The Alzheimer’s Disease Sequencing Project (ADSP) Follow-Up Study (FUS)

To view a breakdown of the datasets with whole genome sequencing, go to the ADSP and Affiliates Whole Genome Sequencing Report page.

Quick Navigation:

Introduction

The ADSP Discovery Phase has identified a number of variations in the genomes of individuals affected with AD. These findings are being pursued in the ADSP Follow-Up Study (FUS), funded solely by NIA. The long-term goals of the ADSP FUS are to:

  • Move the field closer to enabling prediction of who will develop AD
  • Fully reveal the genetic architecture of AD in multiple ethnic groups
  • Better understand the underpinnings of AD pathogenesis
  • Aid the quest for therapeutic targets
  • Examine the AD genome in diverse populations

The ADSP Discovery Phase and the ADSP FUS are described under PAR-16-406. The ADSP FUS is leveraging existing infrastructure and collaborations to ensure continuity of ADSP participation. It provides funds for acquisition, archiving, sequencing, quality control, genome wide association studies (GWAS), and data sharing of the large number of samples from individuals affected by AD for WGS, as appropriate. Racial/ethnic diversity continues to be a high ADSP priority. Well-phenotyped participants were selected with an emphasis on autopsy-confirmed and ethnically diverse cases/controls and availability of longitudinal data. Funds are being provided for both sequencing and data analysis. This effort will pursue rare variants as comprehensively as possible, including consideration of statistical power, and exploration of a range of different populations containing those that are currently underrepresented in sequencing studies.

The majority of the samples from the ADSP Discovery and Discovery Extension phases were non-Hispanic white in origin, making the addition of ethnically diverse samples to the study critical to identification of both shared and novel genetic risk factors for AD between populations. Collection and sequencing of ethnically diverse cohorts is emphasized in the ADSP FUS, the goal being that additional existing cohorts with unrelated AD cases that encompass the richest possible ethnic diversity be given the highest priority for inclusion. For the United States this includes augmenting African American, Hispanic, and Asian cohorts.

AD is not a single genetic entity; it is a genetic spectrum with a number of sub-phenotypes (endophenotypes). Endophenotypes will likely vary by ethnicity. Important instances of ethnically unique AD/ADRD genetic variation have been identified in Hispanic and African American cohorts. Variants for AD are rare and can only be identified with a larger number of participants. Variants occur at different frequencies in different populations and certain risk variants may be much easier to detect in some populations. ADSP studies in ethnic groups including African American and Hispanic, remain statistically underpowered, so the genetics of these populations remain largely unstudied. Therefore, a major effort is being undertaken to augment the numbers of cases and controls in ethnically diverse populations in the United States. In order to understand the underlying substructure of the diversity populations, global studies are a key component of this effort.

The global effort brings important population sectors that are not presently well represented in the ADSP including Central and South America, the Iberian Peninsula, Iceland, Africa, and Asia. Examples of the expected types of sequencing and analytical assessments include continuing activities as outlined in the parent FOAs (PAR-19-234 and PAR-17-214). Proposed approaches will not only increase the numbers of participants and the volume of data, but also will require novel methods to perform in-depth and subgroup analyses of diverse ethnic backgrounds, as well as integrated analyses to completely unravel the architecture of the AD genome.

To fulfill the goals of this ADSP FUS, 37 datasets with existing cognitive data with the ability to adjudicate Alzheimer disease status are being whole genome sequenced at the American Genome Center at the Uniformed Services University of the Health Sciences (USUHS) in coordination with existing NIH-funded AD infrastructure including the National Cell Repository for Alzheimer’s Disease (NCRAD), NIAGADS, and the Genome Center for Alzheimer’s Disease (GCAD). Brief descriptions of the cohorts selected for sequencing are provided below. Cohort collection, phenotypic characterization, and whole genome sequencing are funded by the National Institutes of Health. This and additional information about the ADSP can be found on the National Institutes on Aging site.

