APOE epsilon 3/ epsilon 4 heterozygotes have an elevated proportion of apolipoprotein E4 in cerebrospinal fluid relative to plasma,independent of Alzheimer's disease diagnosis

Inheritance of the apolipoprotein E (APOE) epsilon 4 allele is associated with an increased risk of Alzheimer's disease (AD). However, the risk of AD in APOE epsilon 3/ epsilon 4 heterozygotes is variable. We tested the hypothesis that the risk of AD in APOE epsilon 3/ epsilon 4 heterozygotes was linked to the relative levels of expression of apoE4 versus apoE3 protein. We measured the apoE4 isoform and total apoE using two specific enzyme-linked immunosorbent assay (ELISA) kits in three cohorts of plasma samples and two cohorts of cerebrospinal fluid samples from AD, mild cognitive impairment, and control subjects. The apoE4 ELISAs were specific as they did not detect apoE in APOE epsilon 3/epsilon 3 homozygotes and were comparable to the total apoE ELISAs in APOE epsilon 4/ epsilon 4 homozygotes. In APOE epsilon 3/ epsilon 4 individuals, the ratio of apoE4 to total apoE levels was 30-40% in plasma, suggesting a decreased production or an increased metabolism of apoE4 compared to apoE3. Surprisingly, the ratio in the CSF was reversed, with apoE4 accounting for 60-70% of the total apoE. The proportion of apoE4 in these cases did not vary by diagnosis, age of onset, or duration of AD. We conclude that the proportion of apoE4 in plasma is not predictive of AD risk in APOE epsilon 3/epsilon 4 individuals. However, the greater proportion of apoE4 in the cerebrospinal fluid suggests differential production or metabolism of the protein in the central nervous system (CNS), with the apoE4 isoform dominating.     

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 C-I Expression in the Brain in Alzheimer's Disease

The H2 allele of apolipoprotein (apo) C-I is associated with Alzheimer's disease (AD). However, this association is potentially confounded by the linkage disequilibrium of H2 with the epsilon2 and epsilon4 alleles of apoE and of H1 with the epsilon3 allele. To establish plausibility for a direct role for apoC-I in AD, we compared apoC-I and apoE protein and mRNA levels in postmortem specimens of frontal cortex and hippocampus from AD patients with levels in nondemented controls. In H2-allelic individuals (usually also epsilon4 carriers), apoC-I mRNA levels were strikingly lower with AD (by 65%, P < 0.05), but apoC-I protein levels in AD were significantly higher (by 34%, P < 0.05). The opposite direction of the apoC-I mRNA and apoC-I protein level changes in AD in the epsilon4/H2 genotype may reflect decreased clearance of CNS lipoproteins associated with apoE4. In H1/H1 (usually epsilon3/epsilon3) individuals, both apoC-I protein and mRNA were lower in AD. ApoC-I protein levels in hippocampus were nearly twice those in frontal cortex. Immunohistochemistry of hippocampus revealed colocalization of apoC-I protein with the astrocytic marker GFAP. In addition, cultured human astrocytes expressed the mRNA for apoC-I. This study confirms apoC-I expression in the CNS and identifies astrocytes as the source of apoC-I. In addition, it has revealed differences in apoC-I expression based on site, genotype, and disease status that may reflect a role for apoC-I in the pathogenesis of AD.     

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.     

Cognitive asymmetries associated with apolipoprotein E genotype in patients with Alzheimer's disease.

The relationship between apolipoprotein E (apoE) genotype and cognitive performance was examined in 200 patients with probable Alzheimer's disease (AD). Differences between composite measures of verbal and nonverbal functioning were used to define asymmetric patterns of cognition. Patients who were homozygous for apoE epsilon4 demonstrated relatively worse nonverbal as compared to verbal cognitive ability. In contrast, participants who were heterozygous for apoE epsilon4 or who possessed no epsilon4 allele demonstrated relatively equivalent verbal and nonverbal cognitive abilities. Although age and dementia severity also contributed to these patterns, apoE genotype appears to have a significant unique contribution to cognitive performance in these individuals. The epsilon4 allele may thus be associated with a specific neurocognitive phenotype among patients with AD, with the overall pattern of cognitive asymmetry dependent upon epsilon4 dose.     

