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Neurobiology of Aging 41 (2016) 115e121

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Neurobiology of Aging
journal homepage: www.elsevier.com/locate/neuaging

The executive prominent/memory prominent spectrum in
Alzheimer’s disease are highly heritable
Jesse Mez a, Shubhabrata Mukherjee b, Timothy Thornton c, David W. Fardo d,
Emily Trittschuh e, Sheila Sutti f, Richard Sherva g, John S. Kauwe h, Adam C. Naj i,
Gary W. Beecham j, Alden Gross k, Andrew J. Saykin l, Robert C. Green f, Paul K. Crane b, *,
for Executive Prominent Alzheimer’s Disease: Genetics and Risk Factors
(EPAD:GRF), the Alzheimer’s Disease Neuroimaging Initiative (ADNI1)1, and
the Alzheimer’s Disease Genetics Consortium (ADGC)
a

Alzheimer’s Disease Center, Department of Neurology, Boston University School of Medicine, Boston, MA, USA
Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
Department of Biostatistics, University of Washington, Seattle, WA, USA
d
Department of Biostatistics, University of Kentucky College of Public Health, Lexington, KY, USA
e
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
f
G2P Program, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
g
Biomedical Genetics, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
h
Department of Biology, Brigham Young University, Provo, UT, USA
i
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
j
Miller School of Medicine, Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation, Department of Human Genetics,
University of Miami, Miami, FL, USA
k
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
l
IU Health Neuroscience Center, Department of Radiology, Indiana University, Indianapolis, IN, USA
b
c

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 20 October 2015
Received in revised form 11 February 2016
Accepted 13 February 2016
Available online 21 February 2016

Late-onset Alzheimer’s disease (LOAD) can present heterogeneously, with several subtypes recognized,
including dysexecutive AD. One way to identify people with dysexecutive AD is to consider the difference between memory and executive functioning, which we refer to as the executive prominent/
memory prominent spectrum. We aimed to determine if this spectrum was heritable. We used neuropsychological and genetic data from people with mild LOAD (Clinical Dementia Rating 0.5 or 1.0)
from the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging
Initiative. We cocalibrated the neuropsychological data to obtain executive functioning and memory
scores and used their difference as a continuous phenotype to calculate its heritability overall and by
chromosome. Narrow-sense heritability of the difference between memory and executive functioning
scores was 0.68 (standard error 0.12). Single nucleotide polymorphisms on chromosomes 1, 2, 4, 11, 12,
and 18 explained the largest fraction of phenotypic variance, with signals from each chromosome
accounting for 5%e7%. The chromosomal pattern of heritability differed substantially from that of
LOAD itself.
Ó 2016 Published by Elsevier Inc.

Keywords:
Dysexecutive Alzheimer’s disease
Executive function
Memory
Atypical Alzheimer’s disease
Heritability
Genetics

1. Introduction
* Corresponding author at: Harborview Medical Center, Box 359780, 325 Ninth
Avenue, Seattle, WA, 98104, USA. Tel.: 206 744 1831; fax: 206 897 4688.
E-mail address: pcrane@uw.edu (P.K. Crane).
1
Data used in preparation of this article were obtained from the Alzheimer’s
Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the
investigators within the ADNI contributed to the design and implementation of
ADNI and/or provided data but did not participate in analysis or writing of this
report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.
edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
0197-4580/$ e see front matter Ó 2016 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.neurobiolaging.2016.02.015

Alzheimer’s disease (AD) is the most common form of agerelated dementia, and most cases of AD occur late in life, referred
to as late-onset AD (LOAD). Although LOAD subtypes are well
recognized clinically and in research criteria for LOAD (Dubois et al.,
2014), they are typically not considered in analyses aimed at
elucidating the genetic architecture underlying LOAD (see, e.g.,
[Lambert et al., 2013; Naj et al., 2011]). People with dysexecutive AD,

001 10. 2013a... Rey Auditory Verbal Learning Test.9) (12. in which people with relatively intact executive functioning but profoundly poor memory performance are at 1 end. Mez et al. . That difference defines an executive prominent/memory prominent spectrum.0) Vegetable list generation. Beyond the APOE locus.1 (7. Participants ADNI was launched in 2003 by the National Institute on Aging. Participants were either prevalent cases (i. 2013a.1 (2.0) <0. Informed consent was provided by each participant or..6 (1. mean (SD) 3. dysexecutive ADdare at the other. participant evaluation. the National Institute of Biomedical Imaging and Bioengineering. 2011. RAVLT.5 (2.6 (33.9 (3. For prevalent cases. NACC. Data are uploaded to NACC regularly. 2013). judgment.2) ADAS-cog delayed recall.9) Trail making test part B. delay. Weschler Adult Intelligence Scale-Revised. we restricted our sample to people with a Clinical Dementia Rating (CDR) of 0. MMSE. problem solving. We constructed measures of executive functioning and memory from the neuropsychological testing data from these studies and used the difference between these scores as a continuous phenotype among people with LOAD. We excluded participants aged less than 60 years.2%) Global measures CDR 1. National Alzheimer’s Coordinating Center. 5-year publicprivate partnership. standard deviation.8) RAVLT. and genetic characteristics (Dickerson and Wolk. Mez et al.9) ADAS-cog trials 1e3.03 (8.1 (101.7 69. and mental flexibility (Stuss and Alexander. 2012) to cocalibrate neuropsychological data from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI1) and National Alzheimer’s Coordinating Center (NACC) databases.7%) Age in years. mean (SD) 76. reasoning. mean (SD) 17. Data collection was approved by an institutional review board at each site.4) RAVLT. 2007). the Food and Drug Administration. mean (SD) 8. 2012. Each site enrolled participants and collected neuropsychological data using a single neuropsychological battery. mean (SD) 60. imaging.2 (3. 2011.5) (1.5 or 1.. ADNI. biological markers. mean (SD) 13.001 1. Mez et al. and diagnostic criteria for dementia. For incident cases. defined as the fraction of phenotypic variance explained by additive genetic effects. 2011.6 (4.0 360 p-valuea (50.001 (3. Previous work suggests that the APOE ε4 allele (chromosome 19) is less frequent in people with dysexecutive AD than that in people with more typical memory-prominent LOAD (Dickerson and Wolk.2) Memory tests Logical memory. One way to identify people with dysexecutive AD is to consider the difference between executive functioning and memory scores (Dickerson and Wolk. as a $60 million..4 6. Mini-Mental State Examination.001 <0.001 <0.0) APOE ε4 carrier (%)b 203 (67.0 (5. 2013b.3) RAVLT. c An X indicates that the test was not administered.6 217. Mueller et al. Mukherjee et al.9 (4.99) NACC (n ¼ 624) 313 79. we analyzed data from the first visit at which a LOAD diagnosis was made.61 X X X X X X X Xd Key: ADAS-Cog. There were not sufficient indicators of language or visuospatial functioning to derive robust measures of these cognitive domains.7) (3. Executive dysfunction refers to deficits in planning. 