The ADSP Follow-Up Study 2.0 (ADSP FUS 2.0)

The ADSP Follow-Up Study 2.0: The Diverse Population Initiative (PAR-21-212) was launched in 2021 to expand the sample set in ADSP to represent more diverse populations. The long-term goals of the ADSP FUS 2.0 are to:

  1. move the field closer to enabling prediction of who will develop AD;
  2. fully characterize AD subtypes by studying endophenotypes in diverse populations;
  3. better understand the differences in the genetic underpinnings of AD pathogenesis among diverse populations; and
  4. identify specific therapeutic targets based upon diverse population.

Numbers of Hispanic/Latino and Black/African American participants in the US remain insufficient to provide statistical significance for identification of rare or very rare variants. Variants in the Alzheimer’s genome are largely rare or very rare in the population. It is estimated that for 80% certainty for single variant testing for rare variants, ~16,100 cases and ~16,100 controls are needed for a variant with a minor allele frequency of 0.5% in the population; single variant testing for rare variants indicate that for 90% certainty, ~18,500 cases and ~18,500 controls are needed for each population for a variant with a minor allele frequency of 1% in the population. To ensure that there are sufficient numbers of study participants to achieve statistical power for analysis of rare or vary rare variants in the three largest diversity cohorts’ AD/ADRD genome given the available funding, the primary focus of the ADSP FUS 2.0 is on Hispanic/Latino, Black/African American, and Asian populations. Consortia are leveraging cohorts already recruited or in planning for recruitment to obtain sufficient numbers; sharing diversity data across consortia is essential to the success of this effort. Genetic samples and phenotypic data that are analyzed by the ADSP are provided by several consortia, initiatives, centers, and studies.

ADSP FUS Cohort Descriptions

The A4 Study was designed as a three-year, placebo-controlled, randomized clinical trial to test whether anti-amyloid treatment can slow the rate of cognitive decline in older individuals from diverse ethnic-racial backgrounds (non-Hispanic White, African American and Latino/Hispanic) with evidence of amyloid accumulation on screening PET scans. The ADSP-FUS has sequenced over 3,400 participants from the study.

The Alzheimer’s Disease Research Center (ADRC) Cohorts, which includes Black/African American, Amerindian, and Latino/Hispanic specific cohorts, are selected from the National Institute on Aging’s ADRC’s, a network of 38 academic centers across the United States focused on AD and Alzheimer’s Disease Related Dementias research.

The Alzheimer’s Disease Center Autopsy (ADRC) Cohort includes 1,500 cases with autopsy and 1,372 controls from the National Institute on Aging’s ADRC’s. These individuals are well phenotyped and increase the currently underpowered non-Hispanic White sample with WGS data from the ADSP Discovery and Discovery Extension Phases (1,212 cases and 524 controls).

The Alzheimer’s Disease Genetics Consortium (ADGC) African-American Cohort, is a cohort of 1,240 cases and 1,643 controls collected from several cohorts including from the GenerAAtions Study, Indianapolis-Ibadan Study, Rush University, University of Miami, Case Western Reserve University, North Carolina A & T University, and The Mirage Study.

The Amish Protective Variant Study, based at Case Western Reserve University and the University of Miami (Cummings et al. 2012; D’Aoust et al. 2015), is being conducted in the Indiana and Ohio Old Order Amish population. This population is an isolated founder population originating from immigration of German and Swiss Anabaptists to the United States in the 1700’s and 1800’s. Approximately 840 individuals from the study have been sequenced and included in the ADSP-FUS.

The ASPREE STUDY (ASPirin in Reducing Events in the Elderly) was an international, randomized, placebo-controlled trial funded by the NIH to determine whether daily low dose aspirin (100 mg) increased survival, free of dementia or physical disability, for healthy older people (>60 years of age) without a history of cardiovascular disease, dementia or significant physical disability at enrollment. It included 19,114 healthy older individuals and the initial completion was in 2018 (McNeil 2018). ASPREE-eXTension (ASPREE-XT) study, funded by the NIA, is an observational follow-up of the same cohort that will be extended from 2019 through 2024. ASPREE and ASPREE-XT has and will continue to determine factors, such as those related to lifestyle, health behavior, environment, genes, blood biomarkers and many others, that may be predictors of good health and longevity or predispose to age-related diseases, but is especially focused upon dementia and cognitive decline.

The Case Western Reserve University (CWRU) Autopsy Cohort was an ADRC clinic-based sample. Medical records are available on all cases and controls, all of who were tested before death for cognitive function.

