liveonearth (liveonearth) wrote,

ApoE genotype effects on CV Dz, Alzheimer's, Immune sys

not widely used
clinical usefulness is still being researched
test only done by reference labs

gene on xsome 19
a class of apolipoprotein found in the chylomicron and IDLs
binds specific receptor on liver and peripheral cells
ApoE is target gene of the liver X receptor
liver X receptor is a nuclear receptor that affects metab of chol, fatty acids, glucose homeostasis

pivotal role of ApoE in AD first identified by Margaret Pericak-Vance
Roses lab at Duke University

essential for the normal catabolism of triglyceride-rich lipoprotein constituents
7 currently ID'd mammalian receptors for APOE
receptors in the evolutionarily conserved low density lipoprotein receptor gene family
relevant for concerns of: CVD, Alzheimer's disease, immunoregulation, cognition

ApoE is polymorphic with three major isoforms, ApoE2, ApoE3, ApoE4
allelic forms differ other only by amino acid substits at positions 112 and 158

E3 allele is Cys-112 and Arg-158
E3 found in ~63% of pop

E2 allele has a Cys at positions 112 and 158 in the receptor-binding region of ApoE
associated with the genetic disorder hyperlipoproteinemia type III
assoc with both increased and decreased risk for atherosclerosis
homozygous E2 may clear dietary fat slowly, have more early vascular disease and type III hyperlipoproteinemia
94.4% of patients with type III hyperlipoproteinemia are E2/E2
only ∼2% of E2/E2 develop type III hyperlipoproteinemia

ApoE E4 allele is Arg at both positions
implicated in atherosclerosis, Alz dz, impaired cognitive fx, and reduced neurite outgrowth (???)

4,4 most risk of AD, more risk of atherosclerosis
3,4 some risk of AD
3,3 normal risk of AD and normal lipid metabolism
2,4 normal risk of AD
2,3 less risk of AD
2,2 more risk of premature vascular dz

used to evaluate risk of CVD
often used in combination with other lipid tests ie chol, lipoprots
mb used to dx type III hyperlipoproteinemia (xanthomas)
mb used to guide lipid tX

known adverse effect of statin drug therapy
statin therapy-->cholesterol depletion-->ApoE def-->myelin depletion-->neuron failure
statins often used when chol and TGs are high
wide variability in response to statins mbdt apo E genotype
ApoE e4 pts are responsive to a low fat diet but statins may not decr LDL-C levels
ApoE e2 pts more have LDLs more responsive to statins??

used to predict probable late onset Alzheimer’s disease (AD) in symptomatic adults
called susceptibility or risk factor testing
ApoE4 is the one at highest risk
other indicators of alz risk: Tau/Aß42 testing
also to assess type of ongoing progressive dementia
first rule out overmedication, vascular dementia (strokes), thyroid disease
E4 variant is largest known genetic risk factor for early-onset Alzheimer's Disease
Caucasian and Japanese carriers of 2 E4s have 10-30x the risk of developing AD by 75 years of age
(relative to no E4 genes)
MOA unknown but appears to relate to beta-amyloid
Apolipoprotein E enhances proteolytic break-down beta-amyloid (intra and extracellular)
E4 is least efficient at this catalysis-->vulnerability to Alzheimer's

40-65% of AD patients have at least one copy of the 4 allele
~60% of those with late onset AD will have ApoE e4 alleles
at least 1/3 of pts with AD are ApoE4 negative
some ApoE4 homozygotes never develop the disease
two e4 allele-->max 20x risk of AD

new study published May 2010 in Proceedings of the National Academy of Sciences United States of America
genotype may influence expression of the disease even when mild
may account for variations in cognitive decline
n=67 APOE ε4 carriers and 24 noncarriers with mild AD
Dxd via sx and CSF profile consistent with pathological AD
E4 carriers:
sig greater impairment of memory retention
E4 greater medial temporal lobe atrophy
greater impairment on tests of working memory, executive control, and word retrieval
noncarriers had greater frontoparietal atrophy

Genome-Wide Association Study of CSF Biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI Cohort
Kim S, Swaminathan S, Shen L, et al
Neurology. 2011;76:69-79

In recent years, cerebral spinal fluid (CSF) levels of beta amyloid and tau have been used as early diagnostic indicators for the development of Alzheimer disease in the future.[1] Although the impact of candidate genes on such markers has been studied, information about the results of the genome-wide association study (GWAS) is limited.

In this investigation, the effect of single nucleotide polymorphisms (SNPs) were assessed under an additive genetic model on each of 5 CSF biomarkers. After first correcting P values of each SNP for multiple comparisons, the researchers looked at SNPs with corrected P values < .01 to identify candidate SNPs that are associated with CSF biomarkers, and then looked at SNPs with uncorrected P values < 10-5 to identify any additional potential candidates.

The results indicated that 4 SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with 1 or more of the CSF biomarkers, and several others were identified as potential candidates.

immune regulation involvements:
APOE suppresses T cell proliferation
macrophage functioning regulation
lipid antigen presentation facilitation (by CD1) to natural killer T cell
modulation of inflammation and oxidation

Tags: alzheimers, cardiovascular, genetics, statins

  • Post a new comment


    Comments allowed for friends only

    Anonymous comments are disabled in this journal

    default userpic

    Your reply will be screened

    Your IP address will be recorded