2006. 4. list B. mean (SD) 15. and possible LOAD have been detailed elsewhere (Morris et al.6) <0. mean (SD) 29. 2010).1 (7. The primary goal of ADNI has been to test whether imaging measures. a p-values were obtained using t-tests for continuous variables and Pearson c2 tests for categorical variables. People with LOAD categorized in this way have been found to have distinct clinical. Alzheimer’s Disease Neuroimaging Initiative. Years of education were ascertained by self-report. 1993). 2012).3) Digit span backward.001 3. 2015). Table 1 Participant characteristics Characteristic ADNI (n ¼ 302) Demographic characteristics Female (%) 129 (42.. by legally authorized representatives.2) mean (SD) Logical memory.e. We used neuropsychological and genetic data from 2 large USbased consortia to evaluate the heritability of the executive prominent/memory prominent spectrum among people with LOAD.0 (Morris. mean (SD) 1. 2013a. SD.5 (1... it is unclear to what extent genetic versus nongenetic factors contribute to the executive prominent/memory prominent spectrum among people with LOAD. immediate recall.6 (3.4) Trail making test part A. mean (SD) 8. Snowden et al.9 (3.0 4.1) <0.0) WAIS-R digit symbol. delayed recall. abstraction. 2013).. mean (SD) 1. Because we were interested in mild LOAD. We hypothesized that this spectrum would be heritable and furthermore that the pattern of heritability would be different from that of LOAD itself (Ridge et al. Alzheimer’s Disease Assessment ScheduleeCognitive.0) 0. recognition. d Although NACC administered the MMSE.1. and people with relatively intact memory but profoundly poor executive functioningdthat is. CDR.001 <0. if they lacked capacity to consent.7%) MMSE. 2. present with prominent executive dysfunction.001 21. We also performed a genome-wide association study of the difference between executive functioning and memory among people with LOAD. 2013b.3 (3. trials 1e5.2%) 0. mean (SD) 3. Overview We used a well-validated psychometric approach (Mukherjee et al. / Neurobiology of Aging 41 (2016) 115e121 a LOAD subtype. organization. mean (SD) 187.2. mean (SD) 23. and nonprofit organizations. scores for recall in particular were not available.4) Executive functioning tests Animal list generation.. We estimated the heritability of this phenotype by chromosome and compared this chromosomal pattern of heritability with recently published chromosomal heritability estimates for LOAD (Ridge et al. probable LOAD.. were given a LOAD diagnosis at a follow-up study visit).. Ossenkoppele et al.e.001 (59. mean (SD) 0. Recruitment.9 X (4.2 (3.. mean (SD) 23. private pharmaceutical companies.1%) <0.3) (84.8 24. b 18 people were missing APOE genotype data.9) (39. Weiner et al. Table 1 shows the executive functioning and memory tests administered. WAIS-R. 2005.. attention. were given a LOAD diagnosis at their initial study visit) or incident cases (i.5) RAVLT.91 (0. ADNI and NACC have similar neuropsychological batteries. mean (SD) 5. Mez et al.02 <0. mean (SD) 0.001 0.1 (12. we analyzed data from the baseline visit. Methods 2.4) RAVLT.4%) 438 (70.116 J. Mukherjee et al. NACC developed and maintains a large relational database of standardized clinical research data collected from the 29 National Institute on Aging efunded AD Centers and AD Research Centers.0) <0. 2. however.0 (%) 128 (42.5 (1.6 (1.3) c Clock drawing. We used Genome-wide Complex Trait Analysis (GCTA. immediate. 2007). the Uniform Data Set.6 (2. mean (SD) 7.. 2011) to calculate a lower bound for narrowsense heritability. Clinical Dementia Rating Scale.0 14. and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment and mild AD.. which include several tests of executive functioning and memory.6) MMSE recall.1 (1.4) <0.3) Education in years. Yang et al.

