VIEW Genetics of Alzheimer Disease in the Pre- and Post-GWAS Era Nilüfer Ertekin-Taner*

Ertekin-Taner Alzheimer’s Research & Therapy 2010, 2:3 http://alzres.com/content/2/1/3 REVIEW Genetics of Alzheimer disease in the pre- and post-GWAS era Nilüfer Ertekin-Taner* substantial genetic component that has an estimated Abstract heritability of 58% to 79% [4], and the lifetime risk of AD Since the 1990s, the genetics of Alzheimer disease (AD) in fi rst-degree relatives of patients may be twice that of has been an active area of research. The identifi cation the general population [5]. Families with autosomal of deterministic mutations in the APP, PSEN1, and PSEN2 dominant transmission of AD were described in the genes responsible for early-onset autosomal dominant literature in the 1980s [6]. In the early 1990s, segregation familial forms of AD led to a better understanding of analysis studies suggested the presence of Mendelian, the pathophysiology of this disease. In the past decade, autosomal, dominant risk factors under lying the risk of the plethora of candidate genes and regions emerging early-onset AD, whereas a more complex model possibly from genetic linkage and smaller-scale association involving polygenes and environmental factors emerged studies yielded intriguing ‘hits’ that have often proven for late-onset AD (LOAD) [7,8]. Th e identifi cation of diffi cult to replicate consistently. In the last two years, homology in the Aβ peptide isolated from brains of 11 published genome-wide association studies patients with AD and trisomy 21 (Down syndrome) and (GWASs) in AD confi rmed the universally accepted localization of the amyloid precursor protein (APP) to role of APOE as a genetic risk factor for late-onset AD chromosome 21 [9,10], where linkage to disease risk was as well as generating additional candidate genes that mapped in early-onset familial AD (EOFAD) families require confi rmation. It is unclear whether GWASs, [11,12], led to the discovery of fi rst autosomal dominant though a promising novel approach in the genetics missense mutations in APP segre gat ing with disease risk of complex diseases, can help explain most of the [13]. Th is was followed by identi fi cations of autosomal underlying genetic risk for AD. This review provides a dominant EOFAD mutations in the presenilin 1 (PSEN1) brief summary of the genetic studies in AD preceding [14] and PSEN2 [15,16] genes, on chromosomes 14 and 1, the GWAS era, with the main focus on the fi ndings respectively. Th e summary of EOFAD mutations is from recent GWASs. Potential approaches that could maintained at the Alzheimer Disease and Frontotemporal provide further insight into the genetics of AD in the Dementia Mutation Data base [17,18]. Accordingly, there post-GWAS era are also discussed. are currently 32 mutations in APP, 177 in PSEN1, and 14 in PSEN2, identifi ed in 86, 392, and 23 families, respectively. Collectively, the EOFAD mutations in these Genetics of Alzheimer disease in the pre-GWAS era three genes account for less than 1% of all AD. Early-onset familial Alzheimer disease Aβ, the major peptide constituent of senile plaques, is Alzheimer disease (AD), the most common dementia, cleaved from APP fi rst by β-secretase, then by the γ- currently aff ects an estimated 35 million patients world- secretase complex, of which presenilin is a required wide [1] and is characterized by extracellular accumu la- compo nent. Despite the rarity of APP and PSEN mutation of the amyloid β (Aβ) peptide in senile plaques and tions, their functional evaluation in transfected cells intracellular accumulation of the abnormally hyper- [19,20], transgenic animals [21,22], and human plasma phosphorylated tau forming neurofi brillary tangles in the [23] identifi ed elevations in Aβ levels, increased Aβ42/ brain [2,3]. Th ere is evidence from familial aggregation, Aβ40 ratio, or fi brillogenesis, which constituted the transmission patterns, and twin studies that AD has a cornerstone of the amyloid cascade hypothesis [24]. Accordingly, increases in the toxic forms of Aβ lead to a *Correspondence: [email protected] cascade of events – including infl ammation, synaptic Mayo Clinic Florida, Departments of Neurology and Neuroscience, 4500 San Pablo loss, ionic imbalance, and abnormal phosphorylation of Road, Birdsall 210, Jacksonville, FL 32224 USA proteins (including tau) – culminating in cell death and underlying clinical dementia. Th ere exist alternative © 2010 BioMed Central Ltd © 2010 BioMed Central Ltd hypo theses suggesting tau [25] or dominant negative loss Ertekin-Taner Alzheimer’s Research & Therapy 2010, 2:3 Page 2 of 12 http://alzres.com/content/2/1/3 of presenilin function [26] as additional pathophysiologic APOE has a stronger eff ect in younger ages (from mechanisms underlying AD. younger than age 70 to eighties) and longitudinal