The Case Western Reserve University (CWRU) Rapid Decline Cohort (Cohen et al. 2015) represents patients with rapid decline. Through the National Prion Disease Pathology Surveillance Center, CWRU has identified 300+ aged individuals who have classical AD pathology upon autopsy but whose course is very short: from six months to three years. This course is more typical of a prion disease; however, these individuals have been tested for and do not have any prion disease. The amyloid in the amyloid plaques has a slightly different protein structure, suggesting that that rpAD has a different genetic architecture than typical late-onset AD (LOAD). Additionally, sequencing of the APP gene did not identify any novel or known pathogenic variation. rpAD has not been genetically examined and the 300+ autopsy confirmed AD cases would significantly increase the pool of confirmed cases. Substantial clinical data are available on most cases, and additional samples of blood, plasma, CSF and RNA are available on a subset, greatly increasing their potential value.

The Center for Cognitive Neuroscience and Aging (CNSA) at the University of Miami is a center focused on the valuation, management, treatment and care for older persons and their families with memory and other brain disorders affecting cognition. 343 individuals from CNSA have been sequenced and included in the ADSP-FUS.

The Cuban American Alzheimer’s Disease Initiative (CuADI) is a convenience sample ascertained through community outreach to Alzheimer’s and adult day care centers in Southern Florida, lay conferences, and Neurology and Memory Disorders clinics. All participants underwent a standard protocol which included collection of sociodemographic information, detailed clinical history, and cognitive screening (3MS). In addition, behavioral measures (GDS, CSDD, and NPI-Q) and functional (ADL) assessments are available. Standard neurocognitive data is available on all individuals.

The Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) Study is a study of late-onset AD patients with Caribbean-Hispanic ancestry being conducted at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York City (Vardarajan et al. 2014). Families and unrelated individuals were recruited as a part of a family-based study: Estudio Familiar de Influencia Genetica en Alzheimer, based in the Dominican Republic. All individuals undergo standard neuropsychological tests and neurological examinations to verify their clinical status and for diagnoses based on NINCDS-ADRDA criteria for probable or possible LOAD.

The ADGC Early Onset Alzheimer Disease (EOAD) Cohort is a sample set consisting of ~1,400 EOAD cases available through the Alzheimer Disease Genetics Consortium (ADGC). All samples are early onset (AAO<65), with available DNA and phenotyping (through the Uniform DataSet). This sample set is expected to have minimal known mutations (APP, PSEN1, PSEN2, SORL1 etc). A significant subset of the sample has autopsy information and/or information on family history providing the opportunity to generalize variants identified to neuropathological endophenotypes and to assess whether variants identified are unique to families multiply affected by the disease or also play a role in sporadic EOAD.

The Gwangju Alzheimer’s and Related Dementias (GARD) Cohort is a prospectively followed sample of persons in a senior citizen’s community located in the South Korean southwestern city of Gwangju. A large portion of the cohort has been evaluated with the Seoul Neuropsychological Screening Battery (SNSB) and had a brain MRI scan, and some participants have had PET-amyloid imaging. Previous studies of this cohort include GWAS for AD (Kang et al. J Alzheimers Dis. 2021; 82(4):1451-1460) and brain MRI traits (Park et al. Transl Psychiatry 2021; 11:590). Another study identified a SNP in the APOE promoter that modifies the effect of the ε4 allele and may explain differences in the AD/ε4 across East Asians, Caucasians and African Americans (Choi et al. J Clin Med 2019; 8:1236). Whole genome sequencing is being performed for 4,000 subjects (2,000 AD cases and 2,000 controls. The GARD sample will be among the largest Asian cohorts with WGS data.

The Indianapolis-Ibadan Study of Aging is a longitudinal study begun in 1991 in Indianapolis, Indiana and Idikan Ward of Ibadan city, Nigeria (Hendrie et al. 1995; Osuntokun et al. 1995). Study participants in the Ibadan cohort belong to the Yoruba ethnic group who inhabit south-western Nigeria and extend to neighboring Benin Republic to the west, which is the primary origin of the African ancestry in African Americans. The Ibadan portion of the study currently has 79 cases, 176 MCI, and 759 controls aged 65 years or older that have been sequenced and included in the ADSP-FUS. The African American samples from the Indianapolis cohort have been sequenced in the ADSP as part of the ADGC AA cohort. The AD cases from this cohort are the first and only African AD cases with WGS, making their sequencing an essential first step towards inclusion of this completely unrepresented group in AD research.

