National Institute on Aging - Late Onset Alzheimer's Disease Family Study: Genome-Wide Association Study for Susceptibility Loci

Alzheimer disease is the most common neurodegenerative disorder of the elderly affecting an estimated five million Americans. Genetic factors contribute to the risk for disease with heritability estimates ranging from 57% to 79%. More than a decade ago, the ε4 variant of APOE was identified and remains the most consistently replicated genetic variant influencing the risk of late onset Alzheimer disease. A segregation analysis suggests there may be four additional genes influencing the age-at-onset of Alzheimer disease. In 2007 there were 968 association studies in 398 candidate genes reported, but none replicated consistently. There are many reasons for the lack of consistency, but one important reason for the lack of progress is the paucity of a sufficient number of well characterized families and patients available to the entire scientific community. The extensive effort and expense required to ascertain such a population has been addressed by the NIA-LOAD Family Study. Its goal is to identify and recruit families with two or more siblings with the late-onset form of Alzheimer's disease and a cohort of unrelated, non-demented controls similar in age and ethnic background, and to make the samples, the clinical and genotyping data and preliminary analyses available to qualified investigators world-wide. Genotyping by the Center for Inherited Disease Research (CIDR) was performed using the Illumina Infinium II assay protocol with hybridization to Illumina Human 610Quadv1_B Beadchips. This genotyping represents the largest collection of families ever assembled with Alzheimer's disease combining the NIA-LOAD Genetics Initiative Multiplex Family Study, the National Cell Repository for Alzheimer's Disease (NCRAD) with additional controls from the University of Kentucky. These genotyping results will serve as a focal point for future research that will identify all of the remaining genetic variants in Alzheimer's disease.

• Study Weblinks:
  • The Alzheimer's Disease Genetics Initiative
  • The National Cell Repository for Alzheimer's Disease (NCRAD)
• Study Design:
  • Case-Control
• Study Type:
  • Family
  • Longitudinal
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 5220
• Subject Sample Telemetry Report (SSTR)

Families

There must be two individuals in the family for which biological samples are available.

1. Proband
   • A diagnosis of Definite (autopsy confirmed) AD by established neuropathological criteria¹ or Probable AD or Possible by NINCDS-ADRDA criteria²
   • Age at onset (AAO) or age at diagnosis of ≥ 60 years
   • Individual was evaluated in person and diagnosed by an NIA-funded Alzheimer's Disease Center/approved institution or by staff associated with the Center/institution; or the autopsy was done at an Alzheimer's Disease Center/approved institution
   • Biological samples available (see 4)
2. Second Family Member
   • A sibling of the proband
   • A diagnosis of Definite AD¹, Probable AD, or Possible AD by NINCDS-ADRDA criteria²
   • AAO or age at diagnosis ≥ 60 years
   • Preferred that individual be evaluated in person, but a diagnosis by medical records and telephone interview is acceptable
   • Biological samples available (see d)
3. Other Family Member
   • A sibling, half-sibling, parent, offspring, aunt, uncle, niece/nephew, or first cousin of the proband
   • A diagnosis of Definite AD¹, Probable AD, Possible AD by NINCDS-ADRDA criteria²; a less definitive diagnosis of questionable dementia; MCI; or unaffected
   • If affected, AAO of dementia or age at diagnosis ≥ 50 years
   • If unaffected, must be ≥ 50 years
   • Preferred that the individual be evaluated in person, but a diagnosis by medical records and telephone interview (affected) or telephone interview (unaffected) is acceptable
   • Biological samples available (see d)
4. Biological samples
   • Fresh blood
   • Immortalized cell lines
   • Autopsy material: 3 to 5 grams of FROZEN cortex, fixed samples are not acceptable

¹CERAD, Braak, Khachaturian, NIA-RI or other established criteria
²NINCDS-ADRDA criteria (McKhann et al., 1984, Neurology 34:939-944)

Cases

• A diagnosis of Definite (autopsy confirmed) AD by established neuropathological criteria¹ or Probable AD by NINCDS-ADRDA criteria²
• Age at onset (AAO) or age at diagnosis of ≥ 60 years
• Individual was evaluated in person and diagnosed by an NIA-funded Alzheimer's Disease Center/approved institution or by staff associated with the Center/institution; or the autopsy was done at an Alzheimer's Disease Center/approved institution
• Biological samples available.

Controls

The minimum age for controls is 60.

• Controls are defined as individuals without subjective complaints of memory loss or cognitive decline and whose neuropsychological test performance falls within the range of norms for age and education.
• The absence of cognitive impairment must have been documented within the last year either by neuropsychological testing or semiquantitative neurological or psychiatric examination.
• Controls should not have a history of major neurological or psychiatric disorders and no life-threatening conditions.
• Controls should not have a current diagnosis of schizophrenia, bipolar disorder, major depression, OCD, anxiety/panic disorder.
• Controls should not have a current diagnosis or history of PD, AD, MS, brain tumor, and HD.

Evaluation of Controls

• A clinical and neuropsychological evaluation will be completed. The study visit includes: a blood draw, an interview to obtain family history and clinical and demographic information.
• Controls will be assessed every two to three years.
• Autopsy will be obtained if possible.

