Apolipoprotein E genotype of a Portuguese control population and Alzheimer's disease patients

The present work first describes the frequency of APOE alleles and genotypes in Portuguese populations in relation to AD pathology. We genotyped a group of late onset sporadic AD cases, their pairwise controls and a larger group of randomly selected individuals, to assess the distribution pattern of APOE alleles in the Portuguese population. APOE ?4 relative frequency may significantly vary among different populations—a fact which should be taken into consideration for the correct evaluation of the cossegregation of this allele with AD pathology. We observed a frequency of 0.087 ± 0.029 of the APOE ?4 and 0.043 ± 0.021 of the APOE ?2 allele in the Portuguese random population which as expected showed a marked prevalence of the APOE ?3 form (0.870 ± 0.035). In the AD patients the APOE ?4 allele frequency was significantly higher (0.360 ± 0.081) than in the controls (χ₂ = 31.000, p < 0.00001, df = 2). Consistently APOE ?3 allele frequency (0.640 ± 0.081) was significantly lower than in the controls while APOE ?2 was absent in the studied AD population. Taken together our results demonstrate that the Portuguese population is characterized by a relatively low frequency of the APOE ?4 allele, in good agreement with previous observations of a gradient of ?4 allele frequency in Europe, decreasing from North to South. Several lines of evidence point at APOE?e4 allele as a major genetic susceptibility factor in AD. The APOE ?4 allele was significantly higher [odds ratio (OR) = 5.93, 95% CI 3.55–9.91] in the Portuguese AD patients than in the random non-demented population. The genotype analysis of the Portuguese AD patients here described reveals a marked, increased frequency of ?4 homo- and heterozygous individuals consistent with an APOE ?4 zigosity effect as a further genetic trait predisposing to AD development.     

A DLST genotype associated with reduced risk for Alzheimer's disease

Recent studies suggest that variants of the DLST gene alter the risk of AD. DLST encodes the core subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex, which is deficient in AD. The authors report that in 247 US white subjects, homozygosity for DLST A19,117, T19,183 was associated with a reduced risk of AD (odds ratio [OR] = 0.35, p = 0.018). The reduced risk was marked in subjects who did not carry the apolipoprotein (APOE)-4 allele (OR = 0.16, p = 0.014). Further study of DLST in AD appears warranted.     

Isolated hallucinosis in Alzheimer's disease is associated with African-American race

OBJECTIVES: The aim of this investigation was to study the relationship between isolated hallucinosis and race in Alzheimer's disease. METHODS: This was a cross-sectional, case control study carried out at the Neuropsychiatry Service, outpatient clinic at the Johns Hopkins School of Medicine, USA. The participants were 237 community-residing patients with probable Alzheimer's disease according to NINCDS/ADRDA criteria were included in the study. 9 patients with isolated hallucinosis were compared to a control group of 228 patients who had neither delusions nor hallucinations. Patients with only delusions or both delusions and hallucinations were excluded based on prior research. Patients were assessed clinically for the presence of hallucinations using the DSM-IV glossary definitions. They were also rated on standardized measures of cognitive impairment, depression, functional impairment, and general health. RESULTS: There was a significant association between hallucinations and race in patients with Alzheimer's disease. Before adjustment for other variables, the African-American race conferred a 5.5-fold (95% CI = 1.4-21.6; p = 0.02) increased risk for isolated hallucinosis. After adjustment for multiple other variables, this risk increased further to 27.2-fold (95% CI = 1.6-457.3; p = 0.02). CONCLUSIONS: African-American patients with Alzheimer's disease are more likely to have isolated hallucinations than Caucasian patients even after statistical adjustment for multiple confounding variables, which might distort this association. This finding has implications for our understanding of the etio-pathogenesis of hallucinations in Alzheimer's disease and for meeting health service needs of African-American patients.     

Apolipoprotein E genotype and noncognitive symptoms in Alzheimer's disease.

BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 allele confers significant risk for Alzheimer's disease and is associated with a greater amyloid burden in the brain. Future treatments may target molecular mechanisms associated with this allele, and it is important to define any phenotypic characteristics that correspond to this genotype. We sought to clarify the relationship between ApoE status and noncognitive symptoms in Alzheimer's disease patients. METHODS: Possible and probable Alzheimer's disease patients from a clinical trial (n = 605) were assessed with the 10-item Neuropsychiatric Inventory cross-sectionally prior to treatment, and their ApoE genotype was determined. Among the population studied, the following numbers with specific genotypes were studied: 23-2/3, 17-2/4, 209-3/3, 288-3/4, 68-4/4. RESULTS: When correlations were controlled for the patient's level of cognitive impairment, there was no relationship between epsilon 4 dose and any of the 10 noncognitive symptoms assessed, including psychosis, mood changes, and personality alterations. CONCLUSIONS: Among patients with comparable disease severity, the epsilon 4 allele does not confer additional psychiatric morbidity.     

Apolipoprotein E genotype and concomitant clinical features in early-onset Alzheimer's disease

We have studied the relationship between the apolipoprotein E gene (APOE) and the development of myoclonus, tremors, rigidity and seizures in 168 patients with probable early-onset Alzheimer's disease (AD). There was a statistically significantly lower risk of tremor for carriers of the 4 allele of APOE. This allele was also associated with an increased risk of myoclonus. Our findings suggest that there may be differences in progression and clinical appearance in early-onset AD related to the APOE genotype.     

Apolipoprotein E epsilon4 allele is associated with Parkinson disease risk in a Mexican Mestizo population.

We investigated the association between apolipoprotein E (APOE) alleles and genotypes and Parkinson disease (PD) in 229 unrelated Mexican Mestizo PD patients and 229 controls. Results showed that both APOE-epsilon4 allele and APOE epsilon4/epsilon3 genotype are associated with PD (OR = 1.736, P = 0.011; OR = 1.688, P = 0.019, respectively). Mean age at onset of PD was not associated to any APOE allele or genotype, but was significantly earlier in familial PD when compared to sporadic cases (P = 0.025).     

Apolipoprotein E epsilon4 is associated with neuronal loss in the substantia nigra in Alzheimer's disease

Apolipoprotein E epsilon4 (ApoE epsilon4) is associated with an earlier age at onset of Alzheimer's (AD) and possibly Parkinson's disease, suggesting a general role for ApoE epsilon4 in neuronal plasticity. Among 31 prospectively assessed subjects with pathologically confirmed AD (without Lewy bodies), epsilon4+ subjects had a longer duration of disease (by 2.8 years, p = 0.04). Only cell loss in the substantia nigra (p = 0.002) was associated with epsilon4. Neither neurofibrillary tangles nor plaque counts were associated with epsilon4. Cell counts of pigmented neurons in single midbrain sections in epsilon4+ specimens were 72% of those in epsilon4- substantia nigra (p = 0.04). These findings confirm that cell loss in the substantia nigra is associated with epsilon4 in AD. Copyrightz1999S.KargerAG,Basel     

Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer's disease: a volumetric MRI study

Asymmetry of brain structures is common to many species and is even present in utero. Some developmental, pathological, and dementing diseases are associated with alterations in normal anatomical asymmetries. Anatomical asymmetries, however, have been only superficially studied in Alzheimer's disease. Recent evidence indicates that the allele epsilon4 of the apolipoprotein E (ApoE), a well known risk factor for Alzheimer's disease, might play a part in determining some brain morphological changes both in normal carriers and in patients with Alzheimer's disease. This study evaluated the effect of the ApoE genotype on hippocampal asymmetry in patients with Alzheimer's disease carrying 0, 1, and 2 copies of the allele. Volumetric right-left differences of the hippocampi were computed in 28 right handed patients with Alzheimer's disease (14 -/-, 9 epsilon4/-, and 5 epsilon4/4) and 30 controls without detectable cognitive deficit. In controls, the right hippocampus was larger than the left, whereas in patients with Alzheimer's disease this asymmetry was progressively reduced with increasing gene dose of the epsilon4 allele, and the asymmetry was reversed in the epsilon4/4 Alzheimer's disease group. The mean right-left volume differences were: 1.2, 0.7, 0.2, and -1.0 in controls, -/-, epsilon4/-, and epsilon4/4 patients, respectively (sex adjusted p for trend=0.017). The data indicate a dose dependent effect of the ApoE epsilon4 allele on hippocampal volume asymmetry in Alzheimer's disease.     

