Apolipoprotein E genotype as a risk factor in Japanese patients with early-onset and late-onset Alzheimer's disease

Recent studies have provided evidence of an association of apolipoprotein E (apoE) epsilon 4 allele and late-onset sporadic Alzheimer's disease (AD). Some studies have shown the possibility that apoE epsilon 4 is a risk factor of developing AD in early-onset type. We have analyzed the apoE gene polymorphism in a sample of 310 Japanese AD subjects and 237 age-matched Japanese controls. We divided the sporadic AD patients into two subgroups of 237 late-onset (> 65 years) and 73 early-onset (< or = 65 years) patients, and into three subgroups according to their apoE genotype, no epsilon 4, one epsilon 4, and two epsilon 4 alleles. Our data confirmed an association between epsilon 4 allele and early-onset AD and late-onset AD. The odds ratios (95% confidence interval) referred to no epsilon 4 allele for AD were 3.4 (1.7-7.0) for one epsilon 4 allele and 20.3 (2.5-166.6) for two epsilon 4 alleles in early-onset type, and 6.7 (3.9-11.3) for one epsilon 4 allele and 19.0 (2.5-145.6) for two epsilon 4 alleles in late-onset type. These ratios were significantly increased in both early-onset AD and late-onset AD. Kaplan-Meier survival analysis, which estimates the age of onset for subjects with no, one, and two epsilon 4 alleles in early-onset and late-onset type, revealed a significant dose effect where each additional epsilon 4 allele made the age of onset earlier (p < 0.0001). The age of onset is 9.7 years earlier for two epsilon 4 bearers and 3.9 years earlier for one epsilon 4 bearers than no epsilon 4 bearers in late-onset AD, 2.9 years earlier for two epsilon 4 bearers and 1.4 years earlier for one epsilon 4 bearers than no epsilon 4 bearers in early-onset AD. Moreover, we studied an association between apoE epsilon 2 allele and early-onset AD and late-onset AD. There was a significantly decreased frequency of apoE epsilon 2 allele in patients with late-onset AD (p = 0.026), although the frequency of apoE epsilon 2 was not changed significantly in early-onset AD (p = 0.360). The odds ratios referred to no epsilon 2 allele for AD were 1.9 (0.6-5.7) for one epsilon 2 allele in early-onset type, and 0.4 (0.2-0.9) for one epsilon 2 allele in late-onset type. Our study suggested the difference in the effect of apoE genotype on developing AD between early-onset and late-onset type in Japanese patients.     

Increased acetylcholinesterase activity in the CSF of Alzheimer patients carrying apolipoprotein epsilon4 allele

We measured CSF acetylcholinesterase (AChE) activity in 57 Alzheimer's disease (AD) patients with different apolipoprotein E (apoE) genotypes at the early stage of the disease, and in 11 non-demented controls. The AChE activities of the whole AD group did not differ from those of controls. However, analysis of variance over the AD subgroups with two, one or no epsilon4 alleles and controls showed significant differences (p < 0.0001); the AD patients with two epsilon4 alleles had higher AChE activities than controls and AD patients with one or no epsilon4 and also the AD patients carrying one epsilon4 allele had higher AChE activities than the AD patients without the epsilon4 allele. The study suggests that cholinergic metabolism is altered in proportion to the number of apoE epsilon4 alleles. The different degree of AChE activity in relation to the number of epsilon4 alleles might have an impact on AD patients' responses to cholinesterase inhibitors.     

