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. 2025 Apr-Jun;12(2):111-120.
doi: 10.18203/2349-3259.ijct20251032. Epub 2025 Apr 11.

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  1 , Terry E Goldberg  2   3 , Philip D Harvey  4 , Angela J Hanson  5 , Jeffrey Motter  3 , Howard Andrews  3 , Min Qian  6 , Renjie Zhang  2 , Meaghan Janis  2   3 , P Murali Doraiswamy  1   7 , Davangere P Devanand  2   3
Affiliations

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 et al. Int J Clin Trials. 2025 Apr-Jun.

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).

Keywords: ATN; Alzheimer’s disease; Blood-based biomarkers; Computerized cognitive training; MCI; MRI.

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Conflict of interest statement

LAW, HA, JM, MQ, RZ, MJ and TG report no disclosures. Dr. Hanson serves on an advisory board for Novo Nordisk. Dr. Harvey has served as an advisor to BMS, Boehringer-Ingelheim, Merck, Minerva Neuroscience, and WCG. He receives royalties from WCG Endpoint solutions and is Chief Scientific officer of i-Function, whose products are not used in this trial. PMD has received recent grants, through Duke University, from NIH, DOD, USC, Columbia, and the Cure Alzheimer’s Fund as well as gifts from Wrenn Trust and Gates Ventures. PMD has received fees for speaking or advisory services from Lumos Labs, Keel Digital, Cornell, Transposon Therapeutics, Prospira, Alzheon, Neurology Live and uMETHOD; PMD owns shares or options in uMETHOD, Evidation, Alzheon and MarvelBiome. PMD serves as a board member at AHEL Ltd and Live Love Laugh Foundation. PMD is a co-inventor on patents for dementia. DPD serves as a consultant on advisory boards to Acadia, BioXcel, Eisai, and GSK

Figures

Figure 1:
Figure 1:
Study design of COGIT-2 RCT in MCI.
Figure 2:
Figure 2:. Key study aims and outcome measures.
ADAS-Cog14: Alzheimer’s disease assessment scale cognitive subscale 14; FAQ: functional assessment questionnaire; PACC5: preclinical Alzheimer’s cognitive composite-5; ADCS-ADL-PI: Alzheimer’s disease cooperative study activities of daily living prevention instrument; Nfl: neurofilament light; pTau217: phospho-tau 217.
See this image and copyright information in PMC

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