Clinical trial NCT05704309: The Diabetes Prevention Program Outcomes Study AD/ADRD Project
Official title: Alzheimer's Disease and Alzheimer's Disease Related Dementias in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Outcomes Study AD/ADRD Project
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Diabetes
Alzheimer Disease
Dementia, Vascular
Dementia
PreDiabetes
Lead sponsor: George Washington University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2023-01-30
Enrollment: 1976
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The DPPOS (2002-2022) is a 25-center observational study that started as the DPP randomized controlled clinical trial (1996-2001). The DPP demonstrated the ability to reduce the development of T2D with intensive lifestyle or metformin compared with placebo among persons with PreD. The combined DPP and DPPOS have followed the original DPP cohort for a mean of 23 (range 21-25) years as of 2022. For this project, we expect that the cohort will have 1979 participants, with approximately two thirds with T2D of precisely known duration. Forty-eight percent of the cohort are ethnic and racial minorities that are at relatively higher risk of AD/ADRD compared with non-Hispanic whites, and 71% are women.

Brief summary: The DPPOS AD/ADRD project will address the overarching question: What are the determinants and the nature of cognitive impairment among persons with pre-diabetes (PreD) and type 2 diabetes (T2D), who are a high-risk group for cognitive impairment and represent a large fraction of the United States (US) population? This U19 proposal addresses the National Alzheimer's Project Act goal to "prevent, halt, or reverse AD" in the high-risk group of persons with pre-diabetes and type 2 diabetes, who represent over half of the population aged 60 years and older in the US.

Detailed description: DPPOS AD/ADRD focuses on one of the most important, complex questions in Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) research: What are the determinants and the nature of cognitive impairment among persons with pre-diabetes (PreD) and type 2 diabetes (T2D), who are a high-risk group for cognitive impairment and represent a large fraction of the United States (US) population? Despite knowledge that persons with PreD and T2D are a high-risk group for cognitive decline, mild cognitive impairment (MCI), and dementia, the risk factors, mechanisms, and neuropathology of cognitive impairment in persons with PreD and T2D remain unclear. Gaps in knowledge on cognitive impairment in PreD and T2D include: (a) the role of AD and/or non-AD neuropathology beyond vascular contributions to cognitive impairment and dementia (VCID); (b) the role of glycemia, related metabolic factors such as hyperinsulinemia, and traditional micro and macrovascular complications of PreD/T2D; (c) the role of glucose-lowering medications, primarily metformin; and (d) the role of physical activity, physical function, and frailty, key in PreD and T2D. The 4 interrelated projects will address these gaps, leveraging the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS) cohort and its detailed PreD/T2D phenotyping, adding state of the art AD/ADRD phenotyping. The DPPOS cohort currently has a mean age of 72 years, with 76% over the age of 65. Thus, the cohort is in a period of the lifespan when the development of cognitive decline, MCI, and dementia accelerates. This extensively phenotyped cohort represents an estimated 50 million Americans. To address this proposal's complex interrelated questions, the study has two waves of state-of-the-art AD/ADRD phenotyping during the proposed 5-year funding period, including comprehensive cognitive assessments and syndrome adjudication and plasma and brain imaging biomarkers of AD/ADRD. The study will address the complex overarching question of our project through the following aims: (1) To establish 5 cores to support the 4 integrated scientific projects: An Administrative Core, a Clinical Operations and Procedures Core, a Cognitive Assessment and Adjudication Core, a Neuroimaging and Plasma Biomarkers Core, and A Biostatistics and Data Infrastructure Core: (2) To conduct 4 integrated projects focused on key aspects of the central question of this proposal: Project 1 will examine the association of cognitive decline, MCI, and dementia in the DPPOS cohort with biomarkers of neuropathology and brain insulin signaling, and with sociodemographic and behavioral factors; Project 2 will examine the associations of cumulative glycemia, related metabolic factors, and microvascular and macrovascular complications, with cognitive syndromes and biomarkers of neuropathology; Project 3 will examine the association of cumulative exposure to metformin and other T2D medications with cognitive syndromes and biomarkers of neuropathology; Project 4 will evaluate the association of trajectories of physical activity, physical function and frailty with cognitive syndromes and biomarkers of neuropathology.

Eligibility criteria: Inclusion Criteria:

* All surviving participants originally randomized in the Diabetes Prevention Program
* For Brain Imaging subcohort, only participants aged 55 years and older and those without contraindication to MRI will be included. Contraindications to MRI include the inability to lie flat, claustrophobia, and the presence of indwelling metallic objects, medical or non-medical, that are not 3T MRI compatible.

Exclusion Criteria:

-

Primary outcomes:
measure: Cognitive Diagnoses
timeFrame: Sept 2022 to October 2026
Secondary outcomes:
measure: ptau-181
timeFrame: Sept 2022 to October 2026
measure: Aβ42/40 ratio
timeFrame: Sept 2022 to October 2026
measure: Neurofilament Light Chain (NfL)
timeFrame: Sept 2022 to October 2026
measure: Glial fibrillary acidic protein (GFAP)
timeFrame: Sept 2022 to October 2026
measure: Amnestic cognitive decline
timeFrame: Sept 2022 to October 2026
measure: Non-amnestic cognitive decline
timeFrame: Sept 2022 to October 2026
measure: White matter microstructure
timeFrame: March 2023 to October 2026
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: SW American Indian Center - Phoenix
state: Arizona
city: Alhambra
country: United States
facility: University of California Los Angeles
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Washington
country: United States
facility: Medstar Health Research Institute
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Honolulu
country: United States
facility: University of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Baton Rouge
country: United States
facility: Pennington Biomedical Center
state: Louisiana
city: Lutherville
country: United States
facility: Johns Hopkins University
state: Maryland
city: Rockville
country: United States
facility: Biostatistics Center, George Washington University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Shiprock
country: United States
facility: SW American Indian Center - Shiprock
state: New Mexico
city: Zuni
country: United States
facility: SW American Indian Center - Zuni
state: New Mexico
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Memphis
country: United States
facility: University of Tennessee
state: Tennessee
city: San Antonio
country: United States
facility: University of Texas Health Science Center San Antonio
state: Texas
city: Seattle
country: United States
facility: University of Washington, VA Puget Sound Health Care System
state: Washington
Study officials:
affiliation: Columbia University
name: Jose Luchsinger
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: David Nathan
role: STUDY_CHAIR
affiliation: George Washington University
name: Marinell Temprosa
role: PRINCIPAL_INVESTIGATOR
References: