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Alzheimer Disease:Genetic and

Environmental InfluencesChandra A Reynolds, University of California, California, USABased in part on the previous version of this eLS article AlzheimerDisease (2005) by Chandra A Reynolds and Michael Crowe.

Alzheimer disease (AD) is a complex, progressive neuro-

degenerative disease. Prevalence of AD is expected to

grow substantially, although predictions may shift given

future treatment interventions or higher levels of

engagement in lifestyle delaying factors that may reduce

risk. Several mutations have been characterised and sus-

ceptibility genes implicated as playing a role in the dis-

order. The apolipoprotein E (APOE) e4 allele remains the

best-established susceptibility gene for late-onset AD.

Although a substantial proportion of the liability for AD

may be accountedfor by genetic factors, heterogeneity or

differences in aetiology are important to consider. Envir-

onmental factors probably play a significant role, such as

education, head injury and nonsteroidal anti-inflamma-

tory drugs (NSAIDs) use, as well as obesity, diabetes,physical activity and cognitively engaging leisure activ-

ities. The extent to which susceptibility genes interact

with environmental factors may provide further clues to

aetiology. Lastly, a developmental longitudinal per-

spective on the salience of particular risk and protective

factors across the life course may illuminate etiologies

and potential points of intervention.

Introduction

As knowledge of human genetics has progressed sub-stantially since the 1990s, and indeed rapidly in the last 5years, knowledge regarding the genetics of Alzheimer dis-ease (AD) has also accumulated rapidly. One major con-clusion drawn from this line of research is that theaetiologyof AD is complex. It is now widely believed that multiple

genes as well as multiple environmental factors areinvolved in the development of AD. These genetic andenvironmental factors may act independently or synergis-

tically. Thus, current genetic research is aimed not only atfinding new genes and gene pathways related to AD butalso at examining genegene and geneenvironmentinteractions.

General characteristics

AD is a devastating disease and is also a tremendous publichealth concern. It is the number one cause of dementia inolder adults (Alzheimers Association, 2012). Typically,the initial and primary observable characteristic of AD is aprogressive and irreversible decline in memory. This

decline in memory is accompanied by deterioration in atleast one or the other area of intellectual functioning, suchas language, visualspatial skills and judgment and rea-soning (McKhann et al., 2011). Emotional and personalitychanges are also common (McKhann et al., 2011). Recent

diagnostic criteria and guidelines disseminated by theAlzheimers Association and the National Institute onAging in 2011 revise and expand the criteria used over the

past three decades (Sperling et al., 2011). The new diag-nostic criteria recognise three stages of AD: (1) dementiadue to Alzheimers, (2) mild cognitive impairment (MCI)and (3) preclinical Alzheimers, whereby biological changesemerge over time, up to decades ahead of any clinical signs.

To diagnose probable AD dementia, the cognitive deficitsmust represent a gradual decline frompreviousfunctioninglevels, unexplained by other major psychiatric disorders ordelirium,and must be severe enoughto interfere with socialand occupational functioning (McKhann et al., 2011).MCI includes relative declines in cognitive functioningwith impairments in one or more areas of intellectualfunctioning, but individuals maintain independence indaily activities of living (Albert et al., 2011).

Onset of AD symptoms is often difficult to pinpointbecause deterioration is gradual. People in close contactwith someone beginning to develop AD may not notice

changes for some time. Memory impairment, especiallyimpairment of the ability to retain new information, is

Advanced article

Article Contents

. Introduction

. Inheritance and Population Genetics

.

Aetiological Heterogeneity

. Environmental Factors

. Conclusions

Online posting date: 15th January 2013

eLS subject area: Neuroscience

How to cite:

Reynolds, Chandra A (January 2013) Alzheimer Disease: Genetic andEnvironmental Influences. In: eLS. John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0005243.pub2

eLS & 2013, John Wiley & Sons, Ltd. www.els.net 1


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usually the first symptom to be noticed in persons with AD(McKhann et al., 2011). After diagnosis, AD patients maylive an average of 48 years (Alzheimers Association,2012). As the disease progresses, there is a gradual loss ofabilities that eventually includes the inability to performmany basic activities of daily life, such as taking a bath or

dressing (Alzheimers Association, 2012). Death is oftendue to other ailments that result from a greater suscepti-

bility to illness or due to AD-related complications such asthe inability to swallow (Alzheimers Association, 2012).

Although AD primarilyaffects those over theage of 65,it

can also occur in younger people. A distinction is com-monly made between early-onset, or onset before age 60,and late-onset cases of AD. Early-onset patients are morelikely than late-onset patients to havea first-degree relative,such as a parent or a sibling, who also has the disease(Silverman et al., 2005). This finding may point to a pos-sibly greater contribution of genetic influences for early-versus late-onset AD. In further support for the distinctionbetween early and late onset is the finding that the diseasemay progress more rapidly in those with early-onset AD(Reitz et al., 2011).