Multiple SNPs within and surrounding the apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels

The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21-87 years of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE epsilon4 and correlation between SNPs (linkage disequilibrium). APOE epsilon4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.     

Modulation of apolipoprotein D and apolipoprotein E expression in rat hippocampus after entorhinal cortex lesion.

Apolipoprotein (apo) D is a member of the lipocalin family of proteins. Although its physiological function is unknown, apoD is thought to transport one or more small hydrophobic ligands. A second apolipoprotein, apoE is known to play an important role in lipid transport, and apoE genetic polymorphism has been shown to be associated with susceptibility to Alzheimer's disease. Both apoD and apoE are expressed in the central nervous system (CNS) and both proteins accumulate at sites of peripheral nerve injury due to increased local synthesis. The two proteins may have overlapping or complementary functions within nervous tissue. In order to define the role of apoD within the CNS, we have studied the regional distribution of apoD and apoE mRNA and protein within the normal rat brain and the changes in apoD and apoE expression in the hippocampus of rats after entorhinal cortex lesion (EC lesion). Within the brains of normal rats, apoD expression in the hippocampus was as high as 180-fold that of the liver. ApoD mRNA levels in other areas of the rat brain ranged from 40 to 120 times the hepatic levels. The distribution of apoE gene expression within the brain was similar to that of apoD, but was much lower than hepatic apoE expression. When rats were subjected to EC lesion, the apoD message increased by 54% at 4 days post lesion (DPL) in the ipsilateral region of hippocampus while apoE mRNA levels (ipsilateral and contralateral) decreased by 43%. At 6 to 8 DPL apoD mRNA in the ipsilateral hippocampus remained elevated (42% above controls) whereas the apoE mRNA levels increased to about 15% above those of controls. At 14 and 31 DPL, both apoD and apoE expression was similar to controls. The increase in immunoreactive apoD in hippocampal extracts was more dramatic. At 1 DPL, immunoreactive apoD levels were already 16-fold higher than those in extracts of non-lesioned animals and, at 31 DPL, levels were still 8-fold higher than those of control animals. Finally, we have demonstrated that the levels of apoD in the brains of apoE-deficient mice are 50-fold those of wildtype control mice. ApoD clearly has an important function within the CNS in both normal and pathological situations.     

Genetic variation in apolipoprotein D and Alzheimer’s disease

Apolipoprotein D (apoD) is a lipoprotein-associated glycoprotein, structurally unrelated to apoE, that transports small hydrophobic ligands including cholesterol and sterols. Levels are increased in the hippocampus and CSF of Alzheimer's disease (AD) patients. We tested whether variation in the APOD gene affects AD risk. Four single nucleotide polymorphisms (SNPs) were investigated (in map order): exon 2, 15T-->C encodes an amino acid substitution Phe-->Ser at codon 15; intron 2, -352G-->A; intron 3, +45C-->T; intron 4, +718C-->T, determined by SNaPshot assay. SNP frequencies for 394 eastern Finnish AD patients were compared with those found for 470 control subjects, dividing subjects also into early-onset AD (EOAD; < or = 65 years) and late-onset AD (LOAD; >65 years) groups. The -352G allele was associated with a significant 3-fold increase in the risk of EOAD (OR: 2.7; 95% CI: 1.1-6.5). The -352G containing haplotypes were more common for EOAD cases (TGCC: 0.48 vs 0.41; TGCT: 0.08 vs 0.01 (p = 0.002). In the Grade-of-membership analysis, APOD genotype frequencies at each SNP site and disease status were used to construct two latent groups: the affected group carried -352 as GG or GA and +45 CC, was often women and enriched in APOE epsilon4. Each method suggested that the -352G allele frequency is higher for EOAD in the eastern Finnish population.     

Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients

One of the major histopathological hallmarks of Alzheimer's disease (AD) is redundant senile plaques mainly composed of beta-amyloid (Abeta) aggregates. Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP (sAPP) and Abeta. We examined the cerebrospinal fluid (CSF) for alpha- and beta-secretase cleaved sAPP (alpha-sAPP and beta-sAPP) in 81 sporadic AD patients, 19 patients with mild cognitive impairment, and 42 healthy controls by using newly developed sandwich enzyme-linked immunosorbent assay methods. We found that neither the level of CSF-alpha-sAPP nor CSF-beta-sAPP differed between sporadic AD patients and healthy controls. These findings further support the conclusion that there is no change in APP expression in sporadic AD. However, the level of CSF-beta-sAPP was significantly increased in patients with mild cognitive impairment compared to controls. We also investigated the relationship between the CSF level of alpha/beta-sAPP and Abeta(42) and the apoE epsilon 4 (apoE4) allele. Significantly lower levels of CSF-alpha-sAPP were found in AD patients possessing one or two apoE4 alleles than in those not possessing the apoE4 allele. Neither the levels of CSF-beta-sAPP nor CSF-Abeta(42) differed when comparing ApoE4 allele-positive with allele-negative individuals.     

Apolipoprotein D in the aging brain and in Alzheimer's dementia

Apolipoprotein D (apoD) levels were examined in the temporal cortex as well as an assessment of the location of apoD positive cells within the brain by immunohistochemical and biochemical methods in young control (YC), aged control (AC), and Alzheimer's demented (AD) probands. Scattered apoD positive astrocytes and oligodendrocytes were found throughout the white matter by immunohistochemistry. ApoD immunoreactivity was also observed in the cerebellar oligodendrocytes of the YC group. There was faint positive apoD staining in scattered cortical astrocytes and a few neurons in the same group. In contrast, some of the AC and all of the AD probands had intense and frequent apoD immunostained cortical astrocytes and pyramidal neurons. The cortical senile plaques and neurofibrillary tangles were apoD immunonegative. No quantitative differences were found between the cortical apoD levels in the AC and AD groups, determined by immunoblotting. ApoD detected in the brain tissue was different in molecular weight (29 kDal) from that seen in CSF or in the serum (32 kDal). Our results indicate apoD is present in the human brain, especially in glial cells, and has increased abundance in the elderly and AD subjects.     

The impact of our genes: consequences of the apolipoprotein E polymorphism in Alzheimer disease and multiple sclerosis

Epidemiological studies provide strong evidence that susceptibility to multiple sclerosis (MS) is in part genetically determined. Likewise the heterogeneity in clinical manifestations, temporal course, severity, and in the pathological processes of MS are probably also influenced by our genes. Apolipoprotein E (apoE) polymorphism has been considered a candidate for impacting on MS because of its numerous functions related to brain tissue and evidence for an association with a variety of cerebral disorders, specifically Alzheimer's disease (AD). The apoE alleles epsilon2, epsilon3, and epsilon4 are known to impact differently on aspects such as neuronal growth and repair, neuroprotection and inflammation. After a review of the strong association of the apoE polymorphism with AD, we review the results on MS. These are far less homogenous but have gained support from morphologic and metabolic measures obtained with magnetic resonance imaging indicating a greater extent of brain destruction with the apoE epsilon4 allele. Evidence for a protective role of the epsilon2 allele in MS is weak. In view of the association with AD it is tempting to speculate that neuropsychologic functioning in MS might be even more strongly related to the apoE polymorphism and especially to the epsilon4 allele than other deficits, but few data on this issue are yet available. While part of the association of the apoE polymorphism with AD is supposed to be caused by apoE-isoform dependent effects on amyloid-beta deposition, no single pathogenetically relevant mechanism has yet been confirmed for MS. In summary we presently may assume only subtle effects of the apoE polymorphism on the course of MS. These effects are probably further modulated by other genes and need further investigation.     