Costs of cancer research: financial and personal

INTRODUCTION: The HLA-A2 allele has recently been considered as a risk factor in AD by advancing the age at onset of the disease, especially in subjects who were homozygous for the apoE epsilon4 allele. MATERIAL AND METHODS: We examined the distribution of apoE genotypes and A2 allele as a function of age at onset in 109 patients with sporadic and familial AD. RESULTS: In the early onset (< or =60 years) and late onset (>75 years) AD groups, there was, respectively, a 2.2 year and a 2.7 year earlier onset in the A2 positive cases. Age effect was not apparent in the middle onset (61-75 years) AD group. The effect of A2 allele on the age at onset was not different between familial and sporadic AD cases. The presence or absence of the A2 allele did not modify mean age at onset in the groups homozygous and heterozygous for epsilon4, and in cases with no epsilon4 alleles. CONCLUSION: Though the sample size was small, there is a trend in favor of an A2 effect on age at onset. Additionally, there is no evidence of interaction between A2 and apoE epsilon4 alleles on age at onset of AD.     

Effect of a chronic high-salt diet on whole-body and organ sodium contents of Dahl rats

A prior history of depression and the epsilon 4 allele of apolipoprotein E (APOE) have each been associated with development of Alzheimer's disease (AD). In a sample of 142 elderly twins from a large study of dementia, we examined the relation of major depression, APOE genotype and AD using time-dependent proportional hazards models. Compared against the risk for AD with no history of depression and no epsilon 4 allele, the risk ratio for AD with two epsilon 4 alleles was 2.87 (C.I. = 1.56-5.28), with one epsilon 4 allele, 1.82 (C.I. = 1.09-3.04) and with late-onset depression and no epsilon 4 allele, 2.95 (C.I. = 1.55-5.62). There was no suggestion of an interaction between prior depression and APOE genotype in their effects on AD risk. Results were similar when the sample was stratified by twin pair, so that a single genetic marker is unlikely to explain the relation among depression, APOE, and dementia. Risk ratios declined substantially with increasing intervals between the onset of depression and AD. Thus, for many individuals, the association of depression and AD may reflect the occurrence of prodromal depressive symptoms rather than a true risk relationship.     

Laparoscopic management of a noncommunicating uterine horn in a patient with an acute abdomen

INTRODUCTION: The presence of the apolipoprotein E4 allele (apoE4) has been recognized as a risk factor for the development of presenile and senile forms of Alzheimer's dementia (AD). MATERIAL AND METHODS: The apoE alleles frequency of 71 normal controls (NC), 60 demented controls (DC) and 50 senile type AD subjects was determined by polymerase chain reaction in order to get data about the apoE polymorphism of the Hungarian AD population. RESULTS: The apoE3/3 genotype was the most common in all groups. The apoE4 frequency was significantly higher (28%) in the AD group than that was (7% and 9%) in the NC and DC populations, respectively. No apoE4 homozygotes were found in the DC group and the number of heterozygotes was lower in the DC than in the AD group. CONCLUSION: The results are in good agreement with others in the literature and support the occurrence of an increased apoE4 allele frequency in Hungarian senile AD population.     

Alzheimer's disease: interaction of apolipoprotein E genotype, family history of dementia, gender, education, ethnicity, and age of onset

We evaluated 197 patients with predominantly late-onset Alzheimer's disease (AD) who belonged to several ethnic groups and analyzed the relationship of age of onset of AD to the presence or absence of several risk factors in this entire group of patients. The apolipoprotein E (apoE) epsilon 4 allele frequency, which was 29% in all patients (compared with the reported population mean of 13.7%, p < 0.001, did not vary significantly between ethnic groups but declined significantly with increasing age. The apoE epsilon 2 allele frequency was 3%, compared with the reported population mean of 7.4% (p = 0.001). The frequency of a positive family history of dementia in first-degree relatives (FH +) (overall 45%) did not vary significantly between ethnic groups. ApoE epsilon 4-positive (epsilon 4+) patients tended to have a higher FH + rate (58%) than apoE epsilon 4-negative (epsilon 4-) patients (40%) (p = 0.02). When the potential risk factors of gender, education, FH+ status, and epsilon 4+ status were examined together in a multiple linear-regression analysis, FH+ and epsilon 4+ status (but not gender or education) were significant (they were both associated with an earlier age of onset of AD). In a post-hoc analysis, we found a reduced age of onset in women, but not men, who were both FH + and epsilon 4+. Additionally, those probands who were epsilon 4+ were more likely to inherit the disease from their mothers than their fathers. The mechanism by which epsilon 4+ and FH+ status operate as risk factors may be by their effect on the age of onset of AD.     