Prevalence

Prevalence of AD (number of current cases) increases

dramatically after age 60. Indeed, the prevalence appears todouble every 56 years between the ages of 60 and 90 years(Brookmeyer et al., 2011). The prevalence of AD isapproximately .9% in those aged 6569 years and morethan 26% in those aged 90 years and older (Colantuoniet al., 2010). The overall prevalence in those aged 60 yearsor older is approximately 67% in North America(Colantuoni et al., 2010), and worldwide the prevalence isapproximately 4.5% (Colantuoni et al., 2010).

Successive generations of people are now living longer,and this increase in longevity suggests that the prevalenceof AD will continue to rise over this century, quadruplingby 2050 (Brookmeyer et al., 2011). Of the entire popu-lation, those of 85 years of age and older are both thefastest-growing group of people and most at risk fordeveloping AD. However, future prevalence is difficult toestimate. Factors that may plausibly contribute to risk ofAD, such as low education may be less frequent in suc-

cessive cohorts. There may also be research advances intreatment or prevention that would counter otherwiseincreasing rates of disorder (Brookmeyer et al., 2011).Thus, prevalence may not increase to the extent that manyprojections have estimated despite the expected growth inthe elderly population.

Neuropathology

In addition to clinical symptoms, there are pathologicalchanges that are consistently found in the brains of peoplewith AD. Alois Alzheimer first described the primary signsof AD brain tissue pathology in 1907 (see Perl, 2010). He

observed clusters of proteins in the brain that are nowconsidered to be pathological hallmarks of AD. He also

noticed brain atrophy, or shrinking of the brain due toneuronal death, another hallmark sign of AD. Neuronalcell loss, amyloid plaques and neurofibrillary tangles arethe three predominant neuropathological characteristics ofthe AD brain (Perl, 2010).

Neuronal cell loss is most pronounced in the hippo-

campus and cerebral cortex (Mattson, 2004). The hippo-campus is an area of the brain that is involved in memory,

whereas the cortex is thought to be involved in judgment,reasoning, memory, language and other higher-orderthought processes. The question of what causes these cellsto die is central to understanding AD. Formation of pla-ques and tangles is believed to be responsible for much ofthis neuronal loss, but the proposed explanations for thisprocess remain controversial (Nelson et al., 2012).

Amyloid plaques, which are sometimes also referred bysubtypes as diffuse or neuritic plaques, form betweenneurons in the synapses (Nelson et al., 2012; Perl, 2010).Synapses are the spaces between neurons into whichneurotransmitters (chemicals used for communicationbetween neurons) are released. The plaques consist ofaccumulations of degenerative nerve endings and othermaterials, with a core of beta-amyloid (Ab; Perl, 2010). Abpeptide fragments are cleaved from a much larger amyloidprecursor protein (APP) that is thought to be involved innerve growth and repair. However, it is a toxic version ofthe Ab peptide that has been detected in plaques (Mattson,2004; Perl, 2010). Compared with diffuse plaques, neuriticplaques contain deteriorating or distended neuritic struc-tures (axons and dendrites) and accumulations of abnor-mal tau protein products (Nelson et al., 2012).

Amyloid plaques may interfere with communicationbetween neurons,due to damaged neurites and synapses, aswell as cause cell death (Mattson, 2004). Some studies havesuggested that Ab deposits may disturb calcium levels,whereas others suggest that Ab plaques may be related tothe generation of free radicals that damage cells (Mattson,2004). Amyloid plaques are accompanied by an inflam-matory response, that is, activation of astrocytes, micro-glial cells and expression of cytokines, which may provokeneuronal damage (Nelson et al., 2012). Another possibilityis that APP malfunctioning leads to neuronal damage andcell loss (Nelson et al., 2012). If this is true, the amyloiddeposits may be a result of cell loss rather than a primary

cause.Neurofibrillary tangles are also made up of protein

clusters; however, unlike the amyloid plaques, they arefound withinthe nerve cell body. The protein that makesupthese tangles is called tau; alterations in tau may lead todeficient axonal transport and defective microtubule

structure (Mattson, 2004). It is believed that the neurofi-brillary tangles impede energy metabolism, movement ofnutrients and communication within and between nervecells by disturbing the affected cells microtubule structure(Mattson, 2004).

Feasible hypotheses regarding the associations among

plaques, tangles, neuronal death and AD have been putforth, most notably the amyloid cascade hypothesis and

Alzheimer Disease: Genetic and Environmental Influences

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newer hypothetical models termed the AD pathophysio-logical cascade (Sperling et al., 2011; Figure 1), but much

additional research is needed to fully understand ADaetiology. Although there is a strong correlation betweenneurofibrillary tangle density and AD severity, thereappears to be a negligible correlation between the amountof amyloid in the brain and AD severity (Nelson et al.,2012). That said, the amount of neuritic plaques appear tocorrelate morewith measuresof cognitive dysfunction thandiffuse plaques (Nelson et al., 2012). In fact, a number of

people show no clinical symptoms of dementia beforedeath despite the presence of plaques and tangles found onautopsy (Nelson et al., 2012). These observations in parthave led to the revised diagnostic criteria and guidelinesbriefly described above (Sperling et al., 2011).

