Dominantly Inherited Alzheimer Network (DIAN)

Overview

The purpose of this study is to identify potential biomarkers that may predict the development of Alzheimer's disease in people who carry an Alzheimer's mutation.

Detailed description

Dominantly inherited Alzheimer's disease (AD) represents less than 1% of all cases of AD and is an important model for study because the responsible mutations have known biochemical consequences that are believed to underlie the pathological basis of the disorder. Three major hypotheses will be tested:

* First, that there is a period of preclinical (presymptomatic) AD in individuals who are destined to develop early-onset dementia (gene carriers) that can be detected by changes in biological fluids and in neuroimaging correlates in comparison with individuals who will not develop early-onset dementia (non-carriers). * Second, because all identified causative mutations for AD affect the normal processing of amyloid precursor protein (APP) and increase brain levels of amyloid-beta 42 (Aβ42), the sequence of preclinical changes initially will involve Aβ42 (production and clearance; reduced levels in cerebrospinal fluid \[CSF\]), followed by evidence for cerebral deposition of Aβ42 (amyloid imaging), followed by cerebral metabolic activity (functional imaging), and finally by regional atrophy (structural imaging). * Finally, that the phenotype of symptomatic early-onset familial AD, including its clinical course, is similar to that of late-onset "sporadic" AD.

The following specific aims will be used to test these hypotheses:

1. Maintain the established international DIAN registry of individuals (MCs and non-carriers (NC), symptomatic and asymptomatic) who are biological adult children of an affected parent with an APP, PSEN1, or PSEN2 mutation causing AD and assess participants every 2 years with the uniform DIAN protocol. 2. Recruit to the registry 50 new asymptomatic participants, both MCs and NCs, in Year 1 of the next budget period to maintain the total DIAN cohort at \~250 individuals. These new participants will include those who are more than 15 years younger than the estimated age of symptomatic onset (EAO) to explore the earliest observable biomarker changes of preclinical AD. 3. Maintain the integrated DIAN database and biospecimen repository to disseminate data and tissue to qualified investigators (within and outside of DIAN) in a user-friendly manner and to permit analyses within, between, and among the various data domains that will include:

1. In asymptomatic MCs (using NCs as controls), determine the temporal ordering and rate of intraindividual change in clinical, cognitive, imaging, and fluid biomarkers of AD prior to EAO 2. In symptomatic MCs, compare the clinical and neuropathological phenotypes of ADAD to those of LOAD, using datasets such as ADNI. 4. Utilize the DIAN cohort and its database and biospecimen repository to support new scientific studies, including use of exome chip technology to examine potential modifiers of age at symptomatic onset. Pursue other new scientific initiatives that are funded independently of the DIAN grant but are conducted within the DIAN infrastructure at no cost to DIAN including: Dermal fibroblasts and induced pluripotent stem cells (iPSCs), examine biomarker surrogates for neurogeneration in CSF including Visinin-like protein-1 (VILIP-1), Tau seeding assay, Stable Isotope Leucine Kinetics (SILK) in DIAN participants, determine the exact Abeta species that underlie AD pathology using Mass spectrometry, exome sequencing on all DIAN participants to search for both positive and negative modifiers of EYO, and amyloid imaging crossover to \[18F\]florbetapir. 5. Provide genetic counseling to any and all DIAN participants who wish to learn their mutation status and, for those who decide to learn their status after counseling, provide genetic testing by Clinical Laboratory Improvement Amendments (CLIA)-approved laboratories (i.e., outside of DIAN).

Primary outcome measures

• Positive predictive power of a biomarker or group of biomarkers [Time frame: Variable follow-up assessment based on age in relation to age at onset of affected parent.]
• Biomarkers obtained by blood draw, lumbar puncture, MRI, FDG PET, PET amyloid imaging [Time frame: Variable follow-up assessment based on age in relation to age at onset of affected parent]
• Clinical markers also examined from clinical interview and cognitive testing [Time frame: Variable follow-up assessment based on age in relation to age at onset of affected parent]

Eligibility criteria

Inclusion criteria

• Written informed consent obtained from participant and collateral source prior to any study-related procedures.
• Aged 18 (inclusive) or older and the child of an affected individual (clinically or by testing) in a pedigree with a known mutation for ADAD.
• Cognitively normal to very mild or mild cognitive impairment (CDR score range 0-1.0). Primary enrollment will focus on the recruitment of asymptomatic adult children who are more than 15 years younger than the estimated age of symptom onset. Enrollment of new participants with moderate cognitive impairment is allowed with the prior approval of the DIAN Coordinating Center.
• Has two persons who are not their full-blooded siblings who can serve as collateral sources for the study.
• Fluent in a language approved by the DIAN Coordinating Center at about the 6th grade level (international equivalent) or above.

