Apolipoprotein E epsilon4 and age at onset of sporadic and familial Alzheimer disease in Caribbean Hispanics

BACKGROUND: The primary effect of the apolipoprotein E epsilon4 (APOE epsilon4) allele is on the age at onset of Alzheimer disease (AD). OBJECTIVE: To investigate whether the presence of the APOE epsilon4 allele can account for the earlier age at onset of familial AD (FAD) compared with sporadic AD (SAD). DESIGN: Population-based, case series ascertained in a prospective study of aging and dementia in Medicare recipients aged 65 years or older. SETTING: Clinics in northern Manhattan and in the Dominican Republic and Puerto Rico. PARTICIPANTS: There were 680 Caribbean Hispanic subjects: 111 patients with FAD, with at least 1 family member with dementia; 163 patients with SAD; and 406 elderly persons without dementia or other illnesses. Main Outcome Measure Age at onset of dementia was examined in relation to frequency of APOE epsilon4. Sex, education, and medical risk factors for stroke, hypertension, diabetes, and heart disease were examined as effect modifiers. RESULTS: The mean age at onset of AD was significantly lower in FAD than in SAD, and a statistically significant dose effect of the APOE epsilon4 allele was present for age at onset in FAD (P = .001) but not in SAD. The age at onset in patients homozygous for the APOE epsilon4 allele with FAD and SAD was similar. Compared with SAD, the major difference was younger age at onset in patients with FAD who were heterozygous for the APOE epsilon4 allele and those without an APOE epsilon4 allele. CONCLUSIONS: Apolipoprotein E epsilon4 had a consistent lowering effect on age at onset of FAD, but this was attenuated in SAD. This suggests that among individuals with a family history of AD and the APOE epsilon4 allele, additional genetic or environmental factors may accelerate the onset of dementia.     

Presence of an APOE4 allele results in significantly earlier onset of Parkinson's disease and a higher risk with dementia.

The epsilon4 allele of the apolipoprotein E gene (APOE4) has been consistently associated with a greater risk of Alzheimer's disease (AD) as well as an earlier onset of AD. It is possible that APOE4 may also play a role in the etiology of other neurodegenerative disorders, such as Parkinson's disease (PD). APOE genotype, age of onset, disease duration, smoking history, and dementia status were collected for families with PD, yielding 324 Caucasian families with complete information. Logistic regression employing one individual per family and including age of onset and disease duration as covariates demonstrated a significantly increased risk of dementia for those individuals having inherited at least one epsilon4 allele (OR=3.37; P=0.002). Survival analyses also demonstrated a significantly earlier age of onset for those subjects with at least one epsilon4 allele (59.7 years) as compared with those homozygous for the more common epsilon3 allele (62.4 years; P=0.009). Thus, consistent with previous studies, we find evidence that the presence of an epsilon4 allele results in significantly earlier onset of PD and a greater likelihood of dementia. It appears the similarities between PD and AD may be due to an overlap in the diseases' genetic etiology.     

Apolipoprotein E polymorphism and age of onset for Alzheimer's disease in a bi-ethnic sample

OBJECTIVE: This study examined the association between the Apolipoprotein-E epsilon4 allele (APOE epsilon4) and age of disease onset in a bi-ethnic sample of community dwelling Alzheimer's disease (AD) patients. DESIGN: Cross-sectional study of AD patients evaluated at a University-affiliated outpatient memory disorders clinic. SUBJECTS: A clinic-based cohort of white non-Hispanic (WNH; n=601) and white Hispanic (WH; n = 359) patients diagnosed with possible or probable AD according to NINCDS-ADRDA diagnostic criteria. MEASURES: Global cognitive functioning of the subjects was evaluated using the Mini-mental State Exam. The age of onset of AD was calculated from the patient's current age minus the reported duration of disease obtained from a knowledgeable family member. RESULTS: A significant relationship was discovered between APOE epsilon4 and age of onset for WNH, with lower ages of onset among patients carrying the epsilon4/epsilon4 and epsilon3/epsilon4 genotypes in relation to patients with the epsilon3/epsilon3 genotype. The results revealed a more modest effect for APOE genotype in the WH cohort, with a lower age of onset witnessed among epsilon4 positive patients (epsilon2/epsilon4, epsilon3/epsilon4 and epsilon4/epsilon4 genotypes) in comparison to epsilon4 negative patients (epsilon2/epsilon2, epsilon2/epsilon3 and epsilon3/epsilon3 genotypes). CONCLUSION: The association between the epsilon4 allele and earlier age of onset was more pronounced in WNH compared to WH patients, suggesting the impact of APOE polymorphism on clinical phenotype may be different for distinct ethnic groups in the U.S.     

