Clinical trial NCT03507257: Longitudinal Early-onset Alzheimer's Disease Study Protocol
Official title: Longitudinal Early-onset Alzheimer's Disease Study Protocol
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Early Onset Alzheimer Disease
Alzheimer Disease
Mild Cognitive Impairment
Keywords: Cognitively Normal
Amyloid
Plaques
Neuroimaging
Biomarkers
Cognition Disorder
Dementia
Tau
Early Onset Alzheimer's Disease
Alzheimer's Disease
Mild Cognitive Impairment
Lead sponsor: Indiana University
Sponsor class: OTHER
Collaborators: name: Alzheimer's Therapeutic Research Institute
name: National Institute on Aging (NIA)
name: Alzheimer's Association
First posted: 2018-04-25
Enrollment: 850
Sex: ALL
Minimum age (years): 40
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Cognitively Impaired Participants (ie: Early Onset Alzheimer's Disease (EOAD) and Early Onset non-Alzheimer's Disease (EOnonAD)) and Cognitively Normal (CN) Control Participants

Brief summary: The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a non-randomized, natural history, non-treatment study designed to look at disease progression in individuals with early onset cognitive impairment. Clinical, cognitive, imaging, biomarker, and genetic characteristics will be assessed across three cohorts: (1) early onset Alzheimer's Disease (EOAD) participants, (2) early onset non-Alzheimer's Disease (EOnonAD) participants, and (3) cognitively normal (CN) control participants.

Detailed description: The LEADS study is a non-randomized, natural history, non-treatment study. Enrolled participants must be 40 - 64 (inclusive) years of age, with MCI due to AD or probable AD dementia (cognitively impaired participants) or have no significant memory impairment (cognitively normal \[CN\] participants).

Approximately 850 participants with cognitive impairment (650 with early onset Alzheimer's Disease \[EOAD\] and 200 with early onset non-Alzheimer's Disease \[EOnonAD\]) and 100 CN participants will be enrolled at approximately 20 sites in the United States. At approximately 5 sites outside of the United States, approximately 400 cognitively impaired participants and 10 CN participants will be enrolled. Cognitively impaired participants will take part in the study for 48+ months; CN participants will take part in the study for 24+ months.

Participants will undergo longitudinal clinical and cognitive assessments, computerized cognitive tests, biomarker and genetic tests, PET (FDG, amyloid and tau) and MRI brain scans, and optional cerebrospinal fluid (CSF) collection. Participants will be invited to consider autopsy brain donation

The primary objectives of the LEADS study are to:

* collect longitudinal assessments and biomarker data in individuals with early onset cognitive impairment (EOAD / EOnonAD) and cognitively normal (CN) controls;
* to compare baseline and longitudinal cognitive and functional characteristics, between EOAD and CN, and EOAD and Late Onset Alzheimer's Disease (LOAD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI); and
* to study the associations of longitudinal clinical and cognitive assessments with multimodal imaging and biofluid markers that capture different elements of the AD pathophysiological cascade

Eligibility criteria: Inclusion Criteria for Cognitively Impaired (EOAD and EOnonAD) Cohorts Only:

1. Meets NIA-AA criteria for MCI due to AD or probable AD dementia
2. Have a global CDR score ≤ 1.0
3. Have capacity to provide informed consent (IC) or has a legal authorized representative or guardian who provides IC
4. Age between 40-64 years (inclusive) at the time of consent
5. Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends at least 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI
6. Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
7. Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan
8. Fluent in English or Spanish if enrolled in the U.S.
9. Fluent in English, Spanish, Dutch or Swedish for sites outside the U.S., according to site's spoken language(s).

Inclusion Criteria for Cognitively Normal (CN) Cohort Only:

1. Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living
2. Have a global CDR score = 0
3. Have capacity to provide informed consent
4. Have a Mini-Mental State Exam score between 26-30 (inclusive). Exceptions may be made for participant with less than 8 years of education at the discretion of the Site PI
5. Age between 40-64 years (inclusive) at the time of consent
6. Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI
7. Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
8. Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan
9. Fluent in English or Spanish if enrolled in the U.S.
10. Fluent in English, Spanish, Dutch or Swedish for sites outside the U.S., according to site's spoken language(s).