Exclusion criteria

• Under age 18
• Medical or psychiatric illness that would interfere in completing initial and follow-up visits
• Requires nursing home level care
• Has no one who can serve as a study informant

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

United States · 8 centers

• Mayo Clinic Jacksonville — Jacksonville
• Indiana University-Indiana Alzheimer Disease Center — Indianapolis
• Brigham and Women's Hospital — Boston
• Washington University in St. Louis School of Medicine — St Louis
• Columbia University — New York
• University of Pittsburgh — Pittsburgh
• Butler Hospital — Providence
• University of Washington — Seattle

Australia · 3 centers

• Neuroscience Research Australia — Sydney
• Mental Health Research Institute, University of Melbourne — Melbourne
• Sir James McCusker Alzheimer's Disease Research Unit, Edith Cowan University — Perth

Japan · 3 centers

• Niigata University — Niigata
• Osaka City University — Osaka
• Tokyo University — Tokyo

Argentina · 2 centers

• Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) — Salta
• Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia" (FLENI) Insti — Buenos Aires

Germany · 2 centers

• German Center for Neurodegenerative Diseases (DZNE) Munich, and University Hospital Ludwig — Munich
• German Center for Neurodegenerative Diseases (DZNE) Tübingen and Hertie-Institute for Clin — Tübingen

Brazil · 1 center

• Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo — São Paulo

Canada · 1 center

• McGill University Research Centre for Studies in Aging — Verdun

Colombia · 1 center

• Grupo Neurociencias de Antioquia — Medellín

Mexico · 1 center

• Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suarez" — Mexico City

Netherlands · 1 center

• Amsterdam UMC — Amsterdam

South Korea · 1 center

• Asan Medical Center — Seoul

Spain · 1 center

• Hospital Clinic Barcelona — Barcelona

United Kingdom · 1 center

• Institute of Neurology, Queen Square — London

Publications

• Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006 Aug 8;67(3):446-52. doi: 10.1212/01.wnl.0000228230.26044.a4. PMID 16894106
• Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007 Mar;64(3):343-9. doi: 10.1001/archneur.64.3.noc60123. Epub 2007 Jan 8. PMID 17210801
• Godbolt AK, Cipolotti L, Anderson VM, Archer H, Janssen JC, Price S, Rossor MN, Fox NC. A decade of pre-diagnostic assessment in a case of familial Alzheimer's disease: tracking progression from asymptomatic to MCI and dementia. Neurocase. 2005 Feb;11(1):56-64. doi: 10.1080/13554790490896866. PMID 15804925
• Morris JC, McKeel DW Jr, Storandt M, Rubin EH, Price JL, Grant EA, Ball MJ, Berg L. Very mild Alzheimer's disease: informant-based clinical, psychometric, and pathologic distinction from normal aging. Neurology. 1991 Apr;41(4):469-78. doi: 10.1212/wnl.41.4.469. PMID 2011242
• Galvin JE, Powlishta KK, Wilkins K, McKeel DW Jr, Xiong C, Grant E, Storandt M, Morris JC. Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study. Arch Neurol. 2005 May;62(5):758-65. doi: 10.1001/archneur.62.5.758. PMID 15883263
• Wagemann O, Li Y, Hassenstab J, Aschenbrenner AJ, McKay NS, Gordon BA, Benzinger TLS, Xiong C, Cruchaga C, Renton AE, Perrin RJ, Berman SB, Chhatwal JP, Farlow MR, Day GS, Ikeuchi T, Jucker M, Lopera F, Mori H, Noble JM, Sanchez-Valle R, Schofield PR, Morris JC, Daniels A, Levin J, Bateman RJ, McDade E, Llibre-Guerra JJ; Dominantly Inherited Alzheimer Network. Investigation of sex differences in m PMID 37740921
• Prescott JW, Doraiswamy PM, Gamberger D, Benzinger T, Petrella JR; Dominantly Inherited Alzheimer Network. Diffusion Tensor MRI Structural Connectivity and PET Amyloid Burden in Preclinical Autosomal Dominant Alzheimer Disease: The DIAN Cohort. Radiology. 2022 Jan;302(1):143-150. doi: 10.1148/radiol.2021210383. Epub 2021 Oct 12. PMID 34636637
• Gordon BA, Blazey TM, Su Y, Hari-Raj A, Dincer A, Flores S, Christensen J, McDade E, Wang G, Xiong C, Cairns NJ, Hassenstab J, Marcus DS, Fagan AM, Jack CR Jr, Hornbeck RC, Paumier KL, Ances BM, Berman SB, Brickman AM, Cash DM, Chhatwal JP, Correia S, Forster S, Fox NC, Graff-Radford NR, la Fougere C, Levin J, Masters CL, Rossor MN, Salloway S, Saykin AJ, Schofield PR, Thompson PM, Weiner MM, Holt PMID 29397305

Identifiers

NCT: NCT00869817 · IA0147 · U19AG032438

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