8. and those with memory> 1 SD worse than executive functioning. 2006) to derive principal components based on common genotyped SNPs across studies. 2009) to perform genome-wide imputation of allele dosages separately for each cohort using the December 2010 1000 Genomes European ancestry reference panel (build 37) (Abecasis et al. We addressed cryptic relatedness within and across studies using KING software (Manichaikul et al. or in the preparation. review. those with memory 0. Gibbons et al.9 years older. and ε4 alleles were genotyped separately (Naj et al. and could better differentiate rates of decline between participants with mild cognitive impairment with and without AD cerebrospinal fluid signatures (Crane et al.7.. For descriptive purposes we defined 5 groups: those with executive functioning >1 standard deviation (SD) worse than memory. 2012). The largest proportion of people with LOAD had memory scores >1 SD worse than executive functioning scores (44% in ADNI and 40% in NACC). We included age. had 1. for ADNI. whereas a negative score reflects more executive than memory impairment. We estimated heritability for our difference score with a mixed linear model that included all SNPs and treated their effects as random effects.. was more strongly associated with ADrelated imaging parameters. We only included individuals of self-reported European ancestry.. 2009.5e1 SD worse than executive functioning. for quality control (QC). Gibbons et al.. we sought to maximize measurement precision for executive functioning by including as many indicators that reflected executive functioning as were available in the battery.5 SD of each other. San Diego. 2. 2010) after performing linkage disequilibrium pruning on post-QCegenotyped SNPs. NACC participants. as there were too few with non-European ancestry to derive meaningful results. Role of the funding sources The funders of the study had no role in the design and conduct of the study. management. 2013). 2011).. 2008). We then calculated executive functioning and memory scores for all NACC participants using ADNI-EF and ADNI-Mem parameters. quality control. on average. Overlapping test items between NACC and ADNI shown in Table 1 served as anchor test items administered in both studies. The distribution of the difference between executive functioning and memory among people with LOAD is shown in Table 2.3. This measurement precision comes at the expense of including indicators that may also reflect abilities in other domains such as visuospatial abilities or language (Gibbons et al. Sizable proportions had executive functioning scores 0. USA) were used for genotyping. and imputation Methods for acquisition and processing of genotype data have been previously described (Naj et al. with the same analytic framework as for the heritability analyses. Inc.. We subtracted memory scores from executive functioning scores to create a difference score. 2011. rs7412) that define the ε2. 2009. we previously developed composite memory (ADNI-Mem) and composite executive functioning (ADNIEF) scores using modern psychometric approaches (Crane et al. the collection.. 2012. rs429358. Narrow-sense heritability calculations Narrow-sense heritability is defined as the proportion of phenotypic variance explained by additive genetic effects.. Construction of the phenotype: the difference between executive functioning and memory scores among people with LOAD Among ADNI participants. Compared with individual test scores. Cocalibration refers to combining test scores across studies into a single metric. Potkin et al.6. We cocalibrated ADNI-Mem and ADNI-EF scores with NACC item level data to obtain composite executive functioning and memory scores from NACC participants on the same metric as ADNI participants based on methods we previously We used linear regression in PLINK (Purcell et al. Lower scores for ADNI-Mem and ADNI-EF reflect poorer performance. A positive difference score reflects more memory than executive impairment. and interpretation of the data.5e1 SD worse than memory. 3.. We only included imputed SNP dosages with imputation quality 0. / Neurobiology of Aging 41 (2016) 115e121 2. population substructure. We excluded participants if reported sex differed from the sex designation established by X-chromosome analyses. 2007) and obtained a common set of 4. Genotyping. call rate <95%. ε3. 2012).5e1 . ADNI-Mem and ADNI-EF encompass performance on all of the ADNI executive functioning and memory neuropsychological tests in Table 1.01. 2012). 2. 2012). We used IMPUTE2 (Howie et al. the Human610-Quad BeadChip. 2010). CA. and conducted analyses across all chromosomes and for each chromosome separately using GCTA software (Yang et al.... We included directly genotyped SNPs and imputed SNPs as dosages.5.4. the Human660-Quad or the OmniExpress BeadChips (Illumina.. each composite score was as good or better at detecting change over time. 117 published (Crane et al.405 SNPs after a strict postimputation QC that excluded SNPs with minor allele frequency <0.. As explained in the initial ADNI-EF article. 2. we excluded SNPs with minor allele frequency <0.2 fewer years of education.01 or call rate <98% on the combined data set. We used structural equation modeling with Mplus software (Muthen and Muthen. Saykin et al. Before imputation. Our final “unrelated” data set (n ¼ 926) excluded third degree or closer relatives (kinship coefficient 0.. and for NACC. Saykin et al. We evaluated population substructure in the 2 cohorts together.819. Other phenotypes We used the same framework to estimate heritability of executive functioning alone and memory alone.. Briefly. Results Table 1 shows demographic and clinical characteristics and neuropsychological test performance among ADNI and NACC participants.J. 1998e2004) to parameterize relationships between anchor test items. sex. The 2 APOE single nucleotide polymorphisms (SNPs. 2011. 2007) to perform a GWAS using the difference between executive functioning and memory. were somewhat more impaired on the CDR and Mini-Mental State Examination and were more impaired on all neuropsychological tests administered in both cohorts except logical memory delayed recall. We used EIGENSTRAT (Price et al. 2. those with executive functioning 0. or approval of the article. We combined the 2 data sets using PLINK (Purcell et al. genotyping platform and 3 principal components as fixed effects. Potkin et al.50 in both data sets.. 2012. were 2. analysis. We removed outliers whose genetic profiles were inconsistent with European ancestry.. those with executive functioning and memory within 0. or not in HardyeWeinberg equilibrium (p < 106). Genome-wide association study (GWAS) 2. Mez et al. had a higher proportion of women. 2010)... We plotted chromosome-level findings alongside those previously published for LOAD (Ridge et al.0442).

