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Linkage analysis on LOAD families had previously suggested the existence of a susceptibility factor on chromosome 19q13.1-q13.3 (Pericak-Vance et al 1991 Subsequent analysis revealed an increase of the apolipoprotein (APOE) ε4 allele in familial cases compared to controls (Strittmatter et al 1993 (APOE – gene; ApoE – protein). Interestingly, ApoE immunoreactivity is observed with amyloid plaques and NFTs (Namba et al 1991 reviewed by Dickson 1997

There are three common alleles of the APOE gene ε2, ε3 and ε4, and the protein isoforms differ in their amino acids at positions 112 and /or 158: ε2 (Cys112, Cys158), ε3 (Cys112, Arg158) and ε4 (Arg112, Arg158). The ε4 allele exhibits a dose effect both in increasing risk (Strittmatter and Roses 1996 and in decreasing AAO (Corder et al 1993 although it represents only 7-9% of the variance in AAO of familial AD (Daw et al 2000 It exerts its greatest effect on AD between the ages 60 and 80 years (Farrer et al 1997 Beyer et al 2002 It is the only consistently replicated genetic factor for LOAD but it does not determine risk; 50% of ε4 carriers do not develop LOAD, and likewise, 50% of LOAD patients do not carry the ε4 allele. Studies have shown that APOE accounts for less than 50% of the total genetic effect in AD (Roses et al 1995 although incidence rates are race specific, with the ε4 allele being a higher risk factor Japanese > Caucasian > African-Americans and Hispanics (Farrer et al 1997 Evans et al 2003 Harwood et al 2004 In contrast to ε4, the APOE ε2 allele has a protective effect in late-onset familial and sporadic AD. Its effect in early-onset sporadic AD is unclear (van Duijn et al 1995 Scott et al 1997b

Recent studies provide evidence for differential expression of APOE (Beyer et al 2002; reviewed by Laws et al 2003). Four promoter polymorphisms have been identified and at least three of these impart some regulatory effect on the expression of APOE (reviewed by Laws et al 2003 It is possible that these polymorphisms may influence disease risk.

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