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.

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).