Apolipoprotein E and beta-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent.

The epsilon4 allele of apolipoprotein E (apoE) is associated with increased risk for the development of Alzheimer's disease (AD), possibly due to interactions with the beta-amyloid (Abeta) protein. The mechanism by which these two proteins are linked to AD is still unclear. To further assess their potential relationship with the disease, we have determined levels of apoE and Abeta isoforms from three brain regions of neuropathologically confirmed AD and non-AD tissue. In two brain regions affected by AD neuropathology, the hippocampus and frontal cortex, apoE levels were found to be decreased while Abeta(1-40) levels were increased. Levels of apoE were unchanged in AD cerebellum. Furthermore, levels of apoE and Abeta(1-40) were found to be apoE genotype dependent, with lowest levels of apoE and highest levels of Abeta(1-40) occurring in epsilon4 allele carriers. These results suggest that reduction in apoE levels may give rise to increased deposition of amyloid peptides in AD brain.     

Apolipoprotein E and β-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent

The ε4 allele of apolipoprotein E (apoE) is associated with increased risk for the development of Alzheimer's disease (AD), possibly due to interactions with the β-amyloid (Aβ) protein. The mechanism by which these two proteins are linked to AD is still unclear. To further assess their potential relationship with the disease, we have determined levels of apoE and Aβ isoforms from three brain regions of neuropathologically confirmed AD and non-AD tissue. In two brain regions affected by AD neuropathology, the hippocampus and frontal cortex, apoE levels were found to be decreased while Aβ_1–40 levels were increased. Levels of apoE were unchanged in AD cerebellum. Furthermore, levels of apoE and Aβ_1–40 were found to be apoE genotype dependent, with lowest levels of apoE and highest levels of Aβ_1–40 occurring in ε4 allele carriers. These results suggest that reduction in apoE levels may give rise to increased deposition of amyloid peptides in AD brain.     

Apolipoprotein E genotype in familial Parkinson's disease

APOE genotypes were compared in 57 cases of familialParkinson's disease, 46 cases of sporadic Parkinson's disease, and387controls. The frequency of the APOE allele ε4 was similar inpatients with Parkinson's disease and controls, but the APOE alleleε2, thought to be protective for dementia, was significantly more frequent in patients with sporadic Parkinson's disease than in controls. This is the first study of Parkinson's disease to include familial cases. It confirms the absence of association between the APOEallele ε4 and this disease.

     

Cognitive impairment in Alzheimer's disease is modified by APOE genotype

AIM: We examined whether impairment in specific cognitive domains in Alzheimer's disease (AD) differed according to APOE genotype and age at onset. METHODS: Cognitive functions of 229 consecutive AD patients were assessed using Visual Association Test (VAT), Memory Impairment Screen+ (MIS+), VAT object naming, fluency test and Trail Making Test (TMT). Dementia severity was assessed using MMSE. ANOVAs were performed with APOE genotype and age at onset as independent variables and sex, education and MMSE as covariates. RESULTS: 28% of patients were APOE epsilon4-negative, 58% heterozygous and 14% homozygous. A significant association between APOE genotype and VAT and MIS+ was found when correcting for sex and education. An interaction effect between APOE genotype and age at onset on VAT and VAT object naming was found, with young carriers performing worse than young noncarriers. By contrast, when additionally correcting for MMSE, a significant association between APOE genotype and VAT object naming, TMT-A and TMT-B was found, with noncarriers performing worse than carriers. CONCLUSION: Memory was more impaired among APOE epsilon4 carriers than among noncarriers. By contrast, naming, executive functions and mental speed were more impaired among APOE epsilon4 noncarriers. This suggests that the APOE genotype modifies the clinical phenotype in terms of cognitive impairment in AD.     

Apolipoprotein E genotype in patients with alzheimer's disease: Implications for the risk of dementia among relatives

Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the ?4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack ?4 and many persons having ?4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first-degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of ?4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one ?4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of ?4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one ?4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex-modification effect of the E4 isoform on disease susceptibility.