Inheritance and Population Genetics

Genetic risk and heritability

An important question for AD researchers is: to whatdegree can the disease be attributed to genetic influences?The lifetime risk of developing AD is 1012% (Goldmanet al., 2011). Being genetically related to someone with ADraises ones own risk for the disorder. People who have afirst-degree relative with AD have a lifetime risk of

developing dementia that is 24 times higher than thosewho do not have a family history of dementia (Goldman

et al., 2011). In terms of population-based statistics, therelative contribution of genes and the environment to the

risk of AD can also be calculated.Heritability and environmentality are estimates of how

much genetic and environmental factors, respectively,contribute to the underlying liability for a disease (vanDongen et al., 2012). An assumption is that there is some

theoretical threshold of risk. It is only when this thresholdis exceeded that the disorder will appear. It is possible thatthe cumulative (and possibly interactive) effects of genetic

and environmental risk factors may push a person over theAD threshold, leading to onset of the disease.

Twin studies are valuable for studying heritability forbehavioural traits including AD. In twin studies, threecomponents are typically estimated on the basis of the

similarity (e.g. concordance rates) of monozygotic (MZ)and dizygotic (DZ) twin pairs (van Dongen et al., 2012):heritability; shared environmental influences or experi-ences shared by twin pairs; and unique or nonsharedenvironmental influences. These components can be esti-mated using twins because MZ twins are genetically iden-tical and DZ twins share half of their segregating genes onaverage (van Dongen et al., 2012). Given that one twin hasAD, the extent to which MZ and DZ pairs differ in theprobability that the twins partner also has AD is an indi-cation of genetic effects.

Relatively few studies have examined the heritability of

AD by using twin samples that are representative of thegeneral population. Since the first registry-based twin study

Hypothetical model of AD pathophysiological cascade

AgeGenetics

Cerebrovascular risk factorsOther age-related brain diseases

Amyloid-accumulation

Synaptic dysfunctionGlial activation

Tangle formationNeuronal death

Cognitive decline

Brain and cognitive reserve? environmental factors

Figure 1 Hypothetical model of the Alzheimers disease (AD) pathophysiological sequence leading to cognitive impairment. This model postulates that

amyloid beta (Ab) accumulation is an upstream event in the cascade that is associated with downstream synaptic dysfunction, neurodegeneration and

eventual neuronal loss. Note that although recent work from animal models suggests that specific forms of Ab may cause both functional and morphological

synaptic changes, it remains unknown whether Ab is sufficient or not to incite the neurodegenerative process in sporadic late-onset AD. Age and genetics as

well as other specific host factors such as brain and cognitive reserve or other brain diseases may influence the response to Ab and/or the pace of progression

towards the clinical manifestations of AD. Reproduced from Sperling et al. (2011), p. 283, with permission from Elsevier.




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by Kallman (1956), on senile dementia, researchers usingfour different twin registries have published findings on theaetiology of dementia, including AD: the National Acad-emy of SciencesNational Research Council registry(Breitner et al., 1995); the Finnish Twin Registry (Raihaet al., 1996); the Norwegian Twin Registry (Bergem et al.,

1997) and the Swedish Twin Registry (Gatz et al., 2006b).Results from every twin study demonstrate that identical

(MZ) twins have higher concordance rates for AD thanconcordance rates for fraternal (DZ) twins.In other words,if one twin has AD, it is more likely that his or her twin

sibling will also have AD if they are identical twins. Thisconsistent finding points to the importance of genetics inAD. Overall, the evidence from the largest study to date of11 884 twin pairs (Gatz et al., 2006b) suggests that theheritability of AD is between .58 and .79. This means that5879% of the liability of developing AD is due to geneticinfluences. The range of estimates from the other studies is.28 to .60 (Bergem et al., 1997; Breitner et al., 1995; Raihaet al., 1996). Environmentality estimates (the estimatedinfluence of the environment on the development of AD)range from .21 to .42 (Gatz et al., 2006b), with sharedenvironmental factors playing some role in the liability forAD (up to .19). This suggests that some of the influence ofthe environment may represent exposure to similar envir-onmental risk factors by both members of a pair duringchildhood or later in adulthood.

There may be different influences for age of onset of ADthan for overall lifetime risk of developing the disease. Forexample, reports from the Swedish Twin Registry suggestthat there is a high probability of unaffected twin siblings

remaining cognitively intact for at least 3 years followingtheir cotwins AD diagnosis (Gatz et al., 1997). Theunaffected twin sibling may even remain intact for a dec-ade. However, the probability of remaining intact dropssignificantly 15 years after diagnosis of AD in their twinsibling. Findings showedthat the younger the proband, thelonger the time the initially unaffected twin remainedcognitively intact. MZ partners were significantly morelikely than DZ partners to become demented during theperiod from 4 to 12 years after their cotwins diagnosis.These results suggest that different genetic factors mayinfluence age of onset of AD to liability of manifesting AD.

