Longitudinal Early-onset Alzheimer's Disease Study Protocol (LEADS)

Indiana University

Status

Enrolling

Conditions

Alzheimer Disease

Mild Cognitive Impairment

Early Onset Alzheimer Disease

Treatments

Drug: Flortaucipir

Drug: Fluorodeoxyglucose

Drug: Florbetaben

Study type

Observational

Funder types

Other

NIH

Identifiers

NCT03507257

R56AG057195 (U.S. NIH Grant/Contract)

ATRI-003

Details and patient eligibility

About

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.

Full 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

Enrollment

850 estimated patients

Sex

All

Ages

40 to 64 years old

Volunteers

Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Meets NIA-AA criteria for MCI due to AD or probable AD dementia
Have a global CDR score ≤ 1.0
Have capacity to provide informed consent (IC) or has a legal authorized representative or guardian who provides IC
Age between 40-64 years (inclusive) at the time of consent
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
Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
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
Fluent in English or Spanish if enrolled in the U.S.
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:

Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living
Have a global CDR score = 0
Have capacity to provide informed consent
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
Age between 40-64 years (inclusive) at the time of consent
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
Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
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
Fluent in English or Spanish if enrolled in the U.S.
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:

Meets core clinical criteria for non-AD dementia
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
Known CLIA certified mutation in an ADAD gene (APP, PSEN1, PSEN2), or other autosomal dominant genes associated with other neurodegenerative disorders (MAPT, GRN, C9ORF72)
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.)
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).
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)
Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the Site PI)
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
Investigational agents are prohibited 30 days prior to entry
Previous enrollment in a therapeutic trial targeting amyloid or tau.
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)
Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria)
Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder with or without psychotic features
Current history (in previous 6 months) of moderate or severe substance abuse (nicotine or caffeine is allowed)
Suicidal behaviors in the past 12 months or active suicidal ideations
Residing in a 24-hour care skilled nursing facility (at the time of screening)
(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
Deemed ineligible by the Site PI for any other reason

Trial design

850 participants in 3 patient groups

Early Onset Alzheimer's Disease (EOAD)

Description:

* Diagnosis of NIA-AA criteria of MCI due to AD or probable AD dementia * Amyloid positive status (florbetaben PET scan with evidence of elevated amyloid as determined by a central read) * CDR score ≤ 1.0 * flortaucipir (18F-AV-1451) PET scanning

Treatment:

Drug: Florbetaben

Drug: Flortaucipir

Cognitively Normal (CN) Controls

Description:

* Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions and activities of daily living * Mini-Mental State Exam score between 26-30 * CDR score = 0 * flortaucipir (18F-AV-1451) PET scanning

Treatment:

Drug: Florbetaben

Drug: Fluorodeoxyglucose

Drug: Flortaucipir

Early Onset non-Alzheimer's Disease (EOnonAD)

Description:

* Diagnosis of NIA-AA criteria of MCI due to AD or probable AD dementia * Amyloid negative status (florbetaben PET scan with no evidence of elevated amyloid as determined by a central read) * CDR score ≤ 1.0 * flortaucipir (18F-AV-1451) PET scanning

Treatment:

Drug: Florbetaben

Drug: Fluorodeoxyglucose

Drug: Flortaucipir

Trial documents