Catalytic properties of the purified rat hepatic cytosolic cholesteryl ester hydrolase

Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease. In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (> or = 65 years), familial late-onset (FLO) (> or = 65 years), sporadic early-onset (SEO) (<65 years), and familial early-onset (FEO) (<65 years) patients and into three subgroups according to their ApoE genotype zero epsilon4, one epsilon4, and two epsilon4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon4++ allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon4 alleles had earlier age at onset of dementia than those with no epsilon4 allele (63 +/- 9 versus 68 +/- 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon4 allele in the delayed list learning (p<0.05) and from those with zero epsilon4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon4 allele.     

ApoE allele frequencies in Italian sporadic and familial Alzheimer's disease

Recent studies have provided evidence of association of apolipoprotein E (ApoE) epsilon 4 allele and late onset familial and sporadic Alzheimer's disease (AD). Epidemiological studies have established allelic variation at the ApoE locus. We have analyzed the ApoE gene polymorphism in a sample of 446 Italian subjects. Our data confirm a significant association between epsilon 4 allele and sporadic AD. The frequency of epsilon 4 allele in early onset familial AD patients was comparable to control values suggesting that epsilon 4 allele does not represent a risk factor for early onset familial AD (EOFAD). Moreover, we found a not previously reported association between ApoE epsilon 2 allele and sporadic AD and EOFAD.     

Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM Study

Human apolipoprotein (apo) E, a polymorphic protein with three common alleles, epsilon 2, epsilon 3, and epsilon 4, plays an important role in lipoprotein metabolism. This article describes the association of this polymorphism with lipids, apolipoproteins, and lipoproteins with a particular regard to lipoprotein particles, as defined by their apolipoprotein content, as well as the risk of myocardial infarction in a multicenter population-based case-control study (ECTIM study). In the ECTIM study, 574 male patients aged 25 to 64 were examined 3 to 9 months after myocardial infarction in four regions participating in the World Health Organization MONICA project: Belfast (Northern Ireland) and Lille, Strasbourg, and Toulouse (France). Control subjects (n = 722) were randomly selected from the regional populations. The distribution of apoE phenotypes was significantly different across the four control samples (P = .04), with a higher frequency of the epsilon 4 allele in Belfast (14.3%) than in Toulouse (8.2%). The association of apoE polymorphism with biological measurements was studied in the control groups (n = 640) after men with coronary heart disease or those taking hypolipidemic drugs were omitted, with the apoE3/3 phenotype as a reference after adjustment for concomitant factors. Individuals carrying the epsilon 2 allele had lower levels of plasma cholesterol, low-density lipoprotein cholesterol (LDL-C), and apoB and higher levels of triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), apoC-III, apoE, lipoprotein (Lp) C-III:B, and Lp E:B. However, the effect of the epsilon 2 allele on triglyceride, VLDL-C, apoE, and Lp E:B parameters was heterogeneous across the populations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females

Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with APOE epsilon2 and epsilon3, APOE epsilon4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE epsilon4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE epsilon4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE epsilon4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.     

Effects of apoE gene polymorphism on Lp(a) concentrations depend on the size of apo(a): a study of 466 white men