Total serum cholesterol levels and Alzheimer's dementia in patients with Down syndrome

BACKGROUND: The risk for dementia in Alzheimer's disease (DAD) in adults with Down syndrome (DS) is higher than in the general adult population. Hypercholesterolaemia has been reported as a risk factor for DAD in the general population. This study investigated the role of serum cholesterol levels in the onset of DAD in the DS population. METHODS: This study investigated total serum cholesterol levels in 179 DS persons (with and without DAD). The possible association between Apolipoprotein E and amyloid beta1-40 and beta1-42 levels was also investigated. RESULTS: No statistically significant association was found between total serum cholesterol levels and dementia in AD or with amyloid beta levels. However for DS adults with an apoE epsilon4 allele significantly higher serum cholesterol levels were found. CONCLUSION: Hypercholesterolaemia is not a risk factor for DAD in persons with DS. However, DS persons with an apoE epsilon4 allele are susceptible to high serum cholesterol. Such individuals should be screened on a regular basis. Copyright (c) 2008 John Wiley & Sons, Ltd.     

Apolipoprotein E epsilon 4, other risk factors, and course of Alzheimer's disease.

BACKGROUND: The epsilon 4 allele of apolipoprotein E (apoE epsilon 4) is associated with late-onset Alzheimer's disease (AD), but its relationship to various aspects of AD has become increasingly unclear. We studied the relationship of apoE genotype in AD to educational attainment, history of heart disease or head injury, age of onset, gender, severity of illness, depression, psychotic symptoms, rate of dementia progression, and time from initial evaluation to nursing home placement. METHODS: ApoE epsilon 4 genotype was determined for 97 clinically diagnosed AD patients and 61 neuropathologically confirmed cases of AD. RESULTS: Presence of one or more epsilon 4 alleles occurred in 66% of AD cases as compared with 27% in control subjects (allele frequency was .40 for AD, .15 for control subjects). Among AD subjects there was no significant relationship between epsilon 4 alleles and educational attainment, history of heart disease, head injury, age of onset, severity of illness, depression, history of depression, rate of dementia progression, or time to nursing home placement. Marginal correlations emerged between number of epsilon 4 alleles, and delusions (p = .05) and hallucinations (p = .05). There was a trend toward increased epsilon 4 homozygosity in patients with onset between ages 65 and 70 years. CONCLUSIONS: We did not find that individuals with one or two apoE epsilon 4 alleles differed significantly in clinical course of AD from those without epsilon 4 except for a trend toward increased psychotic symptoms in the group as a whole and an increase in epsilon 4 homozygosity in patients with reported symptom onset in the late 60s.     

ApoE epsilon4 genotype is accompanied by lower metabolic activity in nucleus basalis of Meynert neurons in Alzheimer patients and controls as indicated by the size of the Golgi apparatus

We previously found apolipoprotein (apoE) epsilon4-dependent lower metabolic activity in nucleus basalis of Meynert (NBM) neurons in Alzheimer disease (AD). In the present study we examined the metabolic activity in the NBM of 39 mentally intact control subjects with different APOE genotype. The control subjects had either no AD pathology (Braak stage 0) or the very beginning of AD pathology (Braak stage I-II). We used the Golgi apparatus (GA) size as a measure of neuronal metabolic activity. Control subjects carrying an apoE epsilon4 allele showed reduced neuronal metabolism; they had significantly more neurons with smaller GA sizes compared to control subjects not carrying an apoE epsilon4 allele. Only control subjects not carrying an apoE epsilon4 allele had increased neuronal metabolism in Braak I-II subjects. They had more neurons with larger GA sizes compared to Braak 0 subjects, which may reflect a compensatory mechanism. Our data indicate that APOE epsilon4 may act by a lower neuronal metabolism as a risk factor for cognitive impairment in normal aging and early prodromal AD. As the disease progresses into later stages of AD (Braak V-VI) neuronal metabolism strongly diminishes, resulting in neurons with extremely small GA sizes, irrespective of APOE genotype.     

Association between apolipoprotein E epsilon4 allele and apathy in probable Alzheimer's disease

OBJECTIVE: There have been inconclusive results to date on the association between the Apolipoprotein E (ApoE) genotype and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). We investigated whether ApoE epsilon4 allele is associated with NPS in probable AD. METHOD: Data for 197 subjects with probable AD were analysed. The Neuropsychiatric Inventory was used to evaluate the frequency and severity of NPS. Multiple logistic regression models were used to test the association between ApoE genotype and NPS in AD. RESULTS: The ApoE epsilon3/3 genotype was present in 52.3%, epsilon3/4 in 44.1%, and epsilon4/4 in 3.6% of patients. ApoE epsilon4 carriers showed a higher frequency of apathy than non-carriers. After multiple adjustments, the ApoE epsilon4 allele was significantly associated with apathy. CONCLUSION: Our results suggest a relationship between the ApoE epsilon4 allele and apathy in patients with AD.     

Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele.

BACKGROUND: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. METHODS: We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. RESULTS: When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p < .01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p < .01). CONCLUSIONS: The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.     

Oxidative insults are associated with apolipoprotein E genotype in Alzheimer's disease brain

The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with sporadic and familial late-onset Alzheimer's disease (AD). Oxidative stress is believed to play an important role in neuronal dysfunction and cell death in AD. We now provide evidence that in the hippocampus of AD, the level of thiobarbituric acid-reactive substances (TBARS) and the APOE genotype are linked. Within AD cases, the levels of TBARS were found to be higher among epsilon4 carriers while the apoE protein concentrations were lower. The relationship between the levels of TBARS and apoE proteins was corroborated by the results from the APOE-deficient mice, in which the levels of TBARS were higher than those in wild-type mice. Among AD cases, tissues from patients with the epsilon4 allele of APOE displayed lower activities of catalase and glutathione peroxidase and lower concentration of glutathione than tissues from patients homozygous for the epsilon3 allele of APOE. Together these data demonstrate that, in AD, the epsilon4 allele of APOE is associated with higher oxidative insults.     

The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer's disease.

BACKGROUND AND OBJECTIVES: Apolipoprotein E (apoE) has been implicated in regenerative processes in the brain after trauma, as well as in the pathogenesis of Alzheimer's disease. Inheritance of a specific apo epsilon allele (apo epsilon 4) determines in part the risk and the mean age at onset of Alzheimer's disease. ApoE has been found to bind isoform specifically to beta-amyloid protein, the major component of senile plaques, and to the microtubule associated protein tau, which forms paired helical filaments and neurofibrillary tangles. The aim was to further examine the relation between apo epsilon alleles, especially apo epsilon 4, and the development of neuropathological changes associated with Alzheimer's disease. METHODS: Brains of patients with Alzheimer's disease (n = 44) and vascular dementia (n = 11) and of age matched controls (n = 29) were studied. Senile plaques and neurofibrillary tangles in the hippocampus and frontal cortex were quantified. RESULTS: No correlation was found between the number of apo epsilon 4 alleles and the number of senile plaques and neurofibrillary tangles in the hippocampus or the frontal cortex of patients with Alzheimer's disease, or vascular dementia, or control groups. No significant differences in duration or severity of dementia were found between patients with or. without the apo epsilon 4 allele. No increased frequency of apo epsilon 4 was found in vascular dementia. CONCLUSION AND COMMENT: Although the apo epsilon genotype clearly affects whether Alzheimer's disease will develop or not, the present study suggests that it has no influence on pathology or clinical intellectual status, once the dementia has manifested itself. No increased apo epsilon 4 allele frequency was found in neuropathologically diagnosed patients with vascular dementia in whom concomitant Alzheimer's disease can be excluded.     

The -491AA polymorphism in the APOE gene is associated with increased plasma apoE levels in Alzheimer's disease

Recent evidence suggests that a polymorphism in the regulatory region of the apolipoprotein E gene (APOE) is associated with an increased risk for developing Alzheimer's disease (AD) independent of that conveyed by the epsilon4 allele of APOE. Previous work by our group indicated that plasma apolipoprotein E (apoE) levels were elevated in AD, raising the possibility that the -491 genotype might modify AD risk by increasing expression of the APOE gene. In a total of 638 individuals the -491AA genotype was significantly associated with AD (P < 0.005) while the TT genotype was associated with controls (P < 0.005). In 138 individuals the AA genotype showed significantly higher plasma apoE levels, independent of epsilon4 and AD status (P < 0.01) as well as within control and AD groups (P < 0.05). Within the AD group the AA genotype showed increased apoE levels when compared to AA controls (P < 0.0001). These results suggest that the -491 AA genotype is associated with increased plasma apoE levels, providing a potential basis for elucidating how that genotype increases the risk for developing AD.