Familial Alzheimer disease among Caribbean Hispanics: a reexamination of its association with APOE.

OBJECTIVES: To reexamine the association between the apolipoprotein E epsilon4 allele (APOE epsilon4) and familial Alzheimer disease (AD), and to search for novel genes that may be associated with susceptibility in Caribbean Hispanic families with a history of AD. METHODS: Families were identified in Caribbean Hispanic communities in the greater New York City area, the Dominican Republic, and Puerto Rico. Each family in the study cohort included at least 2 living relatives with a history of dementia. All family members underwent neuropsychological testing and medical and neurological examinations to establish the presence or absence of dementia and to specify the type of dementia. RESULTS: Over a 2(1/2)-year period, 203 families were identified. Of these, 19 families had at least 1 family member with onset of dementia before age 55 years, with 8 of the 19 families showing an association with a previously unreported presenilin mutation. Multiple cases of AD were identified in 29 families. Overall, there were 236 affected sibling pairs with AD available for analysis. The average age at onset was 74 years. The presence of APOE epsilon4 was strongly associated with AD. CONCLUSIONS: Both early-onset and late-onset familial AD occur in Caribbean Hispanics. In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics is strongly associated with APOE epsilon4. Future attempts to identify additional susceptibility genes should consider the effects of APOE epsilon4.     

Apolipoprotein E epsilon4 allele differently affects the patterns of neuropsychological presentation in early- and late-onset Alzheimer's disease patients

The presence of the apolipoprotein E (APOE) epsilon4 allele is a definite risk factor for the onset of Alzheimer's disease (AD). Its presence seems to affect especially the memory in the early stage of the disease, but the effect on the progression of the disease and survival is still controversial. Some longitudinal studies could be influenced by variables other than APOE, such as the response to medical treatment, rehabilitation therapy and inclusion of patients at different stages of progression at baseline. Moreover, the inclusion in the same study sample of patients of different ages at onset of the disease (below 65 or above 80 years) appears arbitrary. In our study, we evaluated a population of newly diagnosed untreated AD patients at their first neuropsychological examination and with the onset of their first symptoms not longer than 3 years ago. In order to analyse the different effects of the APOE epsilon4 allele on the different ages at the onset of the disease, we split the study sample into two groups: (1) subjects under 65 years [early-onset AD (EOAD); n = 30] and subjects over 70 years [late-onset AD (LOAD); n = 41], excluding subjects with an age of onset between 66 and 69 years. Our results show that the APOE epsilon4 allele carriers are characterised by a different neuropsychological pattern at the disease onset; however, only in the EOAD group is this effect significant: in EOAD, the epsilon4 allele carriers obtained worse performances in learning, long-term verbal memory and general intelligence tasks. On the contrary, in LOAD patients, the pattern of cognitive impairment at the onset is not dependent on the possession of an epsilon4 allele in the genotype. Such data could suggest a careful control of the study sample concerning age at the onset of the disease since APOE could play a different role in EOAD and LOAD mainly due to the different pathogenic mechanism at the onset and evolution of AD.     

APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer's disease

Apolipoprotein E (APOE) has been extensively demonstrated to be a genetic risk factor for Alzheimer's disease (AD). Associations of APOE genotype have been reported with age at AD onset, rate of decline, and responsiveness to therapy. This study aimed to test these hypotheses in a large study population of AD patients. APOE genotype was determined from 1,528 Caucasian subjects, diagnosed by NINCDS/ADRDA criteria as probable AD patients, enrolled in four international placebo-controlled clinical trials of 3--12 months duration, designed to evaluate efficacy of treatment with galantamine or sabeluzole. In addition to patient demographics and baseline scores for Mini Mental State Examination, scores on the Disability Assessment for Dementia (DAD) and the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) were recorded at the start, during, and at the end of the study. APOE epsilon 4 homozygotes had a significantly lower age at disease onset compared to patients with other APOE genotypes. The epsilon 4 allele was significantly over-represented in females compared to males, and in the group of subjects with an AD family history. Based on longitudinal data of 504 placebo-treated AD patients, the linear annual rate of change in score was 5 points on the ADAS-cog scale and 11 on the DAD scale. The epsilon 4 allele copy number did not influence these rates of decline. Sabeluzole treatment was not effective in the overall group compared to the placebo-treated group, nor in any subgroup stratified by epsilon 4 allele count. Galantamine produced cognitive and functional improvement that were not affected by epsilon 4 allele count. In conclusion, our data confirm a strong association between epsilon 4 homozygotes and age at onset of AD but do not support an effect of epsilon 4 allele copy number on rate of cognitive and functional decline nor on the efficacy of galantamine in patients with AD.     

Apolipoprotein E epsilon4 allele frequency and age at onset of Alzheimer's disease

The age distribution of the epsilon4 allelic form of the apolipoprotein E gene (APOE) was investigated in 630 patients with Alzheimer's disease (AD) with onset age ranging from 35 to 90 years. Overall, mean age at onset in APOE epsilon4 allele bearers was significantly later than that in nonbearers. However, when stratified into early onset AD (EOAD) and late onset (LOAD) groups, mean age at onset in EOAD cases bearing APOE epsilon4 allele was later than that in those EOAD cases without epsilon4 allele, whereas in LOAD mean age at onset in cases bearing APOE epsilon4 allele was earlier than in those without epsilon4 allele. When analysed by decade, it was observed that 37% of the total number of APOE epsilon4 allele bearers, and 43% of total number of cases with APOE epsilon4/epsilon4 genotype fell into the 60-69 years age class. Hence, APOE epsilon4 allele frequency, at 0.44, was highest in the 60-69 years age class, progressively decreasing either side of this age group. APOE epsilon4 allele therefore has its maximum impact between onset ages of between 60 and 70 years.     

APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study

BACKGROUND: Both family aggregation and apolipoprotein E (APOE) epsilon4 allele are well-known risk factors for dementia, but the relation between these two factors remains unclear. OBJECTIVE: To explore whether the risk of dementia and Alzheimer disease (AD) due to a positive family history is explained by APOE genotypes. DESIGN: Community-based cohort study. SETTING: The Kungsholmen district of Stockholm, Sweden. PARTICIPANTS: A total of 907 nondemented people 75 years or older, followed up for 6 years to detect incident dementia and AD cases according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. MAIN OUTCOME MEASURES: Risk of dementia and AD by Cox proportional hazards models after controlling for several potential confounders. RESULTS: Subjects who had at least 2 siblings with dementia were at an increased risk of AD. Individuals with both APOE epsilon4 allele and at least 2 affected first-degree relatives had a higher risk of dementia and AD compared with those without these 2 factors. Similar results were obtained for history of dementia separately in parents or siblings. Among the epsilon4 allele carriers, subjects with 2 or more first-degree demented relatives had increased risk of dementia and AD, whereas no increased risk was detected among non-epsilon4 carriers. CONCLUSIONS: Family history of dementia was associated with an increased risk of dementia and AD in this very old population, but only among APOE epsilon4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE epsilon4 allele.     

Absence of the apolipoprotein E epsilon4 allele is associated with working memory impairment in Parkinson's disease

The apolipoprotein E (APOE) epsilon4 allele has been associated with an increased risk of Alzheimer's disease (AD) and weaker episodic memory among elderly. Although this APOE allele has been linked to earlier onset of Parkinson's disease (PD), an association with dementia in PD has been only inconsistently demonstrated. Given the heterogeneity of cognitive impairment patterns in PD, this study sought to determine whether an association exists between APOE genotype and specific cognitive deficits in PD. The neuropsychological test performance of 42 PD patients without an epsilon4 allele (PD-Non4) and of 20 with at least one epsilon4 allele (PD-epsilon4) was compared to that of 146 elderly control subjects (NC). The PD groups were comparable in overall severity of cognitive impairment and disease duration, but the PD-epsilon4 group was younger, had an earlier disease onset, and contained a higher proportion of persons with dementia. Both PD groups showed wide-ranging cognitive impairments relative to NC. Once age differences between groups were controlled for, the PD groups generally did not differ from each other in cognitive performance. However, only the PD-Non4 group demonstrated working memory/attention impairments (digit span, visual span, Trailmaking test) relative to the NC group. Results suggest that the APOE genotype may influence the cognitive phenotype of PD, and specifically that absence of the epsilon4 allele is associated with working memory impairment. Additionally, results are consistent with prior findings showing an association between the epsilon4 allele and earlier onset of PD and presence of dementia.     