studies may provide more accurate estimates of PAR of APOE Late-onset Alzheimer disease where estimates of 20% were obtained [35,37,38]. Statis- Th e identifi cation of a chromosome 19 risk locus in tical approaches suggesting the presence of AD loci in LOAD families [27] was followed by the discovery of a addition to APOE [39] led to intensive research eff orts in higher frequency of the APOE ε4 allele in LOAD patients the genetics of LOAD. compared with controls [28,29]. APOE is a component of senile plaques [30], binds Aβ [31], can infl uence neuritic Linkage and smaller-scale association studies plaque formation in transgenic mouse models of AD in Generation of the genetic and physical map of the human an isoform-specifi c fashion [32], and is thought to genome [40] largely based on polymorphic tandem contribute to both Aβ clearance and deposition in the repeat regions led to the fi rst-generation genome-wide brain [33]. In vitro and in vivo studies also suggest a role scans in AD as well as many other diseases. Ten inde pen- for APOE in isoform-specifi c synaptogenesis and cog- dent whole-genome linkage and four association studies nition, neurotoxicity, tau hyperphosphorylation, neuro- in AD were completed using microsatellite markers infl ammation, and brain metabolism, although these (reviewed in [35]) between 1997 and 2006. Th ese studies non-Aβ-related mechanisms require further investigation typically used approximately 200 to 400 micro satellite [34]. Unlike the EOFAD mutations that are fully pene- markers, covering the genome at every 5 to 16 centi- trant, APOE ε4 is a genetic risk factor that is neither morgans (1 cM is approximately equal to 1 million base necessary nor suffi cient for the development of AD (see pairs). Th e whole-genome linkage studies were conducted [35] for review of APOE in LOAD). Th e odds that APOE in AD families or sibships collectively composed of about ε3/ε4 genotype carriers have AD is estimated to be two to 100 to 2,000 subjects. Whole-genome association studies four times greater than that of APOE ε3/ε3 carriers, were conducted on AD case-control series composed of a according to population-based association studies in small number of subjects (n is approximately equal to 10 subjects of European origin. Th e odds ratio (OR) to 210, including an approximately equal number of AD increases to approximately 6 to 30 in the APOE ε4/ε4 patients and controls). Th ese studies were hypothesis- genotype carriers. Although there is evidence of a risk free (or hypothesis-generating) in that they provided a eff ect of APOE ε4 in non-Europeans, the estimated eff ect survey of the whole genome without requiring any prior sizes are smaller with less consistent results in African- knowledge or theory about the genes/genomic regions American and Hispanic subjects, which may suggest for their role in AD. All of the studies that were done in diff erent underlying genetic or environmental factors or subjects of European origin identifi ed the APOE region both for these ethnic groups. Th e eff ect of APOE ε4 on chromo some 19 as a risk region in AD. Importantly, appears to be age-dependent, with the strongest eff ect however, they also detected other genetic regions, at observed before age 70. Th e use of APOE as a diagnostic times with a signal stronger than that of APOE. Some of [36] or predictive factor in clinical practice is not these regions were detected in multiple independent warranted. Population attributable risk (PAR) of AD due studies, strongly suggesting the presence of non-APOE to a genetic factor describes the diff erence in rate of AD genetic factors underlying the risk of AD. Loci on in the population between those who are carriers of the chromosomes 6, 9, 10, and 12 [29,35] yielded multiple, genetic risk versus those who are not. Another way to independent, strong signals that led to subsequent fi ne- consider PAR is the amount of decrease that would be mapping eff orts, which have proven diffi cult due to the observed in the incidence of AD if the genetic factor typically large regions identifi ed in these studies covering could be eliminated. It is important to note that the PAR tens of millions of base pairs. Nonetheless, these fi ndings due to a combination of risk factors is usually smaller generated positional and functional candidate genes that than the sum of PARs from multiple risk factors because were assessed in association studies. a person with disease may have more than one risk factor Th e identifi cation of single-nucleotide polymorphisms (that is, the cause of disease in any given case may be (SNPs) in the human genome [41] and development of attributable to more than one factor). Th e estimated high-throughput SNP genotyping technologies galva- LOAD PAR for APOE is 20% to 70% [4,35].

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