and even more had executive functioning scores >1 SD below memory scores (11% in ADNI and 13% in NACC). Standard deviation.003). 4.01) but was not significantly associated with executive b ¼ 0. Mez et al. and narrow-sense heritability for memory was 0. Snowden et al. with the largest signals on chromosomes 1.3).. (b p-value ¼ 0. This study provides evidence that the executive prominent/ memory prominent spectrum among patients with LOAD is highly heritable. number of genes on each chromosome ( b In the same population. and 18. p-value ¼ 0. Recently McLaughlin et al. discussed GCTA versus twin studyebased heritability estimates and noted that GCTA may provide a lower bound on heritability (McLaughlin et al. or the difference between executive functioning and memory scores. 2015). Chromosomal phenotypic variability.. The narrow-sense heritability of the difference between executive functioning and memory was 0. The executive prominent/memory prominent spectrum were much more heritable than executive functioning or memory separately. 2013).22. was highly heritable with a narrow-sense heritability of 0. Although sample sizes for some of these investigations were small. 2011. SNPs on chromosomes 1. The present report is the first to address heritability of the executive prominent/ memory prominent spectrum among people with LOAD.5). 2. 2013). of 926 people with mild LOAD. Because APOE genotype had previously been implicated in the variation in executive functioning and memory in AD (Dickerson Fig.5 SD worse than memory scores. 4. The LOAD executive functioningememory difference score was derived using cocalibrated executive functioning and memory composite scores from the Alzheimer’s Disease Neuroimaging Initiative and the National Alzheimer’s Coordinating Center. with the data available to us.5 SD worse than their memory scores.21.5e1 SD lower than memory Executive functioning and memory within 0. Patients presenting with dysexecutive AD have distinctive pathologic. 11. . 2007).7. NACC.. Mez et al.08. p ¼ 0. Patients with dysexecutive AD had greater frontoparietal cortical thinning than healthy controls or people with more typical memory-prominent AD (Dickerson and Wolk. p-value ¼ 0. p-value ¼ 0. the APOE ε4 allele was associated with more impairment in memory b ¼ 0.... functioning ( b In GWAS analyses.. no SNPs achieved genome-wide significance.10 (standard error ¼ 0. 2005). there are no twin studies we are aware of.1e0. 11. it appeared that people with executive functioning scores worse than memory had similar patterns of findings in these analyses compared with other people with LOAD (p-values: 0.. 2013a. 18% of people with LOAD from ADNI and 22% of people with LOAD from NACC had executive functioning scores at least 0. The executive prominent/memory prominent spectrum. 12. 193 (21%) had executive functioning scores at least 0.68 (standard error ¼ 0. We show data from those evaluations stratified by differences between executive functioning and memory scores in Supplementary Tables 1e4. 2015). 1). The chromosomal pattern of heritability of the executive prominent/memory prominent spectrum was distinct from the previously published pattern of heritability of LOAD (Ridge et al. defined by the difference between executive functioning and memory scores. The chromosomal pattern of heritability for the difference between executive functioning and memory was distinct from that for executive functioning itself and memory itself (See Supplementary Table 5 and Fig. Alzheimer’s Disease Neuroimaging Initiative. narrow-sense heritability for executive functioning itself was 0. A recent article using a similar approach adds additional support to the notion that dysexecutive AD has distinct imaging and clinical characteristics compared to more typical memory-prominent LOAD (Ossenkoppele et al.10. SD below memory scores (7% in ADNI and 9% in NACC).12. p-value ¼ 0. Our calculation of 0$68 may reflect a lower bound for narrow-sense heritability because it does not consider additional genetic effects from rare variants and from gene  gene or gene  environment interactions. the executive functioning score. National Alzheimer’s Coordinating Center. A small case series found that patients with dysexecutive AD had disproportionate amyloid plaque and neurofibrillary tangle burden in the frontal lobes (Johnson et al. p-value ¼ 0. Future studies may address this. 2011). Phenotypic variability explained by each chromosome for the continuous LOAD executive functioningememory difference score (blue) and dichotomous LOAD case-control status (green).68 (standard error 0. we used linear regression under an additive model to test whether the APOE ε4 allele was associated with the memory score. SD. and clinical characteristics compared with patients presenting with more typical memory-prominent LOAD. Phenotypic variance explained by each chromosome was not b ¼ 0. 1). 12. imaging.5e1 SD lower than executive functioning Memory >1 SD lower than executive functioning Total ADNI NACC 34 (11%) 84 (13%) 21 (7%) 54 (9%) 72 (24%) 137 (22%) 41 (14%) 98 (16%) 134 (44%) 251 (40%) 302 624 Key: ADNI. 4. Discussion In this study.003) among people from NACC and ADNI with LOAD. In all. Furthermore.5 SD Memory 0. / Neurobiology of Aging 41 (2016) 115e121 Table 2 Distribution of differences between executive functioning and memory scores Study Executive functioning >1 SD lower than memory Executive functioning 0.12) or the associated with chromosome length ( b b ¼ 0. where combined signals from each of these chromosomes accounted for 5%e7% of the overall phenotypic variance (Fig. 2. and some from ADNI had amyloid PET imaging and/or cerebrospinal fluid biomarker data available.01.11.98). p-value ¼ 0. 1.03) and a larger difference score ( bb ¼ 0.01 (standard error ¼ 0. and 18 accounted for the largest proportion of the phenotypic variance. suggesting some degree of executive prominence.21). p ¼ 0.38. Some participants from NACC had autopsy data available. Patients with dysexecutive AD declined more quickly on measures of cognition and daily functioning compared with patients with the more typical memoryprominent LOAD (Mez et al. see Supplementary Tables 1e4). After controlling for covariates. The LOAD case-control phenotypic variability was derived previously using data from the Alzheimer’s Disease Genetic Consortium (Ridge et al. they suggest that differences between GCTA-based heritability estimates and twin studyebased estimates may be useful to understand missing heritability.12.118 J. and Wolk. 2013b).

