Alexander C. Conley

Digital cognitive interventions (DCIs) have emerged as scalable approaches for treating cognitive dysfunction across psychiatric, neurological, and aging populations. Despite growing evidence of efficacy, little is known about which intervention components drive therapeutic effects or through which neurocognitive mechanisms they operate. As a result, null findings are often difficult to interpret, making it unclear whether interventions failed to engage their intended targets, or whether the targets themselves are not causally related to meaningful outcomes. This limits intervention refinement, comparative evaluation, and precision personalization. Here, we argue that DCI research should shift from broad efficacy testing toward mechanistic trials designed to identify active ingredients—the intervention components responsible for engaging prespecified neurocognitive targets and producing clinically meaningful benefits. We propose adapting dismantling design methodology from psychotherapy research in order to integrate Research Domain Criteria constructs, mechanistic neuroscience, and high-resolution digital behavioral data to identify factors driving cognitive and functional outcomes. This approach aligns with the National Institute of Mental Health experimental therapeutics framework by explicitly linking target specification and target engagement with downstream clinical and functional outcomes. Mechanistic dismantling trials can determine whether specific DCI features, including adaptive difficulty, reward schedules, feedback contingencies, task variability, cognitive targets, and human support, are necessary, sufficient, or synergistic for engaging neural circuitry and producing durable and clinically meaningful transfer. Beyond optimizing intervention design, such studies may transform null or negative trials into mechanistically interpretable findings, while clarifying disease mechanisms and supporting the development of personalized, optimized, and usable DCIs.

BACKGROUND Digital cognitive interventions (DCIs) are increasingly used to address cognitive deficits across psychiatric, neurological, and aging populations. However, the field lacks consensus about which intervention components are causally responsible for cognitive and clinical benefits. This limits interpretation of negative trials, impedes optimization, and constrains personalization. Mechanistic dismantling trials can clarify whether specific DCI features (e.g., adaptive difficulty, reward schedules, feedback contingencies, task variability, specific cognitive target, and human support) are necessary, sufficient, or synergistic for engaging neural circuitry and producing durable generalization. Further, dismantling designs hold potential to more precisely probe underlying disease mechanisms and identify specific neurocognitive processes responsible for clinical impairment in the target population. OBJECTIVE We argue that DCI research should shift from broad efficacy testing to mechanistic studies designed to identify “active ingredients” e.g. the minimal components required to engage a prespecified target and improve clinically meaningful outcomes. We propose adapting dismantling designs from psychotherapy research and integrating them with mechanistic neuroscience, cognitive theory, and high-resolution digital behavioral data. This approach aligns with the National Institute of Mental Health’s Experimental Therapeutics framework by explicitly linking: (1) target specification, (2) target engagement, and (3) downstream clinical and functional benefit. METHODS No Methods RESULTS No Results CONCLUSIONS Mechanistic dismantling trials can clarify whether specific DCI features (e.g., adaptive difficulty, reward schedules, feedback contingencies, task variability, specific cognitive target, and human support) are necessary, sufficient, or synergistic for engaging neural circuitry and producing durable generalization. Further, dismantling designs hold potential to more precisely probe underlying disease mechanisms and identify specific neurocognitive processes responsible for clinical impairment in the target population.

Background: The use of cognitive training as a therapeutic intervention for adults with Mild Cognitive Impairment (MCI) offers the potential for improved cognition without the adverse effects seen in many pharmacological trials. A novel cognitive enhancement strategy is neuroplasticity‐based computerized cognitive remediation (nCCR), which aims to boost cognitive performance by training clinically relevant cortical networks. In MCI patients, the goal is that by engaging networks that support memory function through nCCR, this will produce sustained improvements in functioning. The present study is a preliminary investigation into the feasibility and tolerability of an nCCR intervention called Neuroflex in adults with MCI. Method: This open‐label study required participants to complete 45‐hours of Neuroflex across six weeks. Training was delivered remotely through research tablet computers by study staff coaching over videoconferencing software. During and following the intervention, participants’ completed questionnaires and tasks that assessed potential changes in cognitive performance, which would indicate markers of functional engagement for future randomized trials. Result: The use of Neuroflex was well tolerated, as of the nineteen participants who were enrolled in treatment (11 female, mean age 73.3 ± 9 years), sixteen successfully completed training (completion rate: 84.2 %). Analyses of the open label data has shown improvements in self‐ and informant‐reported functioning, as well as in cognitive performance. Following NeuroFlex training, participants reported higher levels of perceived personal strengths on the Older Adults Self Report ( p = 0.047, d = 0.54), and study partners reported lower levels of dementia symptoms on the Older Adult Behavior Checklist ( p = 0.034, d = 0.58). Participants had improved working memory performance on the 2‐back task following training compared to baseline ( p = 0.028, d = 0.63), and improved accuracy on a go/nogo task ( p = 0.031, d =0.62). Conclusion: These results show that Neuroflex is feasible and well tolerated for use in patients with MCI. The benefits in cognitive performance indicate the potential for using Neuroflex as an augmentation to other therapeutics in adults with MCI and support the further investigation of Neuroflex with a randomized controlled trial.