The effect of APOE epsilon4 allele on cerebral glucose metabolism in AD is a function of age at onset

BACKGROUND: Although the APOE epsilon4 allele is a well-known risk factor for developing AD, the impact of the epsilon4 allele on clinical manifestations in patients with AD is still controversial. One possible reason for this controversy is that previous studies did not consider the effect of patient age at symptom onset. OBJECTIVE: To investigate the possible impact of patient age at onset of AD on the effect of APOE genotype on regional cerebral glucose metabolism (rCMRglc). METHODS: The authors compared rCMRglc between probable AD patients (based on criteria of the National Institute of Neurologic Disease and Stroke/AD and Related Disorders Association) with APOE epsilon4/4 and APOE epsilon3/3 alleles in early-onset (< or =65 years old) and late-onset (>65 years old) groups. In each group, the patients with APOE epsilon4/4 and APOE epsilon3/3 alleles were comparable for age at onset, age at examination, sex, disease duration, education level, and severity of dementia. RESULTS: In the early-onset group, the patients with the APOE epsilon4/4 genotype showed a significant decrease of rCMRglc in the medial temporal lobe and a significant increase of rCMRglc in the inferior parietal and posterior temporal cortices as compared with those patients with the APOE epsilon3/3 genotype. In the late-onset group, there were no significant differences in the rCMRglc pattern between the patients with APOE epsilon4/4 and APOE epsilon3/3 alleles. CONCLUSIONS: The current findings indicate that the impact of the APOE epsilon4 genotype on cerebral glucose metabolism of patients with AD may be a function of age at symptom onset.     

Association between APOE polymorphisms and mesial temporal lobe epilepsy with hippocampal sclerosis.

To evaluate the hypothetical link between apolipoprotein E (APOE) polymorphisms and mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and whether presence of APOE epsilon4 allele shortens the latent period between febrile seizures and epilepsy. A further interest is whether presence of APOE epsilon4 allele has an impact on severity of the disease. Forty-seven patients with MTLE-HS were compared with 62 controls. APOE polymorphisms were determined from lymphocytes by standard methods. Eight patients (17%) and 10 controls (16.1%) were demonstrated to have one APOE epsilon4 allele. There was not any statistically significant difference in APOE epsilon4 frequency between patients and controls (P > 0.05). There was not any difference statistically according to onset age of epilepsy and the presence of APOE epsilon4 allele within patient group. APOE epsilon4 polymorphisms did not influence the severity of epilepsy. APOE epsilon4 polymorphisms had no impact on outcome after surgery. Patients with bilateral memory deficits, bilateral hippocampal atrophy and with bilateral epileptiform interictal EEG transients, were independently compared with patients having unilateral features and there were not any statistically significant differences. This study has found no association between APOE epsilon4 polymorphisms and presentation of MTLE-HS in a group of Turkish patients.     

Accelerated memory decline in Alzheimer's disease with apolipoprotein epsilon4 allele

To investigate a possible effect of the apolipoprotein (APOE) epsilon4 allele on memory decline in Alzheimer's disease (AD), we examined 64 AD patients with the APOE epsilon3/3, epsilon3/4, or epsilon4/4 allele using the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and its subtests at the initial examination and at the 1-year follow-up visit. One-year changes in the scores of the Word Recall subtest, Word Recognition subtest, and total ADAS-Cog were significantly correlated with the number of APOE epsilon4 alleles after controlling for the effects of age, sex, education, test interval, and baseline scores. Findings revealed that APOE epsilon4 allele is related to an accelerated memory decline in AD.     