Two important conclusions are apparent from twin

studies: First, although genetic effects are important,environmental factors also play a role in the developmentof AD. Second, there is a wide range of estimates of theinfluence of genes relative to the environment. This lack ofconsistency may be attributable to at least four majorsources: sample size; age and gender of those in the studysample; and ascertainment bias (bias resulting from howAD cases are identified) (Gatz et al., 2006b).

Gene mutations and susceptibility genesrelated to Alzheimer disease

Several specific genetic abnormalities, or mutations, havebeen found to cause AD. Although certain genetic

mutations assure that one will eventually get the disease,this is not true of susceptibility genes. Susceptibility genesraise the likelihood, or the risk, that one will get the disease.

Mutations

Mutations on three chromosomes have been linked toearly-onset familial AD: chromosomes 21, 14 and 1(Schellenberg and Montine, 2012). The pattern of familialtransmission is consistent with a completely penetrant,autosomal dominant model, assuring that those carryingone of the mutations will develop AD if they live longenough. However, there is a great degree of variability forage of onset and clinical presentation associated with themutations, suggesting that other environmental or geneticfactors modify both the timing and the symptom profile of

the disease presentation.Three specific gene loci have been identified as carrying

multiple mutations: amyloid beta (A4) precursor protein

(protease nexin-II, AD) (APP) on chromosome 21; pre-senilin 1 (AD 3) (PSEN1) on chromosome 14;andpresenilin2 (AD 4) (PSEN2) on chromosome 1 (Schellenberg andMontine, 2012). Down syndrome has also been associatedwith early-onset AD. Those with Down syndrome havethree copiesof chromosome 21 andthereby three alleles forthe APP gene. The consequence of the presenilin and APPgene mutations appears to be an overproduction or faultyprocessing of APP, leading to amplified Ab proteindeposition (Schellenberg and Montine, 2012).

Mutations of the presenilin-1 gene are the most com-mon. Nevertheless, the presenilin and APP gene mutationsoccur infrequently and account for only 15% of AD cases

(Galimberti and Scarpini, 2012). Although most of thepeople with these mutations have early-onset familial AD,a vast majority of those with AD have the later-onsetvariety, which is not attributable to these geneticmutations.

Susceptibility genes

Apolipoprotein E (APOE)

The apolipoprotein E gene (APOE; the protein is APOE),found on chromosome 19,is thesusceptibilitygene with themost support for late-onset AD (Schellenberg and Mon-tine, 2012). Genetic linkage analysis and numerous case-

control association studies have confirmed APOE as animportant risk factor for AD (Schellenberg and Montine,2012). APOE, a cholesterol transporter, has been impli-cated in repair of injury to the central nervous system(Dardiotis et al., 2012; Verghese et al., 2011). Two singlenucleotide polymorphisms (SNPs) make up the primaryAPOE haplotypes which are combinations of alleles fromrs7412 and rs429358. Of three haplotype variants that codefor this protein, denoted e2, e3 and e4, the e3 allele is themost common (Egert et al., 2012), constituting 7488% ofthe APOE alleles in European and predominately whiteNorth American populations. The e4 allele frequency by

comparison ranges from 6.5% to 17%. Allele frequenciesfor e4 vary widely worldwide (510% in Mediterranean




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and Asian populations to nearly 41% in Central Africanpopulations; Egert et al., 2012). Moreover, a strong positivecorrelation exists between increasing northern latitude ande4 allele frequency in Europe (r=.80; Egert et al., 2012).

The APOEe4 allele is linked with an increased risk forAD where e4 frequencies in AD cases are typically double

or even triple that of unaffected individuals (Genin et al.,2011; Schellenberg and Montine, 2012). The presumed

mechanism is that the e4 variant may lead to greaterdeposition of Ab (Schellenberg and Montine, 2012). Mostevidence suggests that the risk of AD increases with the

number of e4 alleles, suggesting a dosage effect. A lowerrisk for AD is associated with the APOEe2 allele (Geninet al., 2011; Schellenberg and Montine, 2012). This indi-cates that theAPOEe2 allele may be protective, though theevidence is weaker than for e4.

The relationship between APOEe4 and AD may be agedependant, with a heightened risk between the ages of 65and 75 years (Blacker et al., 1997). APOE genotype mayexplain 2030% of AD liability or more (Reitz etal., 2011).Thus, other factors must contribute to AD liability thanAPOE status. The association between APOE and AD iswell documented; yet, inheriting either one or twoAPOEe4 alleles does not make it certain that an individualwillget AD. Lifetime risk ofAD by age 85 isestimated tobeas high as 5152% and 6068% for males and females,respectively, that carry two e4 alleles (Genin et al., 2011);thus, many having at least one e4 allele will not developAD. However, nothaving anyAPOEe4 alleles providesnoassurance that an individual will never have AD (Geninet al., 2011).

Genetic testing for APOE

e4 to diagnose or prospect-ively predict AD is currently not recommended (Goldmanetal., 2011). Although APOEe4 is stronglyassociated with

AD, studies have found that APOE genotype alone doesnot provide sufficient specificity as the e4 allele is alsoassociated with other forms of dementia. Furthermore, the

e4 allele is not present in many late-onset AD patients(Genin et al., 2011; Mayeux and Stern, 2012), suggestingthe influences of other genetic or environmental causes.Finally, APOEgenotyping is not considered to be a usefulpredictive genetic test. A majority of people with one and athird toa half withtwo APOEe4 alleles do notdevelopAD(Genin et al., 2011). Thus, test results may cause unneces-

sary apprehension.