Interaction between SARS-CoV-2 Infection and Ancestral genomic Variations in the Risk of Alzheimer’s Disease and Related Disorders (ISAVRAD). ISAVRAD is a longitudinal study of older adult Amerindians from Northern Argentina with or without exposure to SARS-CoV-2 infection to understand the impact of interactions between ancestral genomic variants and infection on the risk of cognitive decline and ADRD. With funding from the Alzheimer’s Association and Fundacion FULTRA, 875 participants over 60 years of age and without pre-infection cognitive impairment were enrolled during the first 18 months of the pandemic; collected data include exhaustive clinical phenotypes, detailed cognitive assessments, plasma for biomarkers and WGS. Additional studies including neuroimaging and expanding the sample to Yoruba participants from Ibadan (Nigeria), Latino participants from the Bronx (New York), Mexican-American participants from Laredo and San Antonio (Texas), and non-tribal Native Americans from Kings County (Washington) are planned.

Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE) is a prospective cohort study launched at Seoul National University (SNU) in 2014 using a similar design and methods as the North American Alzheimer’s Disease Neuroimaging Initiative (ADNI). The KBASE cohort consists of well-characterized participants including cognitively normal (CN) controls with a wide age range (20 to 90 years) and older adults with mild cognitive impairment (MCI) or AD dementia (AD). KBASE included longitudinal collection of clinical, cognitive and lifestyle data, multimodal MRI and PET (amyloid, tau and FDG) neuroimaging, and bio-specimens in Korea during the first phase (“KBASE1”). KBASE2 represents a collaboration between the ADSP, Indiana University, the KBASE team at SNU, USC/LONI and UPENN. Over 1000 whole genome sequences (WGS) of Korean participants will be contributed to the ADSP, and the extensive ADSP multi-ethnic data set will be analyzed. KBASE2 will expand the cohort and continue longitudinal data and sample collection and provide WGS and data harmonization and sharing, analyze longitudinal amyloid, tau, neurodegeneration and vascular (A/T/N/V) imaging biomarkers and analyze multi-omics data for association with A/T/N/V biomarkers for AD to identify dysregulated gene modules and pathways.

The Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD) is a national representative cohort of 4,096 adults 60 years of age and older in India across 18 states and union territories. LASI-DAD is an in-depth study on cognitive aging and dementia drawn from the larger Longitudinal Aging Study in India (LASI). Whole genome sequencing of 2,712 individuals has been completed. These data can be linked to the Harmonized LASI and Harmonized LASI-DAD datasets (available at https://g2aging.org/), offering the opportunity for researchers to gain insight into the aging population in India.

Mexican APP/PSEN Study (Cohort description coming soon.)

The Mexican Health and Aging Study (MHAS), sponsored by the National Institutes of Health (NIH) National Institute on Aging (NIA), is prospective study of health and aging in Mexico that began in 2001 (MHAS 2001). The ADSP FUS will sequence 200 MHAS cases and 2,600 MHAS controls from this study starting in 2019.

The University of Miami Brain Bank Cohort was ascertained through self-referred cases and controls to the University of Miami Brain Endowment Bank, a National Institutes of Health (NIH) NeuroBioBank, one of six designated brain and tissue biorepositories in the nation. Medical records are available on all cases and controls, all of who were tested before death for cognitive function.

The University of Miami John P. Hussman Institute for Human Genomics (HIHG) Brain Bank is a clinic and community outreach sample ascertained in North Carolina, South Carolina and Virginia. The HIHG Brain Bank autopsy individuals followed the typical clinical course of disease.

The Northern Manhattan Study (NOMAS), funded by the NIH’s NINDS, is a study focused on stroke or related neurological syndromes (Sacco et al. 2004). The ADSP FUS will sequence 88 Hispanic cases and 175 Hispanic controls, and 22 African-American cases and 43 African-American controls from this study starting in 2020.

