 and ApoE ε4 in their heterozygote and homozygote composition and prevalence of PD.