Polymorphisms in the genes for the low-density lipoprotein (LDL) receptor ligands, apolipoprotein E (apoE), and apolipoprotein B (apoB) are associated with variation in plasma levels of LDL cholesterol. Lp(a) lipoprotein(a) [Lp(a)] is LDL in which apoB is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined isoforms differing in molecular weight, which are inversely correlated with Lp(a) concentrations in blood. The interaction of apo(a) with triglyceride-rich lipoproteins differs with the size of apo(a), and therefore the effects of apoE gene polymorphism on Lp(a) levels could also depend on apo(a) size. We have investigated the possible effect of genetic variation in the apoE and apoB genes on plasma Lp(a) concentrations in 466 white men with different apo(a) phenotypes. Overall there was no significant association between the common apoE polymorphism and Lp(a), but in the subgroup with apo(a)-S4, concentrations of Lp(a) differed significantly among the apoE genotypes (P = 0.05). Lp(a) was highest in the apoE genotypes epsilon 2 epsilon 3 and epsilon 3 epsilon 3 and lowest in genotype epsilon 3 epsilon 4, and the apoE polymorphism was estimated to account for about 2.4% of the variation in Lp(a). In contrast, in the subgroup with apo(a)-S2 Lp(a) was significantly lower (P = 0.04) in apoE genotype epsilon 2 epsilon 3 than in genotype epsilon 3 epsilon 3. Lp(a) concentrations did not differ among the XbaI (P = 0.65) or SP 24/27 (P = 0.26) polymorphisms of the apoB gene. The expected effects of both apoE and apoB polymorphism on LDL levels were significant in the whole population sample and in subjects with large-sized apo(a) isoforms (P < 0.01), whereas no effect was seen in those with low molecular weight apo(a) isoforms. We conclude that the influence of apoE genotypes on Lp(a) concentrations depends on the size of the apo(a) molecule in Lp(a), possibly because both apo(a)-S4 and apoE4 have high affinity for triglyceride-rich lipoproteins and may be taken up and degraded rapidly by remnant receptors.     

Increasing cerebrospinal fluid tau levels in a subgroup of Alzheimer patients with apolipoprotein E allele epsilon 4 during 14 months follow-up

The concentration of tau protein is elevated in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD), suggesting that CSF tau may be a useful biochemical diagnostic marker for this disorder. We investigated CSF tau concentrations on two occasions in AD (n = 18), mild cognitive impairment (MCI, n = 9) and other dementing disease (OD, n = 9) by ELISA (Innotest hTau Antigen, Innogenetics, Belgium). Tau levels were statistically significant higher in the AD group than in MCI and OD groups on both occasions. Twelve of the AD patients showed increasing values of tau at follow-up and six demonstrated diminished values. All AD patients with increasing tau were carriers of one or two epsilon 4 alleles of the apolipoprotein E (APOE, gene. Of those AD cases with decreasing tau levels only three individuals had the epsilon 4 allele, a difference that was statistically significant (P < 0.05). These findings suggest that there may be apolipoprotein E (apoE) isoform-specific differences of tau regulation in AD.     

Molecular genetics of Alzheimer's disease--presenilin and other genes

We examined mutations of presenilin 1 (PS1), presenilin 2 (PS2) and amyloid precursor protein (APP) in 30 Japanese familial Alzheimer's disease (FAD) and 34 isolated cases of Alzheimer's disease (AD). We found mutations of PS1 in 17% of early onset FAD (H163R, H163R, R269H, E273A, G384A) and in a case (H163R) of isolated AD. The remaining cases were free from mutations in PS1, PS2 and APP. Since only a part of them could he explained by ApoE epsilon 4, we concluded that important genes are missing. We also examined association of apolipoprotein E (ApoE)epsilon 4, allele A of alpha 1-antichymotrypsin (ACT), 5 repeat allele of very low density lipoprotein receptor (VLDLR) and Alzheimer's disease. We confirmed that ApoE espilon 4 is significantly more frequent in both FAD and isolated AD cases than controls. We could not see any significant association in the ACT polymorphism. The 5 repeat allele of VLDLR was slightly but significantly more frequent in AD cases than controls. However, association with ApoE epsilon 4 was not seen in our study.     

