Crossword puzzle training and neuroplasticity in mild cognitive impairment (COGIT-2): 78-week, multi-site, randomized controlled trial with cognitive, functional, imaging and biomarker outcomes

Laura A. Wang; Terry E. Goldberg; Philip D. Harvey; Angela J. Hanson; Jeffrey Motter; Howard Andrews; Min Qian; Renjie Zhang; Meaghan Janis; P. Murali Doraiswamy; Davangere P, Devanand

doi:10.18203/2349-3259.ijct20251032

Authors

Laura A. Wang Department of Psychiatry, Duke University Medical Center, Durham, North Carolina, USA
Terry E. Goldberg Area Brain Aging and Mental Health, New York State Psychiatric Institute, New York, USA; Department of Psychiatry, Columbia University Irving Medical Center, New York, USA
Philip D. Harvey Department of Psychiatry, University of Miami Miller School of Medicine, Miami, Florida, USA
Angela J. Hanson Department of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, USA
Jeffrey Motter Department of Psychiatry, Columbia University Irving Medical Center, New York, USA
Howard Andrews Department of Psychiatry, Columbia University Irving Medical Center, New York, USA
Min Qian Department of Biostatistics, Columbia University Irving medical Center, New York, USA
Renjie Zhang Area Brain Aging and Mental Health, New York State Psychiatric Institute, New York, USA
Meaghan Janis Area Brain Aging and Mental Health, New York State Psychiatric Institute, New York, USA; Department of Psychiatry, Columbia University Irving Medical Center, New York, USA
P. Murali Doraiswamy Department of Psychiatry, Duke University Medical Center, Durham, North Carolina, USA; Duke Center for the Study of Aging and the Duke UNC Alzheimer’s Disease Research Center, Durham, NC, USA
Davangere P, Devanand Area Brain Aging and Mental Health, New York State Psychiatric Institute, New York, USA; Department of Psychiatry, Columbia University Irving Medical Center, New York, USA

DOI:

https://doi.org/10.18203/2349-3259.ijct20251032

Keywords:

Alzheimer’s disease, Computerized cognitive training, MCI, MRI, ATN, Blood-based biomarkers

Abstract

Background: Cognitive training represents an important potential therapeutic strategy for mild cognitive impairment (MCI). In our recently completed trial, crossword puzzles were superior to computerized cognitive training on Alzheimer's disease assessment scale–cognitive subscale-11 (ADAS-Cog11) and function, correlating with decreased brain atrophy over 78 weeks.

Methods: COGIT-2 is a 78-week, multicenter, clinical trial comparing home-based, high-dose crosswords (4 puzzles per week) to low-dose crosswords (1 puzzle per week) and a health education control group in 240 MCI subjects. Crossword puzzles, administered by the CogniFit research platform, have been designed to have a moderate level of difficulty.

Results: The primary outcome is change in ADAS-Cog14 and the main secondary outcome is change in informant reported daily functioning. Additional outcomes include changes in magnetic resonance imaging (MRI) hippocampal volume and cortical thickness as well as changes in plasma neurofilament light and plasma pTau217.

Conclusions: If the efficacy of computerized crossword puzzle training is confirmed in COGIT-2, crosswords training could become a low-cost, home-based, scalable, cognitive enhancement tool for people at risk for Alzheimer’s disease. The dose comparison will provide useful information on the preferred frequency of crossword puzzle training.

Trial Registration: Trial registration number ClinicalTrials.gov identifier (NCT06601933).

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