Dominantly Inherited Alzheimer Network (DIAN)

• 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. ] [ Designated as safety issue: No ]
• 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 ] [ Designated as safety issue: No ]
• 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 ] [ Designated as safety issue: No ]

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.

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. Establish an international, multicenter registry of individuals (mutation carriers and non-carriers; pre-symptomatic and symptomatic) who are biological adult children of a parent with a known causative mutation for AD in the APP, PSEN1, or PSEN2 genes in which the individuals are evaluated in a uniform manner at entry and longitudinally thereafter with standardized instruments.
2. In pre-symptomatic individuals, compare mutation carriers and non-carriers to determine the order in which changes in clinical, cognitive, neuroimaging, and biomarker indicators of AD occur prior to the occurrence of dementia.
3. In symptomatic individuals, compare the clinical and neuropathological phenotypes of autosomal dominant AD to those of late-onset "sporadic" AD (using the data sets established by ADNI and by NACC).
4. Maintain the DIAN Central Archive, an integrated database incorporating all information obtained from individuals in the registry to permit analyses within, between, and among the various data domains and also to disseminate the data to qualified investigators in a user-friendly manner.
5. All DIAN participants who wish to know their mutation status will have the costs of genetic counseling and clinical mutation testing paid for by the grant. The clinical genetic counseling and testing is provided as an optional participant benefit and is not part of the DIAN research design.

Mutation carriers and non-carriers from families with a mutation (which is different from the genetic risk factor Apo-E4) known to cause Alzheimer's disease.

• 1
  Mutation Positive
• 2
  Mutation Negative

• 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.
• 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. Epub 2007 Jan 8.
• 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.
• 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.
• 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.
• Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. Epub 2012 Jul 11.

Inclusion Criteria:

• Age 18 or older
• Child of an individual with a known mutation in a pedigree with autosomal dominant Alzheimer's disease
• Cognitively normal, or if demented, does not require nursing home level care
• Fluent in English or Spanish at the 6th grade level
• Has someone who is not a child of the affected parent who can serve as an informant for the study

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