Mohammed T. Abou-Saleh

PRESENT AND FUTURE TREATMENTS OF AD 319interactions between the receptor for advance glycation endproducts and b-amyloid 36,37 . These observations have supportedthe hypothesis that the neurotoxic effects of b-amyloid aremediated through oxidative stress.Therapeutic agents that reduce oxidative stress may reduce theincidence and slow AD progression. These include non-steroidalanti-inflammatory agents 38–43 ; inhibitors of advanced glycationend product formation 44,45 and a-tocopherol 46 . The benefits in ADof Ginkgo biloba extract may also involve reduction of brainoxidative stress 47 .Neuroprotective actions of oestrogen in women were linked toreduced AD prevalence in some early studies 48 and promptedmany subsequent observational and experimental longitudinalstudies. As yet, no single study has overcome all the methodologicalproblems associated with complex biopsychosocialquestions of this type. A recent meta-analysis of 29 studies onthe putative dementia-protective effects of oestrogen replacementtherapy (HRT) suggested that HRT was linked with reduced riskof dementia (summary odds ratio, 0.66; confidence intervals 0.53–0.82). The authors cautioned that control for potential confoundersmay remove this association 49 . When demographic andhealth confounders were taken into account, HRT was notassociated with cognitive benefits in a large (n=1907) US study 50of post-menopausal women. In the UK, the general practiceresearch database identified women born before 1950, of whom112 481 received HRT and 108 925 did not 51 . Among these subjectsthere were 59 newly diagnosed AD cases, of whom 15 (25%) werecurrent HRT users. Expected HRT use was estimated at 24% andthe authors concluded that this type of cross-sectional observationdid not support a link between HRT and protection against AD.Raloxifene is an oestrogen receptor modulator (mixed agonist/antagonist) that is tissue selective. Potential advantages are that itdoes not stimulate breast or uterine tissue but is active in bone andon lipid metabolism, the last being of specific relevance to thepossible involvement of cholesterol in AD (see below). Osteoporoticpostmenopausal women (n=7478) were entered into a 3year multicentre randomized placebo-controlled trial of raloxifene52 . Mean cognitive scores were similar at baseline and therewere no differences between groups over the study period. Theauthors concluded that, in osteoporotic women, raloxifene did notmodify cognitive function over time.As yet, it is unclear whether oestrogens are involved in AD.Although early observational studies were encouraging, recentlarge-scale and well-conducted studies do not provide cause forcontinuing optimism.LESSONS FROM THE PREVENTION OF HEARTDISEASE AND STROKEHomocysteine and Vascular DiseaseThere is a rare autosomal recessive condition in which very highblood concentrations of total homocysteine are associated withincreased incidence of occlusive vascular disease in adolescence—even in childhood 53 . This disease, homocysteinuria, is caused byone of several genetic defects in the enzymes that metabolizemethionine; these defects occur in methylene tetrahydrofolatereductase (MTHFR) or cystathionine b-synthase (CBS). Prematurevascular disease develops irrespective of the genetic defectand this indicates that homocysteine is probably responsible forthe vascular damage 54,55 . Blood concentrations of homocysteineare also increased (but to a lesser extent) in individuals who areheterozygous for either of these two enzymes, MTHFR and CBS.Inadequate intake of folic acid and vitamins B 6 and B 12 (co-factorsin the metabolism of homocysteine) is also associated withincreased blood concentrations of homocysteine 56–58 . Dietarysupplementation using these vitamins is an important part ofthe treatment of genetically determined homocysteinuria. In thegeneral ageing population, the contributions of genetic polymorphismsand nutritional intake to the determination of plasmahomocysteine concentration (and in turn the risk of vasculardisease) is largely unknown 59 .Epidemiological studies indicate that there is a strong positiveassociation between blood homocysteine concentration and therisk of vascular disease. There is now considerable interest in thepossible role of increased blood homocysteine concentration inbrain ageing and cognitive decline leading to AD 60,61 . Nutritionalfactors are important in the maintenance of cognitive function inlate life and specific dietary deficiencies may be relevant to thefailure to retain mental abilities and progression to dementia 62–66 .Nutritional factors of most interest have been antioxidants,marine oils and fat-soluble vitamins. Maternal and infantnutrition is critical in neurodevelopment; folic acid is involvedin the closure of the neural tube, and maternal folate deficiencyduring pregnancy is associated with neural tube defects. Themaintenance of normal nervous system functioning in adulthooddepends on an adequate consumption of B vitamins, includingfolate, B 6 and B 12 . Acute deficiencies of these water-solublevitamins are linked to neuropathy and psychosis. Age-relatedchanges in metabolic and physiological systems may result in oldpeople obtaining insufficient dietary folate and B 12 or, to anuncertain extent, through mechanisms linked to atrophic gastritis,to failure to absorb these vitamins. In turn, insufficient intake canresult in the accumulation of homocysteine 60 , which is associatedwith greater unexpected cognitive decline and poor quality of life inold people 67 andinAD 68 . A recent review 60 commented on reportsthat low blood concentration of folate and B 12 is associated withpoor memory, impaired and non-verbal abstract thinking in oldpeople. Low folate concentration is associated with poor spatialcopying skills and, in very old age (90–101 years), lower blood folateconcentrationislinkedtoimpairedencodingandretrieval.The mechanisms by which homocysteine could impair mentalfunction are uncertain. Homocysteine can undergo auto-oxidationto various metabolites and ROS (free radicals) that aredirectly toxic to the endothelium and also negatively alter theability of vascular muscles to relax 69,72 . Homocysteine metabolites,such as homocysteic acid and cysteine sulphinic acid, act asendogenous agonists of NMDA receptors, over-stimulatingglutamate receptors and ultimately inducing cytotoxic damageand brain cell death. Homocysteine is also associated withelevated cycline E (a marker of cell division) in the hippocampusof AD sufferers 68 . This raises the possibility that homocysteinemay be involved in neuronal stimulation and trigger proliferativemechanisms, including the induction of new amyloid formation 69 .Currently, studies are under way to determine the cognitive effectsin old people of strategies to reduce blood homocysteine concentrations,and early results are encouraging 70,71 . These strategies, ifeffective, may prove useful in community-based interventions toprevent cognitive decline and dementia in old people.Cholesterol Metabolism and the Risk of DementiaThere is extensive evidence to support a link between lipidmetabolism and dementia. Epidemiological evidence is as follows:(a) there is an established association between apolipoprotein Eallele (APOEe4) polymorphism and AD; and (b) raised systolicblood pressure and high serum cholesterol in mid-life will increasethe risk of AD in late life 73 ; and (c) use of cholesterol-loweringagents (3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors—thestatins) is connected with reduced risk of dementia 74 .These findings were supported by Wolozin et al. 75 when theyobserved a lower prevalence of probable AD in subjects