Apolipoprotein E in Alzheimer's disease and other neurological disorders (original) (raw)
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Genetika, 2001
Allele epsilon 4 of the apolipoprotein E (APOE) gene is associated with higher risk of Alzheimer's disease (AD) in many, though not all, ethnic groups. The APOE allele and genotype frequency distributions were studied in 207 AD patients without cerebrovascular disorders, 62 AD patients with cerebrovascular disorders (combined AD), and 206 control individuals (ethnic Russians from the Russian population). The frequency of allele epsilon 4 in patients with early-onset and late-onset AD was three times higher than in control individuals (p < 0.000001). Compared with control people, patients with cerebrovascular disorders displayed a twofold higher frequency of allele epsilon 4; the difference between the two groups was significant (p = 0.0019). Relative risk of AD in carriers of allele epsilon 4 was five times higher than in carriers of alleles epsilon 2 and epsilon 3 (p < 0.000001). Allele epsilon 2 had a protective effect with respect to AD onset until 65 years of age (p = ...
Annals of the New York Academy of Sciences, 1996
Strittmatter er al. ' reported in 1993 that the APOE €4 allele was associated with an increased risk for developing Alzheimer's disease (AD) in a set of families who appear to have late-onset familial AD. Several groups, including our own, rapidly demonstrated that the overrepresentation of APOE €4 applied to sporadic AD as Given that inheritance of APOE €4 is a risk factor for AD, our goal was to address two important questions: (1) Are there differences in the clinical course or the pathology of the disease if a patient has inherited APOE ~4 ?
Apolipoprotein E and Alzheimer disease: an update on genetic and functional analyses
Journal of neuropathology and experimental neurology, 2000
Exceptional advances have been made in understanding the genetics of how common polymorphisms of the apolipoprotein E gene influence the risk and age of onset of Alzheimer disease (AD). The major genetic susceptibility locus for the common forms of AD, there are 3 common alleles, designated epsilon2, epsilon3, and epsilon4. The inheritance of each dose of APOE4 increases the risk of disease and decreases the age of onset; conversely, the APOE2 allele appears to be protective, by lowering the risk of disease and increasing the age of onset. Testing for the APOE4 allele can be a clinically useful tool in the early diagnosis of cognitively impaired patients suspected of having AD. The APOE4 allele also negatively influences functional recovery following a variety of brain insults. What remains in the study of apolipoprotein E is an explanation of how minor changes in a protein can produce such striking differences in risk and age of onset. In vitro and animal model studies strongly sug...
Apolipoprotein E gene promoter polymorphisms in Alzheimer's disease
Microscopy Research and Technique, 2000
Alzheimer's disease, the most frequent form of senile dementia, presents in the vast majority of cases as a multifactorial trait, where a series of genetic and environmental risk factors converge. The increasing body of data, both epidemiological and functional, is strengthening the evidence that apolipoprotein E (APOE, gene; apoE, protein) is a true susceptibility factor for the onset of the common form of Alzheimer's disease. The E4 isoform of apoE remains to date as the main genetic risk factor for the disease, although the mechanisms responsible for this association are not well understood. It is also clear that apoE4 is not necessary or sufficient to cause the disease, indicating that other risk and protecting factors exist. ApoE is upregulated in response to nervous system injury, suggesting that it could have a neuroprotective role; on the other hand, there is evidence indicating that apoE is neurotoxic when present at high levels. Thus, apoE levels seem to be relevant for the functionality of the protein. The APOE proximal promoter hosts numerous regulatory elements, raising the possibility that polymorphisms in this region could produce variation in apoE levels by altering APOE transcriptional activity, which could finally result in AD susceptibility. We will review here the current evidence on the relationship between APOE proximal promoter polymorphisms, APOE gene transcriptional activity and apoE protein levels, and risk for AD.
Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
Journal of Neuroscience, 2008
Inheritance of the apoE4 allele (4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of 4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of 2/2, 3/3, and 4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; 2/2 Ͼ3/3 Ͼ4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the 3/4 mouse brains. ApoE4 represented 30 -40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between 3/3 and 3/4 mice, implying that the reduced levels of total apoE in 3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from 3/4 human astrocytoma or 3/3, 4/4 and 3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from 4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by 4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or A clearance.
Nature Communications
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, while the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with a low Alzheimer’s dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of the disease.
The influence of Apolipoprotein E genotype on regional pathology in Alzheimer’s disease
BMC Neurology, 2013
Background: Carriers of the ApoE ε4 allele are at a greater risk for developing Alzheimer's disease (AD) and those who do develop AD tend to have a much greater neuropathological disease burden. Although several studies have shown significant differences in AD pathology among ε4 carriers and non-carriers, few have characterized these differences in terms of brain region and neuropathological score frequency. Methods: 566 pathologically-confirmed AD cases who were followed prospectively with antemortem dementia diagnoses (312 ApoE ε4 carriers and 254 ApoE ε4 non-carriers) were compared on the frequencies of neuropathological frequency scores (none, sparse, moderate, frequent) among several different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal) using the CERAD scoring system. Pathology score frequencies were analyzed by carrier status (ε4 carrier vs. ε4 non-carrier) and by genotype (2/3, 3/3, 2/4, 3/4, 4/4). Both analyses investigated pathology score frequencies among different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal). Results: ε4 carriers had a significantly lower age at death (p <0.001) and significantly higher Braak scores (p <0.001) than ε4 non-carriers. Genotype comparison revealed that plaque and tangle pathologies increased in the following pattern, 2/3<3/3<2/4<3/4<4/4, for several brain regions. When stratified by age and ApoE ε4 carrier status, ε4 carriers tended to have significantly more frequent scores across most cortical areas. However, non-carriers age 90 and older tended to have greater plaque pathology than carriers. For tangle pathology, ε4 carriers tended to have significantly more "frequent" scores than non-carriers, except for the hippocampal and entorhinal areas in individuals age 90 and older. Conclusions: ApoE ε4 carriers had a significantly higher percentage of "frequent" scores for plaques and tangles when compared to ApoE ε4 non-carriers for several brain regions. However, ε4 non-carriers age 90 and older tended to have less plaque and tangle pathology in certain brain regions. These results demonstrate that AD pathology may manifest itself differently based on ApoE genotype and suggest that ApoE carriers and non-carriers may have different patterns of AD neuropathology location and density.
Neuroscience Letters, 1999
Using a combination of polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing techniques, we identified a unique missence mutation (T → C) in exon 3 of the APOE gene which resulted in the substitution of pro-28 for leu-28. We screened 1118 White cases of late-onset (Ͼ60 years) Alzheimer's disease (AD) from three independent centers (Pittsburgh = 489, Indiana = 319, Mayo Clinic Rochester = 310) and 1123 controls (607 clinically assessed and 516 individuals randomly ascertained from the general population). Two of the 1123 control subjects had the pro-28 mutation (0.18%). However, this mutation was observed in heterozygous state in 2.66, 2.51 and 1.94% of the AD cases from Pittsburgh, Indiana and Mayo Clinic Rochester, respectively, with an overall frequency of 2.42%. All individuals with this mutation were carriers of the APOE*4 allele and hence the mutation was denoted as APOE*4 Pittsburgh (APOE*4P). Compared with the non-E*4P carriers, the E*4P carriers were associated with an increased risk of AD (odds ratio (OR) 13.2) and this risk remained significant even after adjusting for the known effect of APOE*4 (OR 5.4). The risk associated with the E*4P/E*4 combination was about five times (OR 29.1) the risk attributed to APOE*4 carriers alone (OR 5.7). Our data indicates that the new mutation most likely exists in cis-orientation with APOE*4 and is associated with increased risk of developing AD.
APOE and Alzheimer disease: a major gene with semi-dominant inheritance
Molecular Psychiatry, 2011
Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.