APOE genotype and survival in men and women with Alzheimer's disease

BACKGROUND: The epsilon 4 allele of the APOE gene (APOE) is more frequent in patients with AD than in the general population, but studies are inconclusive as to whether it affects rate of progression or survival. Because survival in AD is generally longer in women than in men, the authors investigated whether APOE affects 10-year survival equally in men and women. METHODS: APOE testing was performed on 125 patients with probable AD enrolled in the Johns Hopkins AD Research Center between November 1984 and March 1987. The 39 men and 86 women were followed at 6-month intervals until censoring (by death or withdrawal from the study) or March 1997. Patients were dichotomized into those with and those without at least one epsilon 4 allele. For each sex, a Cox proportional hazards regression, allowing for delayed entry and covarying for age at onset, was used to examine the effect of epsilon 4 on survival. RESULTS: All patients who died during the study period and had autopsy (n = 92) were found to have definite AD. Average survival from disease onset did not differ by sex (12.1 years in men; 12.3 years in women). In neither sex were differences found between epsilon 4-positive and epsilon 4-negative subgroups in education, duration of AD at entry, or severity of dementia. However, in both sexes the epsilon 4-positive subgroup was approximately 3 years older at onset of AD and at entry to the study than the epsilon 4-negative subgroup. Adjusting for age at onset, the presence of an epsilon 4 allele significantly increased the relative risk of death only for men (RR = 2.69; 95% CI = 1.23 to 5.87). CONCLUSIONS: In this sample of mostly white, well-educated research participants with AD, the APOE epsilon 4 allele was associated with shorter survival in men but not in women.     

APOE and AD concordance in twin pairs as predictors of AD in first-degree relatives

OBJECTIVE: To examine the independent effects of the APOE genotype (APOE) and concordance for AD in twin pairs on the occurrence of AD in first-degree relatives. BACKGROUND: Studies of twins have been undertaken to investigate the influence of genes in a variety of conditions, including AD. A previous study, performed before reports linking APOE to AD, demonstrated an increase in AD among first-degree relatives of twins concordant for AD compared with relatives of discordant twins. METHODS: In a sample of 94 twin pairs the authors examined the association between concordance for AD within the twin pair and family history of AD among first-degree relatives of twins. They then examined the extent to which the presence of the APOE epsilon4 allele in the twin pair explains the association between concordance for AD within the twin pair and family history of AD. RESULTS: Concordance among twins was associated with increased risk of AD among relatives (logrank test, chi2 = 12.558; p = 0.0004), and the presence of at least one APOE epsilon4 allele in each member of the twin pair is also associated with increased risk of AD among family members (logrank test, chi2 = 7.712; p = 0.0055). CONCLUSIONS: APOE genotype explains much but not all of the association between concordance among twins and increased familial risk of AD.     

No association between subjective memory complaints and apolipoprotein E genotype in cognitively intact elderly

OBJECTIVE: This cross-sectional study examined the relationship between subjective memory complaints and the apolipoprotein epsilon 4 allele (epsilon4), a genetic risk factor for Alzheimer's disease (AD), among cognitively normal subjects identified from a community memory screening. DESIGN: The sample comprised 232 consecutive white non-Hispanic older adults who presented to a free community-based memory-screening program at a University affiliated memory disorders center. Participants were classified as cognitively normal based on scores on the age and educated adjusted Folstein Mini-Mental Status Exam (MMSAdj) and a brief Delayed Verbal Recall Test (DRT). Subjects were assessed for APOE genotype, subjective memory complaints (Memory Questionnaire, MQ), depressive symptoms (Hamilton Depression Rating Scale, HDRS), and history of four major medical conditions that have been associated with memory loss (stroke/transient ischemic attack [TIA], atherosclerotic heart disease, hypertension, and diabetes). A hierarchical regression analysis was performed to examine the association between APOE genotype and memory complaints after controlling for a host of potential confounding factors. RESULTS: The APOE epsilon4 allele frequency for cognitively normal subjects was 0.13. Subjective memory complaints were predicted by depressive symptoms and a history of stroke/TIA. They were not associated with APOE genotype, MMSAdj score, DRT score, age, education, gender, and reported history of atherosclerotic heart disease, hypertension, or diabetes. CONCLUSION: The results did not suggest an association between subjective memory complaints and the APOE epsilon4 allele in this sample of cognitively intact subjects. This indicates that memory complaints may confer risk for future dementia through pathways independent of APOE genotype. The results also show that older adults with memory complaints are at increased risk for underlying depression.     

