Mohammed T. Abou-Saleh

320 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYprescribed two different statins (lovastatin and pravastatin).Laboratory evidence also supports an association between lipidmetabolism and dementia. This includes decreased processing ofamyloid precursor protein when cholesterol is removed from cellculture 6 and possible interactions between b-amyloid and lowdensityreceptor-related protein in AD.These observations have prompted renewed speculation alongtwo separate lines. First, dietary manipulation of lipid metabolismmay modify susceptibility to AD in subjects genetically predisposedto AD 77–81 . Second, randomized controlled trials thatcompare statins known to cross the blood–brain barrier withstatins that do not will prove informative in the prevention of AD.Such studies are under way at several centres.A substantial body of epidemiological data supports aproposed causal link between blood cholesterol concentrationsand risk of coronary heart disease. The relationship is somewhatunusual, in that there is a steady increase of coronaryheart disease risk from the lowest to the highest cholesterolconcentrations observed in free-living communities. Some ruralcommunities in China have mean cholesterol concentrationsaround 3 mmol/l and mean coronary heart disease death ratesabout 5% of those seen in England and Wales. Thisobservation has prompted intensive strategies to lower cholesterolin the Western world to concentrations well below thosetypically aimed for. Individuals not previously considered to behypercholesterolaemic now seek cholesterol-reducing regimes inorder to reduce their perceived risk of myocardial infarction. Itis as yet unknown whether these greater than previouslysought-for reductions in cholesterol will be associated withreduced rates of coronary heart disease, as the epidemiologicaldata suggest. Likewise, it is uncertain whether cholesterolloweringregimes reduce the risk of cerebrovascular accidents.Nevertheless, these general principles in the modification ofserum cholesterol concentrations in health and disease seemlikely to inform the use of statins in the prevention andtreatment of dementia 28 .FUTURE STRATEGIESThe cholinergic hypothesis provided a rational basis for drugdevelopment in AD 83 . Some symptomatic relief is consistentlyobserved after the introduction of cholinesterase inhibitors, butsubsequent attempts to improve modification of cholinergictransmission have not brought substantial improvements in rateor extent of response. There is, however, a reasonable expectationthat longer-acting cholinesterase inhibitors with improved safetyprofiles will be available. The proposition that selective cholinergicneuronal death is a primary event in AD pathogenesis hasprompted a search for therapeutic neurotrophic factors specificfor cholinergic neurones.Nerve growth factor (NGF) therapy is an example of this typeof approach. It is based on extensive evidence that NGF is criticalin the maturation and maintenance of cholinergic neurones and apossible modulatory role for NGF in amyloid precursor protein(APP) expression and secretion 84 . So far, problems of drugdelivery have largely thwarted any chance of success. NGF sharesthese problems with other peptide drug delivery to brain sites. Insummary, these are: (a) extra CNS peptide digestion; (b) failure tocross the blood–brain barrier and achieve therapeutic concentrationsin the CNS; (c) inefficient distribution within the CNS; and(d) unwanted actions in CNS. The clinical pharmacology ofneurotrophic factors is in its infancy and, once mature, seemslikely to offer realistic prospects of contributing to AD treatmentand prevention. Uses of neurotrophic mimetics (usually smallsynthetic molecules with growth factor-like activity) are likely toinclude the promotion of neuronal survival and differentiationafter cell-based therapy 85–88 . Antisense strategies in AD therapyface similar problems. They possess considerable potential totarget specific genes but so far none have been found useful inneurodegenerative disease 89 .Current drug development is based largely on better understandingof AD molecular pathology 90 . The ‘‘amyloid cascadehypothesis’’ of AD postulates that amyloid deposition is critical tothe development of dementia and to neuronal death. Interventionsare now proposed to prevent amyloid deposition and, when itoccurs, to cause amyloid to disaggregate and be scavenged fromthe CNS 91,92 . Relatively little attention is paid to the developmentof therapies to prevent neurofibrillary tangle formation. Aseparate strand of research (described above) seeks to protectthe brain against oxidative stress, inflammatory reactions,perturbations of calcium homeostasis, apoptosis and cerebrovascularendothelial function.Figure 58a.1 shows key steps in the processing of APP. Thedeposition of extracellular amyloid is postulated to be the keyevent in AD pathogenesis. Three enzymes are involved; a-, b- andg-secretases. The identification of these secretases raises thepossibility that therapies aimed to modify their function couldbe useful in AD 93 . Several modulators of secretase function havebeen described, but so far none appear to have therapeuticapplications 94 .The prevention of b-amyloid deposition may prove critical inAD treatment. Senile plaques contain not only b-amyloid depositsbut copper and zinc that can be solubilized by Cu/Zn chelators invitro. Recently researchers in Australia and Germany 95 successfullyreduced b-amyloid accumulation in APP2576 transgenicmice (predisposed to b-amyloid deposition). This raises thepossibility that therapies designed to remove brain Cu/Zn maybe valuable in AD.An alternative approach to b-amyloid deposition in AD isbased on the production of antibodies to b-amyloid 96–99 . Thistechnique seeks to dissolve senile plaques after they haveformed and has the potential to prevent their formation. Instudies of transgenic mice (TgCRND8 predisposed to b-amyloidaccumulation), immunization with b-amyloid antibodies produceda marked (around 50%) reduction of b-amyloid in brainand was linked to reduced cognitive impairment 100 . Moredetailed behavioural studies were reported at about the sametime 101 . These concluded that treated mice performedFigure 58a.1 Amyloid precursor protein (APP) is a transmembranecellular adhesion molecule involved in synaptogenesis. It is processed byenzymatic cleavage to yield amyloid fragments (b 50 , b 42 and Ab) of theoriginal APP. Each cleavage enzyme acts at a specific point on APP.b- and g-Secretases cleave at one or other end of the amyloid fragment.a-Secretase cleaves at a point between the two