Other than our own prior analysis of the ADNI data set (Mukherjee et al. It will be important to compare findings across other study designs to determine the extent to which idiosyncrasies in enrollment criteria and research focus may have an influence on findings.. which has a higher proportion of people with APOE ε4 than the general population. 2013a. F. Pfizer Inc. Nevertheless. We were not able to compare findings from the NACC data to those from the ADNI data. we enhanced comparability by restricting study participants to those having a CDR of 0. 119 Although evaluation of the genetic architecture of disease subtypes has been applied in several conditions. ADGC: The National Institutes of Health... That study identified the C9orf72 locus with genome-wide significant findings in people with overlapping motor neuron disease but not in other FTD subtypes and not in the combined group of everyone with FTD. The study also demonstrates that genetic factors associated with LOAD risk appear to be different from genetic factors associated with the executive prominent/memory prominent spectrum among people with LOAD.fnih. Biogen.. Future studies may also consider incorporating data from cognitively normal elderly controls. Samples from the National Cell .. This work confirms and extends previous findings relating to APOE genotype (Dickerson and Wolk. 5. Mez et al.. Future studies should specifically address heterogeneity among people with LOAD. Piramal Imaging. Only a subset of participants in these studies had neuropathology or fluid biomarker data. Conversely. Janssen Alzheimer Immunotherapy Research & Development. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www. CereSpir. genetic analyses of dysexecutive AD have been limited to the APOE genotype (Dickerson and Wolk. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.5 or 1. ADNI is funded by the National Institute on Aging. Lumosity. A recent article on frontotemporal dementia (FTD) used a similar strategy to evaluate genetic architecture of FTD subtypes (Ferrari et al. Less attention has been paid to genomewide genetic analyses of LOAD subtypes.. 2007). 2013a. that people with LOAD with 1 APOE ε4 allele are more likely to have the more typical memoryprominent AD than to have dysexecutive AD.e. i. 2013). This finding should be understood in the context of the sample we studied. providing a more precise estimate of narrow-sense heritability. Inc. mainly stemming from the modest sample size. Novartis Pharmaceuticals Corporation. and through generous contributions from the following: AbbVie. Araclon Biotech. 2014). Alzheimer’s Association. explain a substantial proportion of LOAD’s variability but only a small proportion of the variability of the executive prominent/memory prominent spectrum (Fig.. EuroImmun. To date over 20 genetic loci have been identified to be associated with the risk of LOAD (Lambert et al. EPAD:GRF is funded by the National Institute on Aging. together with those presented here. Although ADNI focuses on early-stage LOAD and NACC includes people from across the LOAD-severity spectrum.. aU01 AG032984. the APOE ε4 effect did not approach genome-wide significance. Meso Scale Diagnostics. The field has been characterized by coordinated efforts to search for variants associated with LOAD risk using ever-larger coalitions of research studies and more genetic variants. Lundbeck. 14. Disclosure statement The authors have no conflicts of interest to disclose. 