Exclusion Criteria for all (EOAD, EOnonAD and CN) cohorts:

1. Meets core clinical criteria for non-AD dementia
2. Two or more first degree relatives with a history of early-onset dementia suggestive of autosomal dominant transmission, unless known pathogenic mutations in APP, PSEN1, PSEN2, MAPT, GRN and C9ORF72 have been excluded
3. Known CLIA certified mutation in an ADAD gene (APP, PSEN1, PSEN2), or other autosomal dominant genes associated with other neurodegenerative disorders (MAPT, GRN, C9ORF72)
4. Contraindications to 3T MRI (e.g., claustrophobia, pacemaker, select aneurismal clip, artificial heart valve, select ear implants, select stents incompatible with 3T MRI, metal fragments or foreign objects in the eyes, skin or body, etc.)
5. Lifetime medical history of a brain disorder other than the disorder causing dementia except for headache (exceptions are allowed at the discretion of the Site PI - e.g., seizure disorder thought to be due to EOAD).
6. MRI scan with evidence of infection or focal lesions, cortical strokes, multiple lacunes (single lacune is allowable unless it meets criteria for strategic lacune affecting cognition)
7. Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the Site PI)
8. Research radiation exposure will be assessed by the study physician. If the candidate participant has had more than one nuclear medicine study in the prior 12 months for research-related purposes, study inclusion will require approval from the PET Core
9. Investigational agents are prohibited 30 days prior to entry
10. Previous enrollment in a therapeutic trial targeting amyloid or tau.
11. Participation in other clinical studies with neuropsychological measures, with the exception of participants who are co-enrolled in the NACC Uniform Data Set (UDS) protocol (Note: This criterion is intended to reduce repeat measures effects during neuropsychological testing. Exceptions are allowed at the discretion of the Site PI)
12. Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria)
13. Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder with or without psychotic features
14. Current history (in previous 6 months) of moderate or severe substance abuse (nicotine or caffeine is allowed)
15. Suicidal behaviors in the past 12 months or active suicidal ideations
16. Residing in a 24-hour care skilled nursing facility (at the time of screening)
17. (For optional lumbar puncture procedure only):

    a. Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the Site PI i. Platelet count \<100,000/ml ii. INR\>1.2 iii. Abnormal PT or PTT at screening b. Contraindications to the procedure, including but not limited to severe degenerative joint disease, deformity of the spine, history of a bleeding disorder c. Suspected elevated intracranial pressure, Arnold Chiari malformation or mass lesion d. Use of the anticoagulant medications such as but not limited to warfarin, rivaroxaban, dabigatran
18. Deemed ineligible by the Site PI for any other reason

Primary outcomes:
measure: Rate of change in cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog13)
timeFrame: Month 0, Month 12, Month 24, Month 36 (EOAD/EOnonAD only) and Month 48 (EOAD/EOnonAD only)
Secondary outcomes:
measure: Rate of change in cognition as measured by the Clinical Dementia Rating - Sum of Boxes (CDR-SB)
timeFrame: CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48
measure: Change in tau deposition as measured by flortaucipir (18F-AV-1451) Positron Emission Tomography (PET) imaging
timeFrame: Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD and EOnonAD amyloid positive participants only)
measure: Change in amyloid deposition as measured by florbetaben using Positron Emission Tomography (PET) imaging
timeFrame: Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD/EOnonAD only
measure: Neurodegeneration as measured by fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) imaging compared to magnetic resonance imaging (MRI)
timeFrame: Month 12 (EOnonAD only) and Month 24 (CN only)
measure: Change in brain structure using magnetic resonance imaging (MRI)
timeFrame: CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24 and Month 36
measure: Change in cerebrospinal fluid (CSF) biomarkers
timeFrame: CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36
measure: Change in plasma biomarkers
timeFrame: CN participants: Month 0, Month 12 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48
Other outcomes:
Locations:
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Miami Beach
country: United States
facility: Wien Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic, Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University, St. Louis
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: Butler Hospital
state: Rhode Island
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Buenos Aires
country: Argentina
facility: Fleni
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Malmö
country: Sweden
facility: Lund University
city: London
country: United Kingdom
facility: University College London
Study officials:
affiliation: Indiana University
name: Liana Apostolova, MD
role: PRINCIPAL_INVESTIGATOR
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