The Peru Alzheimer’s Disease Initiative (PeADI) is being conducted at several sites in Peru including Lima (Marca-Ysabel et al. 2021). The Mestizo population living in Lima, the capital city, is comprised of ~76% of Amerindian, 11% Southern European, and 3% Northern African ancestries, and a smaller proportion of western central Africa, western central Europe, Finland, northern Siberia and Jewish diaspora. Cases will be clinic based and controls will be clinic and community based. With few Amerindian individuals available for study, the inclusion of a Peruvian cohort will enhance the admixture studies proposed in CADRE and other groups in the ADSP analysis phase.

The Puerto Rican 10/66 Study, is an Alzheimer’s Disease International study of dementia in Puerto Rico that began in 2007 (Prince et al. 2007). The ADSP FUS has sequenced ~1560 individuals from this study.

The Puerto Rican Alzheimer’s Disease Initiative (PRADI) is a NIH NIA study of late-onset Alzheimer disease focused on the Caribbean-Hispanic Puerto Rican population. The ADSP FUS will sequence 500 cases and 500 controls from this study starting in 2020.

The Research in African-American Alzheimer’s Disease Initiative (REAAADI) is a NIH NIA study focused on identifying genetic factors for Alzheimer disease within the African-American population in order to detect new targets for drug development and improve accessibility to Alzheimer’s disease education within the community. The ADSP FUS will sequence 300 cases and 300 controls from this study starting in 2020.

The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, sponsored by the NIH’s National Institute for Neurological Disorders and Stroke (NINDS), is a national study of risk factors for stroke in adults 45 years or older that includes measurements of traditional stroke risk factors such as blood pressure and cholesterol levels, and an echocardiogram of the heart (Longstreth 2006).

Stanford (STeP). This cohort contains samples from Brains for Dementia Research (BDR) Genetics project (Dr. Kevin Morgan, PI and Directory of the Alzheimer’s Research UK (ARUK) DNA Consortium and BDR) (Francis et al. 2018). The BDR cohort and program was for planned brain donation across five UK brain banks and one donation point, with standardized operating procedures, following longitudinal clinical and psychometric assessments for people with no cognitive impairment as well as those with dementia. See the Francis et al. publication for a detailed description about the BDR cohort set-up, clinical data, and psychometric assessment measures collected.

The Texas Alzheimer’s Research and Care Consortium (TARCC) includes cases enrolled at several major medical research institutions including Baylor College of Medicine, Texas Tech University Health Sciences Center, University of North Texas Health Science Center, The University of Texas Health Sciences Center at San Antonio, The University of Texas Southwestern Medical Center, and Texas A & M Health Science Center. Individuals must be at least 55 years of age with a diagnosis of probable AD or normal cognition. Information is obtained from the clinical and neurological examination on age at onset of symptoms (if AD patient), family history of dementia in first degree relatives, cardiovascular disease and cardiovascular disease risk factors. Subjects also undergo a battery of neuropsychological tests.

The Wisconsin Registry for Alzheimer’s Prevention (WRAP) Study is comprised of individuals from a registry begun in 2011 that includes more than 1,700 individuals, followed over time, to learn about biological, health, and lifestyle factors that may affect Alzheimer’s disease. The data set includes information on cognition, lifestyle, physical activity, biomarkers, genetics and metabolism.

