Familial Early-onset Alzheimer's disease (EOAD) accounts for only a small proportion of total AD cases (<0.1%), with the majority classed as late-onset Alzheimer's disease (LOAD). There are both genetic and environmental risk factors for this typically sporadic form of AD, which is complex and highly heterogeneous. Twin studies have shown that the pairwise concordance rate for AD is 78% in monozygotic and 39% in dizygotic twins and the estimated heritability is 0.6 (Bergem et al 1997 There can be familial clustering of LOAD and family history of dementia is considered a risk factor, with sibling risk ratios (λs) ranging from 4-5 (Breitner et al 1988 There is no consistent mode of inheritance, although evidence is strongest for autosomal dominant and multifactorial segregation. However, more recently recessive inheritance has been observed (Farrer et al 2003 Sleegers et al 2004 Age is another confirmed risk factor for LOAD, and lifetime risk is 12-19% for women and 6-10% for men over 65 years (Luchsinger and Mayeux 2004 Other reported factors that may influence development of AD are oestrogen levels (Green et al 2005 head injury (reviewed by Jellinger 2004 education, diet (Luchsinger and Mayeux 2004 and physical activity (reviewed by Karsten and Geschwind 2005 Epidemiological studies indicate that cardiovascular disease is a risk factor for LOAD, especially Type II diabetes [T2D].
Identifying the genetic risk factors for LOAD has proven a difficult task (reviewed by Brookes and Prince 2005 The only accepted genetic risk factor is the ε4 allele of the apolipoprotein E (APOE) gene, and it is associated with increased risk for early and late onset sporadic and some late-onset familial AD. Numerous studies have reported identification of further genetic risk factors, but none have been consistently replicated.
In silico simulations have indicated that there may be at least a further 4 susceptibility loci for LOAD, with a magnitude equal to or greater than the ε4 APOE allele, that remain to be identified (Daw et al 2000 Identification of these genes can proceed in two ways. Candidate genes may either be investigated based on their known biological role, or alternatively by their proximity to a region showing linkage or association with the disease.
Given the wide scope of the possible molecular functions of APP and the PS proteins, hundreds of genes could plausibly be chosen as candidate AD genes. The genes that have been investigated are too many to mention here, particularly given the contradictory nature of the reported observations. An excellent summary of the candidate genes to date is given in the review by Rocchi et al (Rocchi et al 2003 However, positive associations have been reported with polymorphisms in the β-secretase (BACE) (Kirschling et al 2003 Nowotny et al 2001 Clarimon et al 2003 Gold et al 2003 the γ-secretase component NCT (Dermaut et al 2002 Aβ degradation proteins, neprilysin (Helisalmi et al 2004 Clarimon et al 2003 Sakai et al 2004 ECE-1 (Funalot et al 2004 ACE (Kehoe et al 2003 [IDE] ; and LRP, an APOE receptor (Kang et al 1997 Lendon et al 1997
At present, thirteen genome scans have been carried out to identify genomic regions that may harbour novel susceptibility genes (Blacker et al 2003 Pericak-Vance et al 1998 2000 Zubenko et al 1998 Kehoe et al 1999 Curtis et al 2001 Hiltunen et al 2001 Li et al 2002 "Olson et al 2002": cgi?cmd=; Farrer et al 2003 Scott et al 2003 Myers et al 2002 Lee et al 2004 A review of these papers, with the exception of an additional genomic screen in a Caribbean-Hispanic population (Lee et al 2004 has been carried out by Bertram and Tanzi (Bertram and Tanzi 2004 (summarised in table 1).
The most consistent genetic evidence has been found with markers on three chromosomes - 9p21, 10q21 and 12p11 – and good biological candidates are found in each of these regions: chromosome 9, VLDL-R (Christie et al 1996 and UBQLN1 (Bertram et al 2005 chromosome 10, IDE (Bertram et al 2000 PLAU (Finckh et al 2003 Ertekin-Taner et al 2005 and CTNNA1 (Ertekin-Taner et al 2003 Busby et al 2004 chromosome 12, α2M (Zappia et al 2002 LRP (Lambert et al 1999 LBP-1c/CP2/LSF (Myklebost et al 1989; Pericak-Vance et al 1997 Lambert et al 2000 and GAPD (Li et al 2004
[Chromosome 10] is especially interesting because recent studies have shown that it may contain a quantitative trait locus (QTL) that regulates plasma Aβ levels (Ertekin-Taner et al 2000 2001 A further report observed that a chromosome 10 locus has the potential to influence AAO of AD (Li et al 2002
For up-to-date information on genetic studies carried out, the Alzgene website is a valuable resource http://www.alzforum.org/res/com/gen/alzgene/default.asp.
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