Emerging genes

APOEe4 is the best-established risk factor for AD(Schellenberg and Montine, 2012); however, other genesare involved. A variety of potential AD neuropathways ledresearchers to examine plausible candidates. As technologyrapidly increased and findings from candidate gene asso-ciation approaches did not generally result in well-repli-cated findings as anticipated, agnostic genome-wideassociation studies (GWAS) became the prominent strat-

egy in which thousands of common genetic variants spreadacross the genome (typically SNP markers) were evaluated

for association with AD (Schellenberg and Montine, 2012).Although APOE and SORL1 were identified as plausiblecandidates given the potential role in Ab protein depos-ition, new genes identified via GWAS appear to be asso-ciated with increased risk of AD after accounting forAPOE (Schellenberg and Montine, 2012). Indeed, several

additional susceptibility genes appear to be important tothe risk of AD, confirming and extending previous esti-

mates that at least four to seven additional susceptibilitygenes may make a significant contribution to late-onset AD(Daw et al., 2000). Altogether 10 confirmed susceptibilitygenes, with nine discovered in the past 5 years via GWAS,are: ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1,MS4A4E/MS4A6A, PICALM and SORL1 (Schellenbergand Montine, 2012). Additional possible candidates haverecently emerged from analytical approaches that take agene-wide approach to evaluating association with the riskof AD rather than singleSNP markers (e.g. FRMD6, Hongetal., 2012).The pathways that some of thenewlyidentifiedsusceptibility genes implicate are briefly highlighted.

The genes APOE, SORL1, CLUand ABCA7play a rolein the lipid metabolism pathway (Schellenberg and Mon-tine, 2012). As summarised above the apoE proteinencoded by APOE, the most well-established susceptibilitygene forlate-onset AD, is the major cholesterol transporterin the brain, although it is expressed elsewhere (that is, inthe periphery); the e4 allele is associated with greater Abprotein deposition (Schellenberg and Montine, 2012). TheSORL1 gene encodes sortilin receptor 1 (SorL1), whichassists in the transport of the APP protein, a precursor ofAb, and also binds to lipoproteins (Schellenberg and

Montine, 2012). Multiple SORL1 SNP variants and hap-lotypes, both common and rare, have been associated withincreased risk of AD (Reitz et al., 2011; Schellenberg andMontine, 2012). The CLU gene, also known as APOJ,codes for apolipoprotein J (APOJ) andlike APOE servesasa cholesterol transporter in the brain and periphery; ApoJis proposed to influence Ab protein deposition (Schellen-berg and Montine, 2012). The ABCA7 gene encodes theadenosine triphosphate (ATP)-binding cassette (ABC) A7transporter and may affect the outflow (efflux) of phos-pholipidsand cholesterol fromcells, mediate the formationof high density lipoprotein (HDL, often referred to as thegood cholesterol) and may be implicated in cell injury

response processes (Schellenberg and Montine, 2012;Tanaka et al., 2011).

Other new susceptibility genes appear to be involved inimmune response, including MS4A4E/MS4A6A as well asCR1 and CD33, both of which encode for cell surfacereceptors. For example, CR1 appears to be involved in theclearance of immune complexes, which are bound anti-bodyantigen formations, and possibly in the clearance ofthe Ab protein (Schellenberg and Montine, 2012).

Other candidates appear to be involved in endocytosis

(e.g. BIN1, PICALM and CD2AP), a process by whichcells absorb or move extracellular protein molecules into

the cytoplasm, or cell adhesion (EPHA1) (Schellenbergand Montine, 2012). Other newly emergent susceptibility




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candidates, implicated using whole-gene methods, may beinvolved in pathways such as glycosylation or cell growth(e.g. FRMD6, Hong et al., 2012). For these and the otherrecently identified GWAS susceptibility genes, furtherresearch is necessary to identify and establish theirspecific functional roles that lead to an increased AD risk

(Schellenberg and Montine, 2012).

Summary

The APOE and SORL1 gene candidates have been con-firmed as increasing-AD risk after having been selected dueto a hypothesisedrole in AD pathogenesis; these geneshaveamassed a relatively greater or lesser body of evidence,respectively, that implicates their involvement in Abprotein deposition. The extent and manner in which thenewly identified susceptibility genes alter the risk of ADor moderate age of onset is yet unclear (ABCA7, BIN1,CD33, CD2AP, CLU, CR1, EPHA1, MS4A4E/MS4A6A,

PICALM, FRMD4A) however, these candidates suggest arole for pathways such as lipid metabolism, immuneresponse and cellular processes important to absorption ofproteins. Moreover, in comparison with APOE, the bal-ance of findings for these 10 additional genes, although

confirmed, suggests that they contribute to a lesser degreeto AD risk. The functional roles of these new susceptibilitygenes remain to be evaluated in future work.