No association between the low density lipoprotein receptor-related protein (LRP) gene and late-onset Alzheimer's disease in a community-based sample

It is now commonly known that possession of the epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for both familial and sporadic Alzheimer's disease (AD), in a dose-dependent way. Other genes that may play a role in AD, either through independent association with the disease or through modification of the existing APOE risk, have been reported with conflicting results. One such gene, the low density lipoprotein receptor-related protein (LRP) gene, was recently reported by two groups to be associated with AD, although the groups identified different risk-conferring alleles. Both studies were based on clinic-derived AD populations (one American, one French), and both reported only marginally significant results. We have genotyped a community-based AD and control population at this LRP polymorphism and find no association between the variants at that polymorphism and the occurrence of AD. Further, despite the biochemical relationship between LRP and the ApoE protein, we find no significant statistical interaction between the alleles at these loci.     

The plasma levels of endothelin in diabetic retinopathy and their changes after treatment with doxium

Apolipoprotein E (APOE) has been identified as a major susceptibility marker for Alzheimer's disease (AD) and it has been proposed that a common polymorphism in the alpha1-antichymotrypsin (ACT) gene increases the risk of developing AD, when the combination of ACT/AA genotype and APOE epsilon4 allele segregate together. The ACT polymorphism was analysed in 218 sporadic late-onset AD patients and 101 healthy control subjects from Eastern Finland. Samples of the ACT polymorphism were divided into three subgroups according to their APOE genotypes and the genotyping of samples was done using the polymerase chain reaction (PCR) method. Any association between the AD group and the controls was tested with the chi2 test. Our data failed to detect any effect of polymorphism in the ACT genotypes associated with the APOE alleles, suggesting that in this population ACT does not increase the risk of AD.     

Development of cervical fat pads following therapy with human immunodeficiency virus type 1 protease inhibitors

Several lines of evidence have suggested a possible involvement of neurotrophic factors in the pathogenesis of neurodegenerative disease. We examined whether a missense mutation (Gly[-63]Glu) of the neurotrophin-3 (NT-3) gene is associated with Alzheimer's disease (AD) in a Japanese sample of 123 patients and 215 controls. We found that homozygotes or heterozygotes for the mutated type (Glu[-63]) were significantly more common among the patients than the controls (P = 0.013, odds ratio 1.77, 95% CI 1.12-2.79). The mutated type was more frequent among the patients than the controls (P = 0.011, odds ratio 1.63, 95%CI 1.11-2.38). This association between NT-3 and AD was more prominent among those who did not carry the epsilon4 allele of the apolipoprotein E gene than those who carried the epsilon4 allele. Our results suggest that the Glu(-63) allele of the NT-3 gene by itself or another mutation nearby which would be in linkage disequilibrium to the mutation is a risk factor for AD.     

Association between apolipoprotein E epsilon4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia

OBJECTIVE: To determine whether the apolipoprotein E epsilon4 allele (apoE epsilon4) is associated with cognitive decline in individuals with and without dementia, we conducted a 4-year longitudinal study of subjects with a range of cognitive function. SETTING: At baseline, respondents (n=511) were randomly selected according to age and Mini-Mental State Examination score from a community-based study of dementia among noninstitutionalized persons aged 65 to 84 years. Respondents were examined at baseline and followed up in 3 annual visits. At baseline, subjects were classified as having normal cognitive function, minimal dementia, or dementia, according to criteria from the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) and the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Of the 511 respondents at baseline, 405 who were examined at least 2 times are included in this analysis. MAIN OUTCOME MEASURES: Cognitive decline was determined by a slope estimating yearly change in score on the neuropsychological test, the CAMCOG (the cognitive section of the CAMDEX), and its sub-scales of memory and nonmemory functions. RESULTS: Among the subjects who had normal cognitive function at baseline, apoE epsilon4 carriers showed a significantly greater decline (P<.001) in score on the CAMCOG compared with noncarriers. Differences in decline on the memory and nonmemory subtests were also significant (P<.001). Rates of cognitive decline were not related to apoE epsilon4 status in the groups with minimal dementia and dementia. CONCLUSIONS: In our community-based sample, apoE epsilon4 was associated with the rate of cognitive decline prior to the clinically symptomatic phase of dementia. Knowing the apoE epsilon4 status of those already symptomatic for dementia may not improve knowledge about a patient's prognosis.     

