Mohammed T. Abou-Saleh

214 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYappear to act as autosomal (i.e. not sex-linked) dominant traitswith nearly complete penetrance 16 . Early reports suggested thatchromosome 14 mutations may account for the majority of earlyonsetfamilial AD cases 17,18 . More recent estimates from population-basedsamples 16,19 have produced conflicting estimates of theproportion of early-onset cases attributable to PS-1 mutations,with some 16 suggesting that PS-1 mutations account for less than20% of such cases (see p. 217 for more discussion of presenilins).A third autosomal dominant locus for AD has been localized tochromosome 1 and termed presenilin 2 (PS-2) 20,21 . To date, PS-2mutations have been identified in only a few families of differentethnicity. In fact, in a population-based sample of early-onset ADcases, it was estimated that PS-2 mutations account for less than1% of the cases 16 . The PS-2 mutations usually provoke onset ofAD symptoms before age 65, but later onsets occasionally occur.The variability in onset age for the PS-1 and PS-2 mutationssuggests the complexity of these otherwise Mendelian traits.Identification of AD mutations on chromosomes 21, 14 and 1has led to major advances in understanding the etiology of thisdisease. It is important to note, however, that these mutationsprobably account in total for less than 2% of all AD cases 22 .Importantly, it appears that they do not account even for themajority of so-called autosomal dominant familial AD 16 . Thus,there are almost certainly other major genes remaining to beidentified in early-onset AD. A separate and, from a public healthperspective, far more compelling issue is the search for othergenetic influences in common, late-onset AD.Apolipoprotein EIn the search for other so-called AD genes, Pericak-Vance andcolleagues 23 reported linkage of disease to a locus on chromosome19 in pedigrees with late-onset AD. Searching through thecandidate genes of the implicated region on chromosome 19,Strittmatter et al. 24 found that the apolipoprotein E gene (APOE),which encodes the lipid transporter apolipoprotein E (apoE), islocated in the same region that showed linkage to familial lateonset AD. Their initial studies showed an increase in amyloiddeposition in elderly individuals with the E4 allele at APOE 24,25 ,and an increased frequency of this allele in both familial andsporadic AD cases 25–29 . Subsequent studies showed that, as thenumber of E4 alleles increases from 0 to 2, the age of onset of ADdecreases 30 . These findings have now been confirmed in over 100studies, including some that extend the findings to early onset AD(for review, see ref. 31). A recent meta-analysis of data on over14 000 subjects from 40 research teams synthesized the findings onAPOE through 1997 32 . That study confirmed the basic findingsnoted above and also replicated some findings that previously hadbeen suggested by select studies. These findings were that theAPOE E2 allele may be associated with lower risk of AD, and thatrisk associated with the E4 allele appears to vary by age, sex, andethnicity. The association between AD and APOE E4 is complex,and it is not clear why some individuals with the E4 allele developthe disease while others do not. But, whatever its precise role, E4 isan important player in the genetics of AD, as various groups havenow estimated that APOE accounts for 57–70% of the geneticcontribution of AD 33–35 . Further discussion of the role of APOEon the risk of AD is provided on pp. 218–19.Other Putative GenesThere are many pedigrees that show intense familial aggregationof either early- or late-onset AD but have no identified mutationand no APOE E4 allele. It seems likely, therefore, that one or moregenes predisposing to AD remain to be discovered. The pursuit ofthese other genes has produced numerous reports of associationsbetween specific genes and AD, but none of these has beenconsistently replicated. Chromosome 12 has been the focal pointof much of this work, since a genomic screen showed a region onthis chromosome may be associated with increased susceptibilityto AD in individuals without an APOE E4 allele 36 . Furtheranalyses by this group has suggested that a region on chromosome12 near the one of original interest may be associated withincreased risk of the Lewy body variant of AD 37 . Other groupshave now demonstrated linkage to regions near the initiallyimplicated chromosome 12 locus, although one such studysuggested that the strongest such association was in individualswith an E4 allele 38 , while the other showed the strongestassociation in those without an E4 allele 39 .Two of the several candidate genes in the region under scrutinyon chromosome 12 have now been shown to be positivelyassociated with AD in at least some studies. The first is the genefor the major apoE receptor in the brain, the low-densitylipoprotein receptor-related protein (LRP) that is selectivelyfound in neurons and reactive astrocytes 40 . This gene, LRP, hasalso been shown to mediate the endocytosis and degradation ofAb 41 . It has two alleles, called C and T. The homozygous Cgenotype appears to be associated with increased risk of AD,earlier onset of AD, and significantly more neuritic plaques atpost mortem, as compared to individuals with at least one Tallele 42 . Several groups have confirmed these results 43–46 , but atleast two have not 47,48 .The other candidate locus encodes a-2 macroglobulin (A2M)and is located just outside the area on chromosome 12 for whichothers have reported linkage 36 . Previous work 41 showed that A2Mis a major LRP ligand and is a serum pan-protease inhibitor thatmediates the clearance and degradation of Ab, the majorcomponent of brain amyloid. At least three different A2Mpolymorphisms have been implicated so far 49–51 . One of thesestudies reported that, in a very elderly Finnish cohort, theassociation with the A2M polymorphism was only evident inneuropathologically diagnosed AD cases, but not in the clinicallydiagnosed AD cases. This particular polymorphism was alsoassociated with an increase in the neocortical b-amyloid proteinload 51 . Unfortunately, a number of other studies have notconfirmed these associations between A2M and AD in severallarge samples 52–56 . Together, these findings suggest that if A2M isassociated with AD, its effect may be limited to subgroups ofsusceptible individuals and that different polymorphisms may beinfluential in each of these subgroups.With so many purported loci and mutations associated withAD, one may wonder about a common thread in the pathogenesisof AD. The pathogenic mechanisms of the APP, PS-1 and PS-2mutations are not completely understood, but each appears to beassociated with increased production of the long form of Ab (Ab-42), relative to the production of the shorter forms (mostly Ab-40)of Ab 57 .Ab-42 seems to be a particularly pathogenic form of Abin AD. Both LRP and A2M are involved in the degradation ofAb. It has been suggested that these links to Ab may be theunderlying common pathogenic event leading to AD for thesegenes 58 .There are reports of numerous other genes throughout thegenome contributing to AD, but none of these findings hasbeen consistently confirmed. A partial list of the contendinggenes includes: a 1 antichymotrypsin (ACT), a gene on chromosome14 59–67 ; the K variant of butyrylcholinesterase (BCHE-K)on chromosome 3 68–72 ; bleomycin hydrolase (BH) on chromosome17 73 (cf. ref 74); the non-amyloid component precursorgene (NACP/a-synuclein) on chromosome 4 75 (cf. ref 76); thehuman leukocyte antigen (HLA) genes on chromosome 6 77,78 ;the FE65 gene on chromosome 11 79 ; the dihydrolipoylsuccinyltransferase (DLST) gene on chromosome 14 80,81 ; the