2014). Inc. 2014). Eli Lilly and Company. Our study has several weaknesses. RC2 AG036528. and Transition Therapeutics. Hoffmann-La Roche Ltd and its affiliated company Genentech. ADNI and NACC are large convenience-based samples.. Inc. Merck & Co. We plan to augment our sample by evaluating neuropsychological and genetic data from additional cohorts. especially congenital heart disease (Cordell et al. it will be important to repeat these analyses among people with biomarker confirmation of AD pathology. no single variant achieved genome wide significance in our genome wide association analyses. likely because of sample size. Larger samples would reduce the standard error.. Snowden et al. Neurotrack Technologies. Fujirebio. BioClinica. This work places those findings in a broader context. Narrow-sense heritability estimates for chromosomes 3. National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC. GE Healthcare. we are not able to firmly conclude that our findings are related specifically to executive functioning and not other domains such as language or visuospatial ability. Snowden et al. its use in neurogenetics is rare (Girard and Rouleau.. LLC. 2007). The pattern of phenotypic variability explained by SNPs on each chromosome differed substantially from that of previously published findings for LOAD. Genetic variation explains at least 2/3s of the variance of this executive prominent/memory prominent spectrum among people with LOAD. Elan Pharmaceuticals. 1). IXICO Ltd.org). Servier. suggest that the disease subtype approach may be a valuable strategy to further our understanding of the genetic architecture of other neurodegenerative conditions (Ferrari et al. Mez et al.. Takeda Pharmaceutical Company.J. and 21 failed to converge. These findings. which include APOE genotypes. chromosome 19 variants. Inc. Because of the cognitive data collected by these studies.. Predictably. the National Institute of Biomedical Imaging and Bioengineering. chromosome 11 variants explain the greatest amount of phenotypic variability for the executive prominent/memory prominent spectrum but only explain a small amount of LOAD’s phenotypic variability.. For instance. Eisai Inc. R01 AG 042437 (P Crane. Conclusions About one-fifth of the people from 2 prominent studies of LOAD have executive functioning scores substantially lower than the memory scores. and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of Southern California. The grantee organization is the Northern California Institute for Research and Education.. NeuroRx Research. 2013). Although we replicated the finding.. including LOAD. 2011.. LLC. Bristol-Myers Squibb Company.. Our results suggest that different genesdand thus different biologydmay be responsible for executive prominence among people with LOAD.. 2012). Inc. our findings strongly support the notion that there is considerable cognitive domain heterogeneity among people with LOAD and that this heterogeneity has a strong genetic component that is distinct from the genetic architecture of LOAD itself. / Neurobiology of Aging 41 (2016) 115e121 though such studies would need a large number of pairs of twins with LOAD and available neuropsychological data. ADNI: Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). Johnson & Johnson Pharmaceutical Research & Development LLC. Alzheimer’s Drug Discovery Foundation. Nevertheless. PI). Mez et al.. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Once larger samples are available. Our results suggest the need for additional work in this area. and variants on other chromosomes contributed substantially more to the variability of the executive prominent/memory prominent spectrum among people with LOAD.. Acknowledgements EPAD: GRF. 7. 2011.0. our analytic strategy is scalable. given our sample size.

