Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-0218 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYPS-1 protein or its message are seen in PS-1 AD. The holoproteinis processed into 17 kDa, C-terminal (CTF) and 27–28 kDa, N-terminal (NTF) fragments which accumulate in 1:1 stoichiometry,in a highly regulated and saturable manner. Cleavage occurswithin the hydrophilic loop, around amino acid 298 2 . PS-1 (2)mutations alter neither the site nor the manner of endoproteolysis,although the cleaved products may accumulate through increasedstability.Amyloid precursor protein (APP) trafficking from Golgi toendosome and plasma membrane—the principal sites of Abproduction—is not affected by PS-1 mutations. PS-1 knockoutmice show normal a- and b-secretase activity, though Abproduction is decreased with accumulation of the C-terminalstub of APP. PS-1 therefore might regulate g-secretase, as part ofthe g-secretase complex, with mutant PS-1 fragments enhancingthis activity 3,4 .CTF and NTF of PS-1 form a stable complex containing GSK-3b and b-catenin 5 . The cellular trafficking, stability and turnoverof b-catenin is altered by PS-1 mutations 3 and these mightinterfere with the binding of GSK-3b to tau, possibly promotinghyperphosphorylation and neurofibrillary tangle formation.PS-1, therefore, probably regulates the sorting and processingof integral membrane proteins, including APP. PS-1 mutationsmay alter protein topology so as to favour APP catabolism alongroutes which, by increasing production and tissue deposition ofAb, facilitate the pathological cascade. Other putative roles forpresenilins could include signal transduction, involving Notch andWnt pathways, during development or apoptosis 4 . Whether thesefunctions are disturbed by PS-1 mutations, with repercussions forthe pathogenesis of AD, is unknown.REFERENCES1. Tanzi R, Kovacs D, Kim T-W et al. The gene defects responsible forfamilial Alzheimer’s disease. Neurobiol Dis 1996; 3: 159–68.2. Selkoe DJ. The cell biology of -amyloid precursor protein andpresenilins in Alzheimer’s disease. Trends Cell Biol 1998; 8: 447–53.3. Nishimura M, Yu G, St George-Hyslop PH. Biology of presenilins ascausative molecules for Alzheimer disease. Clin Genet 1999; 55: 219–25.4. Sisodia SS, Kim SH, Thinakaran G. Function and dysfunction of thepresenilins. Am J Hum Genet 1999; 65: 7–12.5. Weihl C. -catenin and PS1. Alzheimer’s Rep 1999; 2: 195–8.Apolipoprotein-E (APO-E)Dan G. BlazerDuke University Medical Center, Durham, NC, USAStrittmatter et al. 1 found that the gene apolipoprotein-E (APO-E)for the lipid transporter apolipolipoprotein-E is located onchromosome 19 in a region that was demonstrated to have stronglinkage to familial late-onset Alzheimer’s disease (AD). There arethree common alleles formed at the polymorphic APO-E locus,E2, E3 and E4. Each individual inherits one allele from eachparent; thus a person may have an APO-E genotype of E4/E4, E4/E3, E3/E3, and so forth 2 . The E3 allele is the most common andrepresents approximately 78% of all alleles in European andAmerican White populations. The E4 allele frequency is approximately15–16% and the E2 frequency approximately 7%. The riskfor AD is increased and the average age of onset is decreased withincreasing numbers of APO-E E4 alleles. In addition to AD, theE4 allele has been shown to be associated with cardiovasculardisease, renal disease, stroke, decreased ability to recover fromphysiologic challenges such as amnesia and an increase in allcausemortality. Several case-control and incidence studies of lateonsetAD have shown E4 allele frequency to be more frequent incases; 30–50% in both sporadic and familial AD (FAD),compared to the 15% in the general population. The odds ratiofor E4 allele heterozygotes developing AD are approximately 2–5,whereas the odds ratios for E4 homozygotes are 5–18. The E2allele may actually retard the development of AD.Other studies of AD and APOE in different ethnic groupsreport similar associations between the E4 allele and AD.Nevertheless, the frequency of the E4 allele among African-Americans appears to be higher than in Whites, yet the frequencyof AD does not appear to be greater (thus suggesting lessassociation, perhaps, in African-Americans compared to Whites).Despite the association of AD and the APOE-4 allele, mostpersons who experience AD do not express the E4 allele. Inaddition, there have been reports of individuals homozygous forE4 in very late life who nevertheless remain cognitively intact. TheE4 allele is therefore neither necessary nor sufficient to cause AD.For this reason, the E4 allele has been considered a susceptibilitygene. This represents a change in perspective from the typicalapproach to genetic expression for an autosomal dominant orautosomal recessive.Most genetic determinants of health do not derive from a onegene–one disease paradigm, but rather a paradigm in which thephenotypic expression of the genome is best conceived quantitatively.A single polymorphism at a specific locus can lead tomultiple adverse outcomes, outcomes which can be investigated aschanges over time as well as the onset of a specific disease at aspecific point in time. In other words, these are susceptibilitypolymorphisms that are universally distributed in the population,rather than mutations that are uncommon and family-specific. Asingle allele may be sufficient to cause a specific disease, yeteveryone with that allele has a measurable age-dependent risk forthat disease. These susceptibility polymorphisms are thereforesubject to investigation in the way epidemiologists conceiveenvironmental stressors (such as stressful life events) or healthrelatedbehaviors (such as smoking), that is, as risk factors fordisease onset and change. To date, however, few such susceptibilitypolymorphisms have been identified. Studies of thesepolymorphisms have focused almost exclusively upon the associationof an allele with a specific disease or specific adverse outcome,such as mortality. Yet these polymorphisms may increase the risk