References

  • Cohen ML, Kim C, Haldiman T, ElHag M, Mehndiratta P, Pichet T, Lissemore F, Shea M, Cohen Y, Chen W, Blevins J, Appleby BS, Surewicz K, Surewicz WK, Sajatovic M, Tatsuoka C, Zhang S, Mayo P, Butkiewicz M, Haines JL, Lerner AJ, Safar SG. Brain. 2015;138:1009-22.
  • Cummings, A.C., Jiang, L., Velez Edwards, D.R., McCauley JL, Laux R, McFarland LL, Fuzzell D, Knebusch C, Caywood L, Reinhart-Mercer L, Nations L, Gilbert JR, Konidari I, Tramontana M, Cuccaro ML, Scott WK, Pericak-Vance MA, Haines JL. Genome-wide association and linkage study in the Amish detects a novel candidate late-onset Alzheimer disease gene. Ann Hum Genet. 2012;76(5):342-51.
  • D’Aoust LN, Cummings AC, Laux R, Fuzzell D, Caywood L, Reinhart-Mercer L, Scott WK, Pericak-Vance MA, Haines JL. Examination of candidate exonic variants for association to Alzheimer disease in the Amish. PLOS One. 2015;10(2):e0118043.
  • Francis PT, Costello H, Hayes GM. Brains for Dementia Research: Evolution in a Longitudinal Brain Donation Cohort to Maximize Current and Future Value. J Alzheimers Dis. 2018;66(4):1635-1644. doi:10.3233/JAD-180699
  • Hendrie HC, Ch B MB, Osuntokun BO, et al. Prevalence of Alzheimer’s Disease and Dementia in Two Communities: Nigerian Africans and African Americans. Am J Psychiatry. 1995;152(10):1485-92. doi:10.1176/ajp.152.10.1485
  • Longstreth WT. The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study and the National Institute of Neurological Disorders and Stroke (NINDS). Stroke. 2006;37(5):1147-1147. doi:10.1161/01.STR.0000217259.92964.62.
  • Marca-Ysabel MV, Rajabli F, Cornejo-Olivas M, Whitehead PG, Hofmann NK, Illanes Manrique MZ, Veliz Otani DM, Milla Neyra AK, Castro Suarez S, Meza Vega M, Adams LD, Mena PR, Rosario I, Cuccaro ML, Vance JM, Beecham GW, Custodio N, Montesinos R, Mazzetti Soler PE, Pericak-Vance MA. Dissecting the role of Amerindian genetic ancestry and the ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population. Neurobiol Aging. 2021 May;101:298.e11-298.e15. doi:10.1016/j.neurobiolaging.2020.10.003. Epub 2020 Dec 10.
  • McNeil, J.J., Nelson, M.R., Woods, R.L., Lockery, J.E., Wolfe, R., Reid, C.M., Kirpach, B., Shah, R.C., Ives, D.G., Storey, E., Ryan, J., Tonkin, A.M., Newman, A.B., Williamson, J.D., Margolis, K.L., Ernst, M.E., Abhayaratna, W.P., Stocks, N., Fitzgerald, S.M., Orchard, S.G., Trevaks, R.E., Beilin, L.J., Donnan, G.A., Gibbs, P., Johnston, C.I., Radziszewska, B., Grimm, R., Murray, A.M., and ASPREE Investigator Group. (2018). Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N. Engl. J. Med. 16, 1519-1528.
  • MHAS. Data files and documentation (public use): Mexican Health and Ageing Study. http://www.mhasweb.org. Published 2001. Accessed July 20, 2017.
  • Mueller SG, Weiner MW, Thal LJ, et al. Ways toward an early diagnosis in Alzheimer’s disease: the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Alzheimers Dement. 2005;1(1):55-66.
  • Osuntokun, B.O., Sahota, A., Ogunniyi, A.O., Gureje, O., Baiyewu, O., Adeyinka, A., Oluwole, S.O., Komolafe, O., Hall, K.S., and Unverzagt, F.W. (1995). Lack of an association between apolipoprotein E epsilon 4 and Alzheimer’s disease in elderly Nigerians. Ann. Neurol. 3, 463-465.
  • Prince M, Ferri CP, Acosta D, et al. The protocols for the 10/66 dementia research group population-based research programme. BMC Public Health. 2007;7(1):165. doi:10.1186/1471-2458-7-165.
  • Sacco RL, Anand K, Lee H-S, et al. Homocysteine and the Risk of Ischemic Stroke in a Triethnic Cohort: The Northern Manhattan Study. Stroke. 2004;35(10):2263-2269. doi:10.1161/01.STR.0000142374.33919.92.
  • Vardarajan BN, Faber KM, Bird TD, Bennett DA, Rosenberg R, Boeve BF, Graff-Radford NR, Goate AM, Farlow M, Sweet RA, Lantigua R, Medrano MZ, Ottman R, Schaid DJ, Foroud TM, Mayeux R. Age-specific incidence rates for dementia and Alzheimer disease in NIA-LOAD/NCRAD and EFIGA families. JAMA Neurol. 2014;71(3): 315-323.