. Schneider. Meso Scale Diagnostics. Mulder. 1018e1027. Thomas. Setchfield..R. R01 AG15819. Mayo Clinic. M. Pietrini. A. Frisoni.. NIMH MH60451 and by Glaxo Smith Kline. Brook. Support was also from the Alzheimer’s Association (LAF... Mackenzie. Rahman. B. Farrall. Epelbaum. AG025688. R01 AG019085. A. the Medical Research Council. J. local NHS trusts and Newcastle University).. University of California. GE Healthcare. Brooks. AG021547..M. R.. University of Southern California.S. Feldman. P. AG041718.R. McVean.M. I.. M. U01 AG10483. Barnett.. Alzheimer’s Drug Discovery Foundation.. IXICO Ltd. Cairns. NACC. L. and Washington University.M. Psychiatry 82. University of California.. Schofield. DePristo. P30 AG10133. P. Lumosity. S. Thompson. Rohrer. Genet. Clin.. N.A. Devriendt. G. and Transition Therapeutics..C.. Topf.. Nature 491. J. T.L. Blue.H. Northwestern University.D.. Bentham. Takeda Pharmaceutical Company. R01AG041797. Irvine. Carle. Mukherjee. S.. Vellas. R.. Keavney. University of California. J.. A. K. Eisai Inc. Inc.M. G. S. R01 AG026916.. Vanderbilt University. C. R. UO1 AG006781.. M. 2013. P50 AG033514. M. C. D. is supported by Wellcome Trust. B. C.. J. C.South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE). Ramasamy... University of Kentucky. ADNI data collection and sharing was funded by the National Institutes of Health Grant U01 AG024904 and Department of Defense award number W81XWH-12-2-0012. J. Genotyping of the TGEN2 cohort was supported by Kronos Science. 6. Hersenstichting Nederland Breinbrekend Werk.. C.. IIRG-08-89720. G. Waldo. University of Michigan..doi. Gauthier. G... Bateman. TGen. Fujirebio. Blesa. Bishopric. Cappa. 61. 614e629. C. AG019757. Mackin. UO1 HG004610. genetic and cortical thinning characteristics.. A. Indiana University. Auton. P30 AG013846. San Francisco.. LLC. P..L. R01 AG017173. / Neurobiology of Aging 41 (2016) 115e121 Repository for Alzheimer’s Disease (NCRAD). K... Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764. P50 AG005146.T.120 J. D.A. T. Hampel. S. P30 AG028377.. whose help and participation made this work possible. Fenoglio. ADNI is funded by the National Institute on Aging... Durbin. Mungas..... University of Washington... Zelenika. K. H. at http://dx. Galasko. 2012.015. A. NIA LOAD..G. R. Elan Pharmaceuticals. Rabinovici. R01 CA129769. Clarimon.A. Dubois. LLC.A. P50 AG016573.E. T. B. C. Blennow. NeuroRx Research. 2016. O. P30 AG028383. J. Araclon Biotech. E. Crutch..B..D. and through generous contributions from the following: AbbVie.. 45e51. A. 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