NIA-LOAD Genetics Initiative Multiplex Family Study
In 2002, the administration of the National Institute of Aging (NIA) created the NIA-Genetics Initiative for Late-Onset Alzheimer's Disease. As part of that program the NIA-Late Onset Alzheimer's Disease (NIA-LOAD) Family Study was developed for the specific recruitment of individuals from families with multiple family members affected by late onset Alzheimer's disease. Initial recruitment was supported through administrative supplements to 18 institutions federally funded as Alzheimer's Disease Centers. A consortium of 10 sites continues to recruit new families and conduct longitudinal assessments on families and controls.

National Cell Repository for Alzheimer's Disease
The National Cell Repository for Alzheimer's Disease (NCRAD) was established to collect and maintain information and biological specimens on large numbers of genetically informative, phenotypically well-characterized, families having multiple individuals affected with Alzheimer Disease (AD). The goal of NCRAD has been to ensure that researchers have access to the types of families and samples needed to address critical research questions.

• Primary Phenotype: Alzheimer Disease
• Dementia

• Principal Investigators
  • Richard Mayeux, MD, MSc. Columbia University, New York, NY, USA.
  • Tatiana Foroud, PhD. National Cell Repository for Alzheimer's Disease and Indiana University, Indianapolis, IN, USA.
• Co-Investigators
  • Joseph H. Lee, PhD. Columbia University, New York, NY, USA.
  • Ellen M. Wijsman, PhD. University of Washington, Seattle, WA, USA.
  • Robert Green, MD, MPH. Boston University, Boston, MA, USA.
  • Neil Kowall, MD. Boston University, Boston, MA, USA.
  • Lindsay Farrer, PhD. Boston University, Boston, MA, USA.
  • Donald E. Schmechel, MD. Duke University, Durham NC, USA.
  • Deborah Blacker, MD, ScD. Massachusetts General Hospital, Charlestown, MA, USA.
  • John Growdon, MD. Massachusetts General Hospital, Charlestown, MA, USA.
  • Bradley T. Hyman, MD, PhD. Massachusetts General Hospital, Charlestown, MA, USA.
  • Rudolph E. Tanzi, PhD. Massachusetts General Hospital, Charlestown, MA, USA.
  • Bradley Boeve, MD. Mayo Clinic Rochester, MN, USA.
  • Neill Graff-Radford, MD. Mayo Clinic, Jacksonville, FL, USA.
  • Margaret Pericak-Vance, PhD. Miami Institute for Human Genomics, University of Miami, Miami, FL, USA.
  • Jeremy M. Silverman, PhD. Mount Sinai School of Medicine, New York, NY, USA.
  • Michal Schnaider Beeri, PhD. Mount Sinai School of Medicine, New York, NY, USA.
  • Mary Sano, PhD. Mount Sinai School of Medicine, New York, NY, USA.
  • Nancy Johnson, PhD. Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Medical School, Chicago, IL, USA.
  • Marsel Mesulam, MD. Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Medical School, Chicago, IL, USA.
  • Sandra Weintraub, PhD. Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Medical School, Chicago, IL, USA.
  • Eileen Bigio, MD. Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Medical School, Chicago, IL, USA.
  • Jeffrey Kaye, MD. Layton Center for Aging and Alzheimer's Disease, Oregon Health and Science University, Portland, OR, USA.
  • Patricia Kramer, PhD. Layton Center for Aging and Alzheimer's Disease, Oregon Health and Science University, Portland, OR, USA.
  • David A. Bennett, MD. Rush University Medical Center, Chicago, IL, USA.
  • Lindy E. Harrell, MD, PhD. University of Alabama at Birmingham, AL, USA.
  • George Bartzokis, MD. David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • William Markesbery, MD. University of Kentucky, Lexington, KY, USA.
  • Charles Smith, MD. University of Kentucky, Lexington, KY, USA.
  • John Q. Trojanowski, MD, PhD. University of Pennsylvania, Philadelphia, PA, USA.
  • Vivianna Van Deerlin, MD, PhD. University of Pennsylvania, Philadelphia, PA, USA.
  • Steven T. DeKosky, MD. University of Pittsburgh, PA, USA.
  • Robert Sweet, MD. University of Pittsburgh, PA, USA.
  • I. Helena Chui, MD. University of Southern California, Downey, CA, USA.
  • Arousiak Varpetian, MD. University of Southern California, Downey, CA, USA.
  • Ramon Diaz-Arrastia, MD, PhD. University of Texas Southwestern Medical Center at Dallas, TX, USA.
  • Roger Rosenberg, MD. University of Texas Southwestern Medical Center at Dallas, TX, USA.
  • Thomas Bird, MD. University of Washington, Seattle, WA, USA.
  • Murray Raskind, MD. University of Washington, Seattle, WA, USA.
  • Gerard D. Schellenberg, PhD. University of Washington, Seattle, WA, USA.
  • Alison Goate, DPhil. Washington University School of Medicine, St. Louis, MO, USA.
  • John Morris, MD. Washington University School of Medicine, St. Louis, MO, USA.
  • Marcelle Morrison-Bogorad, PhD. National Institute on Aging, Bethesda, MD, USA.
  • Marilyn Miller, PhD. National Institute on Aging, Bethesda, MD, USA.
  • Creighton H. Phelps, PhD. National Institute on Aging, Bethesda, MD, USA.
• Genotyping Center
  • Johns Hopkins University Center for Inherited Disease Research (CIDR), Baltimore, MD, USA.
• Funding Source for Genotyping
  • HHSN268200782096C. "NIH contract High throughput genotyping for studying the genetic contributions to human disease". National Institutes of Health, Bethesda, MD, USA.