Apolipoprotein E and alpha-1-antichymotrypsin genotypes do not predict time to psychosis in Alzheimer's disease

Psychotic symptoms occurring in Alzheimer's disease (AD + psychosis, AD + P) are a marker for a more rapidly deteriorating phenotype. We have developed a polygenic model of AD + P risk, conditioned on the presence of AD. Whether risk genes for AD itself contribute to AD + P risk is not established, although our model predicts they will not. The most important identified genetic determinant of sporadic, late-onset AD is the apolipoprotein E epsilon 4 allele (APOE4). The effect of APOE4 on AD phenotype is to reduce the age of onset of AD. Prior studies examining the association of APOE4 with AD + P have reported conflicting results. However, no prior studies have examined if APOE4 reduces time to onset of psychosis in AD. The objective of this study was to examine the effect of APOE4 and alpha1-antichymotrypsin/AA (ACT/AA) genotypes on time to psychosis onset in subjects with AD. A longitudinal study of psychosis incidence in 316 subjects with AD with no history of current or prior psychotic symptoms at entry was undertaken. APOE and ACT genotyping was conducted per established protocols. Data were analyzed by survival analysis and Cox proportional hazards models. There were no significant associations of APOE or ACT genotypes with time to psychosis onset and no significant interaction of these genotypes with time to psychosis onset. There remained no significant associations after covarying for age, age of AD onset, degree of cognitive impairment, gender, race, and education. This is the first study to examine the genetic prediction of psychosis onset in AD. The findings support the hypothesis that these two genetic determinants of AD risk do not contribute to the risk of development of psychotic symptoms in AD.     

Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE ɛ4 allele

Some patients with early-onset Alzheimer's disease (AD) present with a distinct phenotype. Typically, the first and most salient characteristic of AD is episodic memory impairment. A few patients, however, present with focal cortical, non-memory symptoms, such as difficulties with language, visuospatial, or executive functions. These presentations are associated with specific patterns of atrophy and frequently with a young age at onset. Age is not, however, the only determinant of phenotype; underlying factors, especially genetic factors, seem also to affect phenotype and predispose patients to younger or older age at onset. Importantly, patients with atypical early-onset disease seldom carry the APOE ?4 allele, which is the most important risk factor for lowering the age of onset in patients with AD. Additionally, theAPOE ?4 genotype seems to predispose patients to vulnerability in the medial temporal areas, which leads to memory loss. Conversely, patients negative for the APOE ?4 allele and with early-onset AD are more likely to be predisposed to vulnerability of cerebral networks beyond the medial temporal lobes. Other factors are probably involved in determining the pattern of atrophy, but these are currently unknown.     

Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4

There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an epsilon4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 +/- 6.34); ERT non-users (n = 80, mean age 67.03 +/- 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2-5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE epsilon4 allele. APOEepsilon4 carriers receiving ERT performed no better on episodic memory testing than APOE epsilon4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE epsilon4 allele.     

Individual growth curve analysis of APOE epsilon 4-associated cognitive decline in Alzheimer disease

BACKGROUND: The apolipoprotein E epsilon4 (APOE epsilon4) allele is associated with an increased risk of developing Alzheimer disease (AD). However, findings regarding an association between the APOE epsilon4 allele and the rate of decline in AD have been mixed. OBJECTIVE: To examine the relationship between the APOE epsilon4 allele and the rate of cognitive and functional decline in AD using individual growth curve analyses. DESIGN: Longitudinal cohort study. SETTING: Alzheimer Disease Research Center at Baylor College of Medicine. PATIENTS: A total of 189 patients meeting NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) criteria for probable AD at baseline who underwent annual follow-up evaluations for at least 2 years. MAIN OUTCOME MEASURES: Individual growth curve parameters derived from baseline and follow-up performance on global and specific measures of cognitive and functional abilities. RESULTS: Patients with 2 APOE epsilon4 alleles exhibited a slower rate of decline on measures of global cognitive functioning and functional abilities. No significant association was detected between the APOE epsilon4 allele and the rate of decline on measures of specific cognitive functions. CONCLUSIONS: Although the APOE epsilon4 allele is associated with an increased risk of developing AD, it seems that having 2 APOE epsilon4 alleles is associated with a slower clinical course. These findings are consistent with hypotheses that the biological processes contributing to the onset of AD are different from those involved in determining its clinical course.     

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.