Aetiological Heterogeneity

Gender

Studies of prevalence of AD in different groups areimportant because true differences between populationscan contribute to understanding of the underlying aeti-ology and risk factors. A higher prevalence of AD amongwomen than men has generally been found across epi-demiological studies, 14 17% versus 911% in overalllifetime risk estimates (Genin et al., 2011). Similarly, inci-

dence data (number of new cases of AD) suggest a higherrisk of AD amongwomen than men. In addition to survivaldifferences between men and women, the gender difference

in part may reflect differential gene action conferred inwomen compared with men. For example, APOEe4 hasbeen found to elevate risk of AD for women more so thanfor men (Genin et al., 2011).

Ethnicity

In general, cross-national comparisons suggest variationsin the prevalence of AD (Brookmeyer et al., 2011; Reitz etal., 2011). Studies from Asia tend to report lower preva-lence rates for AD, whereas higher rates are reported inWestern Europe and North America (Brookmeyer et al.,2011; Reitz et al., 2011). However, incidence (new cases) of

AD is relatively similar before age of 75, but differs at olderages likely due to differences in survival rates (Reitz et al.,

2011), where the relative impacts of acute versus chronicillness may vary in contributing to mortality. The preva-lence of AD appears to differ among some groups with thesame ethnic origins but living in different countries (Manlyand Mayeux, 2004). For example, although the prevalenceof AD appears higherin Japanese American menin Hawaii

compared with Japanese men in Japan (c.f., White et al.,1996), it does not differ for Japanese immigrants to Brazil

who arrived before the second World War (Ishii et al., 1999as cited in Manly and Mayeux, 2004). This finding suggeststhat environmental factors, in addition to genetic factors,may play a part in the development of the disease.

Differential risk associated with APOEe4 according toethnicity has been observed. Specifically, APOEe4appears to pose a significant risk to those of European orJapanese origins, but the e4 association may be attenuatedamong African Americans and Hispanics (Manly andMayeux, 2004); conversely, the risk of AD for none4 car-riers may be greater among African Americans and His-panics (Manly and Mayeux, 2004). A higher risk of ADamong African Americans and Hispanics compared withwhites, regardless of APOE status, has been reported(Manly and Mayeux, 2004). This suggests that other gen-etic or environmental influences may play a role in the riskof AD in these ethnic groups.

Environmental Factors

Age, familyhistory of dementia andAPOEe 4 arethe best-established risk factors for late-onset AD (Alzheimers

Association, 2012; Reitz et al., 2011). It is apparent thatnone of the best-established risk factors are reversible orpreventable. However, it is also true that none of these riskfactors assure that one will get AD. In addition, it is knownfrom twin studies that environmental risk factors must alsobe involved in the aetiology of AD. As for the genetic riskfactors for late-onset AD,it is important to remain mindfulthat although some of the described environmental riskfactors may be associated with an increase risk of AD,

observing an association or correlation does not establishcausality.

EducationCurrently, the best-established environmental risk factorfor AD is low education (Sharp and Gatz, 2011). Theeducation effect extends to dementia risk on the whole,albeit AD is the most common form of dementia (Sharpand Gatz, 2011). Determining the nature of the associationbetween education and AD has proved to be difficult.Education may serve as a surrogate for other factors thatcould be related to the risk of AD, such as intelligence,socioeconomic status or lifestyle and health habits (Gatzetal., 2006a). It is not easy to separate education level fromthese confounding variables. However, education is a

stronger predictor of AD or dementia risk where access toeducation is more available, andtherefore more likely to be




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reflective of cognitive capacity and less likely to be con-founded with socioeconomic status (Sharp and Gatz,2011). Also, the association between education and ADmay be partially due to diagnostic bias. Education levelmay affect scores on tests used for screening and dementiaassessment variables (Sharp and Gatz, 2011). Some studies

have found that those with less educationhave lower scoreson neuropsychological tests but not greater functional

deficits or that lower education predicts incident dementiarisk but not subsequent autopsy-defined neuropathology(see Sharp and Gatz, 2011).

The cognitive reserve model has been used to explain theassociation between education and AD (see Sharp andGatz, 2011; Stern, 2009). This idea is related to thethreshold model of dementia. Within this model, theamount of cognitivereserve is associated with the thresholdfor meeting dementia criteria. The amount of brain reservedue to innate factors, prenatal development and early braindevelopment during childhood may be reduced by damageto the brain that occurs over the life span. These processesmay determine whether and when the critical threshold ofviable brain tissue is reached and which dementia isapparent. Less cognitive reserve would mean that fewerchanges would be necessary to reach this threshold com-pared with those with greater cognitive reserve. Low edu-cational attainment may reflect less cognitive reserve(Sharp and Gatz, 2011). Alternatively, higher educationmay reflect engagement in more intellectually stimulatingactivities over the life span (Gatz et al., 2006a), whichwould hypothetically increase cognitive reserve.