Distortion of allelic expression of apolipoprotein E in Alzheimer's disease

The APOE epsilon4 allele is a strong genetic susceptibility factor for Alzheimer's disease. Interaction with other biological factors may modulate the effect of the apoE isoforms. However, previous work suggested that other genetic variability within the APOE locus, influencing the effect of the epsilon4 allele, may exist. Such variability could modify the expression of the APOE gene and, in particular, the level of expression of APOE alleles could be an important determinant of disease pathogenesis. To test this hypothesis we examined the levels of expression of APOE in heterozygotes with AD and in controls, using a new method of semi-quantitation. We report that relative epsilon4 mRNA expression is increased in AD compared with controls and suggest that genetic variability in the neural expression of APOE contributes to disease risk.     

Absence of an apolipoprotein E epsilon4 allele is associated with increased parietal regional cerebral blood flow asymmetry in Alzheimer disease

BACKGROUND: The apolipoprotein E (Apo E) epsilon4 allele has been associated with parietal metabolic abnormalities and asymmetries in asymptomatic subjects at risk for Alzheimer disease (AD). However, previous research has shown minimal effect of the epsilon4 allele on regional cerebral blood flow (rCBF) and metabolism in patients with probable AD. OBJECTIVE: To determine whether the Apo E epsilon4 allele is associated with parietal rCBF abnormalities and asymmetries in patients with probable AD. PATIENTS AND METHODS: Thirty patients with AD with the epsilon4 allele (epsilon4+ AD), 22 patients with AD without the epsilon4 allele (epsilon4- AD), and 14 healthy control subjects underwent single-photon emission computed tomography (SPECT) scanning with 740 MBq technetium Tc 99m hexamethylpropyleneamine oxime. Ratios of parietal-unaffected regions and a left-right parietal asymmetry index were compared between both patient groups. RESULTS: The group with epsilon4- AD was younger (P = .005, Student t test) and had an earlier age of onset (P = .005) than the group with epsilon4+ AD. Analysis of covariance revealed no significant difference in the parietal rCBF ratio, controlling for age of onset and Mini-Mental State Examination score (F(1,48) = 0.06; P = .81). However, contrary to hypothesis, significantly greater parietal rCBF asymmetry was seen in patients with epsilon4- AD (mean +/- SD, 9.7% +/- 5.5%) than those with epsilon4+ AD (6.3% +/- 4.7%; F(1,50) = 5.89; P = .02; analysis of variance). When number of epsilon4 allele copies was considered, this effect appeared to accrue primarily from a difference between patients with 0 and with 2 epsilon4 allele copies. An exploratory analysis of multiple cortical structures suggested that this asymmetry extended to additional regions (superior temporal) and to combined association cortex. CONCLUSIONS: Greater parietal rCBF asymmetry is involved in epsilon4- AD than in epsilon4+ AD. Lack of the epsilon4 allele may be associated with other (as yet undiscovered) genetic or environmental risk factors, which confer greater neuropathological asymmetry.     

Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium

OBJECTIVE: To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. DATA SOURCES: Forty research teams contributed data on APOE genotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. MAIN OUTCOME MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon4, and epsilon4/epsilon4 relative to the epsilon3/epsilon3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. RESULTS: Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8). The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). The APOE epsilon4-AD association in Japanese subjects was stronger than in Caucasian subjects (epsilon3/epsilon4: OR=5.6, 95% CI=3.9-8.0; epsilon4/epsilon4: OR=33.1, 95% CI=13.6-80.5). The epsilon2/epsilon3 genotype appears equally protective across ethnic groups. We also found that among Caucasians, APOE genotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that the APOE epsilon4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex. CONCLUSIONS: The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE epsilon4 and AD in African Americans requires clarification, and the attenuated effect of APOE epsilon4 in Hispanics should be investigated further.