ApoE genotype accounts for the vast majority of AD risk and AD pathology
Section snippets
The risk of AD increases in accordance with apoE genotype such that E4 > E3 > E2
In 1993, a group lead by Alan Roses published a series of papers suggesting that the ε4 allele of the gene encoding apolipoprotein (apo) E has a major association with the risk for Alzheimer’s disease (AD) [8], [46], [47], [50], [54]. In one paper, Corder et al. [8], showed that the Estimated Onset of Distribution is shifted to considerably younger ages in AD cases with ε4/4 genotype (50% by age of onset of 66 y/o), than the ε3/4 (50% by 73 y/o) or the ε3/3 (50% by 86 y/o), and those without an
Relative to apoE2, apoE3, and apoE4 may account for 95% of the risk of AD
In a complimentary paper, Saunders et al. [49], presented clinical data regarding the association of the ε4 allele with AD suggesting that 50% of AD is associated with the ε4 allele. Further, if the relative rarity of the disease among ε2 homozygotes is considered, then the apoE genotype may be seen as being responsible for as much as 95% of AD (Table 1). These findings have been widely replicated (for review, see [3]). However, the relationship between apoE genotype and AD hazard (yearly
ApoE is associated with the pathological hallmarks of AD, i.e. both plaques and tangles
The association of apoE immunoreactivity with amyloid β (Aβ) peptides in extracellular plaques, intracellular neurofibrillary tangles (NFT), and cerebral vessel congophilic angiopathy in brains of AD patients [41] suggests a major role for apoE in the amyloid and neuritic pathology in AD. Indeed, the severity of this pathology is influenced by apoE genotype as illustrated below.
Higher plaque loads in hAPP/E4 than in hAPP/E3 mice
Consistent with the human data described above, apoE has isoform-dependent effects on plaque formation in transgenic mice lacking murine apoE and expressing human amyloid precursor protein with familial AD mutations (hAPP) and human apoE isoforms in astrocytes [24] or neurons [6]. Importantly, these mice express apoE3 and apoE4 at similar levels and were shown to have comparable levels of Aβ1-x (approximation of total Aβ) and Aβ1–42 in the hippocampus [44] at 6 months of age and neocortex at
Differential interaction of apoE isoforms with Aβ peptides in vitro
Overproduction and deposition of Aβ have been suggested to play a central role in AD pathogenesis [18], [51]. In vitro, lipid-free apoE3 and apoE4 can form a sodium dodecyl sulfate (SDS)—and guanidine hydrochloride—stable complex with Aβ peptides, with apoE4 complexes forming more rapidly and effectively [7], [54]. Prolonged incubation (several days) of lipid-free apoE with Aβ peptide results in insoluble, high-molecular-weight complexes that precipitate as fibers. Again, apoE4 forms a denser,
The carboxyl-terminal fragment of apoE may contribute to plaque formation
It was first reported that a carboxyl-terminal fragment (residues 216–299) of apoE (the full-length apoE has 299 amino acids) was co-purified with Aβ from senile plaques [62], [63]. In vitro, this fragment from recombinant apoE could form amyloid-like fibrils, which were Congo-red positive [63]. These results suggest that senile plaques may contain amyloid fibrils formed from both Aβ and the carboxyl-terminal apoE fragment [62], [63]. Thus, the carboxyl-terminal fragment of apoE may contribute
Summary
This review has concentrated on the evidence that supports the relationship between apoE genotype and AD risk. The apoE molecule has been shown to be associated with several factors that lead to AD pathology. In the context of the debate about the association between apoE genotype and AD, it has been shown that this genotype can independently account for as much as 95% of the AD cases in the US. Another consideration is that apoE-ε2 homozygotes may not even develop AD in the absence of other
Acknowledgments
This work was supported by NIH grants R01 AG20904 (JR), P01 AG022074 (YH), and NIA-ADCC Center Grant AG17824 (JWA), EMF grant AG-NS-0201-02 (JR), the Medical Research Service of the Department of Veterans Affairs, and the Sierra-Pacific and Desert-Pacific Mental Illness Research, Education, and Clinical Centers (MIRECC) (JWA).
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