The Diabetes Prevention Program Outcomes Study AD/ADRD Project (DPPOS-4)

Alzheimer's Disease and Alzheimer's Disease Related Dementias in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Outcomes Study AD/ADRD Project

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Diabetes; Dementia; PreDiabetes; Alzheimer Disease; Dementia, Vascular

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.

• Study Type: Observational
• Enrollment (Estimated): 1976

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • SW American Indian Center - Phoenix
  • California
    • Alhambra, California, United States, 91801
      • University of California Los Angeles
    • San Diego, California, United States, 92128
      • University of California San Diego
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20003
      • MedStar Health Research Institute
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Pennington Biomedical Center
  • Maryland
    • Lutherville, Maryland, United States, 21093
      • Johns Hopkins University
    • Rockville, Maryland, United States, 20852
      • Biostatistics Center, George Washington University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
    • Shiprock, New Mexico, United States, 87420
      • SW American Indian Center - Shiprock
    • Zuni, New Mexico, United States, 87327
      • SW American Indian Center - Zuni
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein College of Medicine
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10032
      • Columbia University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • University of Tennessee
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center San Antonio
  • Washington
    • Seattle, Washington, United States, 98108
      • University of Washington, VA Puget Sound Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• 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.

Description

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:

-

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Diagnoses	Classification of normal, mild cognitive impairment or dementia based on NACC UDS	Sept 2022 to October 2026

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ptau-181	Plasma biomarkers for AD/ADRD	Sept 2022 to October 2026
Aβ42/40 ratio	Plasma biomarkers for AD/ADRD	Sept 2022 to October 2026
Neurofilament Light Chain (NfL)	Plasma biomarkers for AD/ADRD	Sept 2022 to October 2026
Glial fibrillary acidic protein (GFAP)	Plasma biomarkers for AD/ADRD	Sept 2022 to October 2026
Amnestic cognitive decline	Based on the SEVLT immediate recall (sum of trials 1-3) and delayed recall (trial 4)	Sept 2022 to October 2026
Non-amnestic cognitive decline	DSST measure	Sept 2022 to October 2026
White matter microstructure	Among ppts in the neuromaging subcohort	March 2023 to October 2026

Collaborators and Investigators

• Sponsor: Marinella Temprosa
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Jose Luchsinger, Columbia University; Study Chair: David Nathan, Massachusetts General Hospital; Principal Investigator: Marinell Temprosa, George Washington University

Publications and helpful links

Helpful Links

• Study website

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2022
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): August 30, 2027

Study Registration Dates

• First Submitted: January 11, 2023
• First Submitted That Met QC Criteria: January 19, 2023
• First Posted (Actual): January 30, 2023

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Neurocognitive Disorders; Endocrine System Diseases; Neurodegenerative Diseases; Hyperglycemia; Tauopathies; Intracranial Arterial Diseases; Intracranial Arteriosclerosis; Leukoencephalopathies; Diabetes Mellitus; Dementia; Prediabetic State; Glucose Intolerance; Alzheimer Disease; Dementia, Vascular
• Other Study ID Numbers: DPPOS AD/ADRD; 1U19AG078558 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will have data in the NACC (National Alzheimer's Coordinating Center) data repository for NACC UDS (Uniform Data Set) data and the rest will be available in the NIDDK data repostiory
• IPD Sharing Time Frame: NACC 2025 and 2027 NIDDK repository 2027
• IPD Sharing Access Criteria: Available to public by application
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: DPPOS
2. Individual Participant Data Set
   Information comments: will be available in 2025

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No