Mohammed T. Abou-Saleh

206 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYdisease may be identified 13 . The slope of the increase with agedepends on the sub-type of dementia. The incidence ofdementia and AD increases steeply with age. The absoluteincidence and the age-related increase in vascular dementia islower. Studies differ concerning the sex-specific risk for AD.After 85 years of age a large difference in incidence wasfound in European studies 14 ; the incidence in womenincreased steadily with age (up to 82/1000 person-years at90 years and older), but flattened out in men (at 25/1000person-years at 90 years and older). In contrast, in USAbasedcohorts 15,16 , the incidence of dementia, or AD,increased in old age with no apparent differences by sex.Sex differences in the risk for AD may be due to differencesin biology, cumulative survival, or behaviour and exposures.Further investigations are needed to clarify the contributionof sex to the risk for AD.EducationThe contribution of education to the risk for AD is stillcontroversial. Some argue that an association reflects confoundingby socioeconomic factors, or diagnostic bias due to poorerperformance on neuropsychological tests by individuals with loweducation 17 . Others argue that education is a marker for biologicalcapacity that modulates when a person reaches the threshold ofclinical dementia 18 . Several studies based on prevalent cases showthat low education is associated with an increased risk for AD 19 .Studies based on incident cases are inconsistent, with someshowing no relation 20 and others showing a relationship 21 of loweducation to increased risk for AD. In one study the increased riskassociated with AD was confined to women 22 .Head TraumaReports on the relation of AD to head trauma with unconsciousnessare inconsistent. Most studies are based on prevalent cases,where a proxy has had to be asked about the case’s history ofhead trauma. These studies have either shown no effect 23 , anincreased risk for AD only in men 24 , or only in women with headtrauma 25 . In a study based on US war veterans with independentlydocumented history of head trauma during the war, therewas a two-fold increased risk for AD 26 . One report suggestedthat head trauma is a risk factor in the presence of theapolipoprotein E*4 allele 27 but two other studies have failed toconfirm this 24,28 .Cardiovascular Risk FactorsOne new area that is being investigated is the relation to AD ofcardiovascular disease and risk factors. Several direct andindirect mechanisms may explain such associations, includingischemia, hypoxia, hemodynamic factors and neurotransmittermetabolism 29 . Studies have reported an increased risk for ADassociated with subclinical measures of atherosclerosis 30 andelevated levels of blood pressure 2 . Indicators of glucosemetabolism, including glucose and insulin levels 3 and diabetes 32have also been associated with an increased risk for AD,although not consistently 33 . In addition, cardiovascular riskfactors have also been shown to increase the risk for AD,including smoking 34,35 and diet 36 . Since this is a relatively newarea of investigation, confirmation of these findings in otherstudies is needed.Steroidal HormonesEstrogen may be linked to AD through several directmechanisms related to amyloid processing, neurotransmittermetabolism, cerebral blood flow or through cardioprotectivepathways 37 . Epidemiologic studies based on prevalent cases areinconsistent, some show a positive effect 38 , others not 39,40 .Prospective studies suggest that estrogen replacement therapy isprotective 41–44 . However, these observational studies may bedetecting an association of AD to healthy behaviour, ashormone replacement therapy users tend to be healthier 45 .Studies examining estrogen effects in men, as well as clinicaltrials, are needed to confirm the association of increasedestrogen levels to a reduced risk for AD.NSAIDsBased on finding remnants of inflammatory processes inneuropathologic material of AD brains, it has been hypothesizedthat anti-inflammatory medications may reduce the risk for AD 46 .There have been many case-control studies based on prevalentcases 47 . Although some of these studies show no effect, those thatdo provide estimates of as much as an 80% reduced risk 48 . Morerecently, several prospective studies have been published, withinconsistent results. Studies with one measure at baseline andsubsequent follow-up found no association 49,50 , and anothershowed a non-significant reduced risk among those using NSAIDsfor 6 months or more within 10 years prior to the diagnosis ofdementia 51 . In the Baltimore Longitudinal Study of Aging, therisk of AD decreased with increasing duration of NSAID use overa 16 year follow-up 52 . As with the estrogen hypothesis, thatpertaining to NSAIDs needs to be tested in controlled clinicaltrials.GeneticsWith time, increasingly more will be known about the genetics ofAD. Currently, several specific mutations have been found infamilial (early onset) cases of AD, including missense mutations inthe b-amyloid precursor protein on chromosome 21 53 andmutations in the presenilin-1 (chromosome 14q) 54 and presenilin-2(chromosome 1) genes 55 . However, these mutations do notaccount for the vast majority of cases, which are sporadic and oflater onset. To date, apolipoprotein is the only identifiedpolymorphism that has consistently been shown to be associatedwith a genetic susceptibility to sporadic and late-age onset AD.Specifically, the e*4 allele increases the risk for AD 56 . Genesinvolved in inflammatory, apoptotic, metabolic, cytoskeletal, andneurotransmission processes are also under investigation 57 .However, their role in modulating the risk for AD needs furtherelucidation. There are examples where a polymorphism is foundto increase the risk for AD in one sample, but the findings cannotbe replicated in others (i.e. such as the polymorphism in the geneencoding a2-macroglobulin 58,59 ). Identification of genetic factorscontributing to AD will not be simple. The majority of cases areprobably a pool of heterogeneous conditions. It is not likely thatthere will be one or two major genes that are identified; rather, thegenetic risk for AD will likely be the product of a number of genesthat make a small contribution to risk.SUMMARYIn the past decade many more prospective population-basedstudies were started and have yielded valuable data. However,