Head injury

History of head injuryis commonlylisted as a probableriskfactor for AD. A metaanalysis of 15 case-control studiesconducted up to 2001 suggested that the risk of AD is

increased 1.5 times given a history of head injury but witheffects more prominent for men at more than two-fold therisk compared with women which showed no significant

elevation in risk (Fleminger et al., 2003). Prospectivestudies of head injury avoid recall biases, though findingsare not clear as to the nature of the increased risk. A studyof American male veterans of the Second World Waravoided theproblem of inaccurate recall by looking at head

injuries that were documented by military hospital records(Plassman et al., 2000), finding that head injury in earlyadulthood was associated with AD in later life. A popu-lation-based study suggested that head injury may hastenthe onset of ADbut did not increase the risk per se (Nemetzet al., 1999).

APOEe4 allele status may moderate the relationshipbetween head injury and AD risk, where recovery fromneurotrauma appears to be less optimal or extended for e4carriers (Dardiotis et al., 2012) and increased Ab depos-ition after head injury has been reported for some indi-viduals (Dardiotis et al., 2012). Indeed, a higher APOEe4

allele frequency has been noted among those with Abdeposition after head injury versus those without Ab

deposition after head injury (Verghese et al., 2011). How-ever, the relatively few available epidemiological studieshave provided inconsistent findings regarding the inter-action between APOEe4 allele status and history of headinjury on AD risk, although some characterise the evidenceof moderation of risk across neurological disorders on the

whole as strong (Verghese et al., 2011). It has been pro-posed that the association between head injury and AD

may be explained by reduced cognitive reserve due to thehead injury (Stern, 2009).

The results for head injury hearken back to the threshold

theory described earlier in this article that cumulative andperhaps interactive effects of genetic and environmentalrisk factors may tip ones risk of AD over a threshold,leading to or hastening the onset of the disease. None-theless, an increased risk due to environmental or geneticsusceptibility factors does not ensure a diagnosis.

Physical activity and ObesityLow physical activity and high body mass index (BMI) areeach associated with higher risks of chronic illnesses thatare in turn associated with poorer cognitive health in latelife, such as cerebrovascular disease and diabetes (Reitzet al., 2011). Moreover, higher midlife BMI and lowerphysical activity, respectfully, predict a higher risk of AD(Reitz et al., 2011). However, a higher BMI in late life maybe related to a reduced risk of AD (Reitz et al., 2011). Suchresults suggest that midlife weight may be particularlysalient to later AD risk. Indeed, higher midlife BMI anddeclines in BMI between mid andlate life maybe predictive

of worse cognitive performance across domains, and inparticular may potentiate decline in speed of processing

(Dahl et al., 2012), altogether leading to a higher risk ofpoor cognitive health in late life.

Exercise, particularly aerobic exercise, shows an overall

benefit to cognition in old age and may be related toincreased brain volume or levels of amyloid which mayaffect brain and cognitive reserve (Erickson et al., 2012;

Hertzog et al., 2009). Whether physical activity mitigatesAD risk irrespective of APOE genotype or is particularlybeneficial to those carrying one or more e4 alleles is notclear (Erickson et al., 2012; Miller et al., 2012). However,self-reported physical exercise engagement appears to be

correlated with amyloid plaque deposition in nondementedadults aged 45 to 88 years (Head et al., 2012), and seden-tariness was particularly negative in terms of increasedamyloid plaque deposition in APOE e4 carriers (Headet al., 2012).

Measurement of physical activity and related healthbehaviours (objective versus self-report), follow-up time,and sample selectivity are important to evaluate in futurework (Miller et al., 2012). Moreover, a life course per-spective on multiple health behaviours including physicalactivity and BMI may prove illuminative as to whether andwhen cognitive benefits depend in part on e4 status or

whether the benefits of physical activity or exercise mayapply equally (c.f., Obisesan et al., 2012).




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Leisure activities

Engagement in a variety of leisure activities has become afocus of research in the last decade and findings havepromoted notions of use it or lose it. Above, the findingson physical activity are discussed and thus cognitive and

socially oriented activities are focused on here. Engage-ment in cognitive activities such as reading, puzzles, cardgames or playing a musical instrument may be beneficial toreducing the risk of AD according to prospective cohortstudies (Hertzog et al., 2009; Reitz et al., 2011). This effectappears to hold even when controlling for other types ofactivities (e.g. Wilson et al., 2007). Similar to the physicalactivity literature, the evidence is less certain as to thebenefits of short-term cognitive exercise versus cognitiveengagement patterns developed and maintained over thelife course. For example, levels of engagement in cogni-tively oriented leisure activities are related to educationalattainment achieved in earlier adulthood (Gatz et al.,

2006a). Moreover, short-term cognitive-training benefitsappear to be specific to the type of cognitive task thatindividuals are trained on rather than showing globalbenefits (e.g. training on speed of processing tasks benefitspeed of processing abilities but does not enhance short-term memory, see Hertzog et al., 2009; Reitz et al., 2011).

Participation in socially oriented activities may be

beneficial to the maintenance of cognitive functioning anda reduced risk of AD (Hertzog et al., 2009), although moreconclusive evidence is needed. Change in cognitive healthmay affect level of participation in leisure activities(Fratiglioni et al., 2004). Thus, when social activities areassessed during the life course may be important toevaluating the directionality of the associations with ADrisk. Moreover, the quality or perceptions of social rela-tionships are not always included in studies of social net-works, which may affect findings (Fratiglioni et al., 2004;Hertzog et al., 2009). Some of the compelling evidence todate includes findings such as: the size of social networks isassociated with higher cognitive performance, particularlyfor memory tasks, and reduced AD-like neuropathology atautopsy (amyloid plaque load and density of neurofibillarytangles) (Bennett et al ., 2006), suggesting that socialinteractions may support cognitive reserve.

Overall, the direction of effect of the associations among

leisure activities is not entirely clear; for example, doesengagement in social, cognitive or even physical activitiesmitigate AD risk by bolstering cognitive or brain reserve ordo they act as a signal of an individuals state of health orcapacity? (cf., Bennett et al., 2006). Moreover, the unique

benefits of leisure activity types are not clear; for example,to what extent does physical activity directly promotecognitive health versus indirectly through social inter-

action components that may be inherent to some physicalactivities? (Miller et al., 2012).

Nonsteroidal anti-inflammatory drugs

Several studies have suggested that the long-term use ofnonsteroidal anti-inflammatory drugs (NSAIDs) may be a

protective factor against AD (McGeer and McGeer, 2007).Activation of factors associated with inflammatory pro-cesses in the brains of AD patients, such as microglialactivation and the presence of inflammatory cytokines,suggests that the possibly protective effect of NSAIDs maynot be spurious. Indeed, an analysis of American twins

discordant for AD reported that the unaffected twin wasmore likely to use anti-inflammatory drugs than the

affected twin (Breitner et al., 1994). However, a recentevaluation of 14 randomised-controlled trials suggests thatNSAIDs are not an effective treatment for already diag-

nosed AD patients (Jaturapatporn etal., 2012).More workis required to understand the role of inflammatory pro-cesses on AD risk andthe (lack of)effectiveness of NSAIDsas a putative treatment of AD.

Summary

The described risk factors and protective factors have

triggered the formulation of interesting hypotheses relatingto the aetiology of AD. Other proposed risk factors, whichvary in terms of empirical support, include history ofdepression, smoking, diabetes, dietary factors (e.g. possiblereduced risk with adherence to a Mediterranean-style diet)

and serum lipid levels (Reitz et al., 2011). Overall, meth-odological issues and complexity in the aetiology of ADmay hinder more definitive conclusions regarding envir-

onmental risk and protective factors for AD. Methodo-logical problems include: biased recall of risk factors;reliance on single reporters (self-report or proxy inform-

ants) without other validation sources; participant dropoutin longitudinal studies; and poor matching of AD cases tocontrol subjects. To some extent, prospective studies haveadded greater weight to some of the putative factors.However, randomised-controlled trials are needed toevaluate many of the possible treatments or interventions(Reitz et al., 2011). Lastly, researchers need to consider themultifactorial bases of the risk factors themselves (vanDongen et al., 2012) in order to understand more clearlytheir relationship to AD risk. Twin designs represent anespecially useful and informative way to progress inunderstanding about interactions between environmentaland genetic risk factors (van Dongen et al., 2012), wherebyanalysis of genotypic background or environmental

exposure can be fully controlled. Overcoming these andother methodological problems will further our knowledgeof risk factor mechanisms and will lead to greater under-

standing of AD aetiology.

Conclusions

Although a substantial portion of the liability of AD maybe accounted for by genetic factors, a significant role forenvironmental factors is likely. Twin studies provide her-itability estimates that suggest that the relative genetic

contribution to the liability for AD may be as high as 79%,though not 100%, implying that environmental influences




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are also important. The APOEe4 allele, the best docu-mented of possible genetic risk factors for late-onset AD,probably accounts forless than onequarterof allAD cases.New evidence for the influence of other genes has emerged,though further research is necessary to evaluate the smallfraction of the genetic risk for the disease that they explain.

Notably,other risk factors andprotective factors appeartoplay a role in AD risk, such as education, head injury and

NSAIDs use. Among the more interesting directions inresearch are geneenvironment interactions. The inter-action of environmental factors with genetic risk may

provide further clues about underlying mechanisms.Studies combining molecular genetics and behaviouralgenetics will be helpful in uncovering the complexities ofgeneenvironment interactions and the roles of specificgenes and risk factors contributing to liability for AD.Moreover, the gap between the small amount of variationcontributed by common susceptibility genes and the sub-stantial heritability observed in twin and family studiesmay be further clarified. Altogether, a developmentallongitudinal perspective on the salience of (and interactionamong) particular risk and protective factors over the lifecourse may increase an understanding of AD etiologiesand illuminate potential points of intervention. See also:Alzheimer Disease, Genetics of; Genetics of Dementia

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Internet-based Forecasting of the Burden of Alzheimers Disease:

iFBAD http://www.biostat.jhsph.edu/project/globalAD/

indexpage2.htm [Accessed 9 September 2012].



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