Due to the high prevalence of Alzheimer's disease (AD) in adults with Down syndrome (DS), trisomy 21 is now considered a genetic form of AD (DSAD). A better understanding of factors that can prevent or delay AD is vital to improve outcomes for adults with DS. In this narrative review, we apply AD and cognitive aging research frameworks to study resistance and resilience in DSAD. Given the variability in the timing of pathology and symptoms, we discuss the evidence supporting the role of genetic, biological, socio‐behavioral, lifestyle, and environmental factors in resistance and resilience to DSAD. We also consider how co‐occurring health conditions in DS may influence resistance and resilience, and how methods from AD research can be applied to DSAD. Ultimately, this framework aims to guide future research and translate findings into clinical interventions to improve outcomes in DSAD.Highlights: Definitions of resistance and resilience in the genetic form of Alzheimer's disease (DSAD) are proposed for guiding the field. Variability in the timing of AD pathology and symptoms suggests the potential for resistance and resilience mechanisms in DSAD. Genetic, biological, socio‐behavioral, lifestyle, and environmental factors have the potential to build resistance or resilience in DSAD. Future research will require longitudinal and experimental designs, life course approaches, and large cohort studies.

Background: Adults with Down syndrome (DS) are at a high risk of developing Alzheimer’s disease (AD) due to the triplication of the amyloid precursor protein on chromosome 21. Despite the high incidence of AD within the DS population, there is less understanding of how AD progresses, although it may be reflected in an accelerated aging phenotype. Compared to typically developing populations, there is less understanding of the decline of cholinergic integrity with aging in adults with DS. In this pilot study we are investigating the impact of cholinergic system integrity using [¹⁸F]‐FEOBV PET on cortical structure and cognitive function in adults with DS. One measure of cognitive function that we used was attention and memory processes recorded by high‐density electroencephalography (EEG).Method: Nine non‐demented adults with DS (4 female, aged 37.8±7.7 years), recruited from the Trial Ready Cohort – Down syndrome, completed an MRI, [¹⁸F]‐FEOBV PET scan and an EEG recording. Participants completed an incidental memory task, a passive memory task with a series of complex images half of which are novel, and half repeated. Oscillatory power across the frontal, central and parietal regions was defined as a repeated–novel power. [¹⁸F]‐FEOBV PET images were coregistered to structural MR images and referenced to the supraventricular white matter. Initial analyses focused on memory‐related evoked power from the delta, theta, alpha and beta frequency bands, and their association with [18F]‐FEOBV PET uptake.Result: Unexpectedly, recognition memory for repeat vs novel stimuli was associated with reduced power for delta, theta and beta bands and increased alpha power. This pattern of results reflect memory processes identified with older adults in the typically developing population rather than an age‐matched sample. Increased cholinergic uptake was associated with this pattern of older age‐like power across all frequency bands.Conclusion: Evoked oscillatory activity on a recognition memory task in a small sample of adults with DS displayed similar characteristics as older adults in the typically developing population. Cholinergic integrity was associated with evoked power during recognition memory. These results demonstrate functional markers of accelerated aging in adults with DS as well as their relationship with cholinergic integrity.

Purpose: Chemotherapy-related cognitive impairment (CRCI) is a distressing and increasingly recognized long-term sequela reported by breast cancer patients following cancer treatment. There is an urgent but unmet clinical need for treatments that improve CRCI. In this context, we proposed the use of a novel cognitive enhancement strategy called Neuroflex to target CRCI experienced by breast cancer survivors. Methods: The primary aim of this pilot study was to evaluate the feasibility and acceptability of Neuroflex, a novel digital cognitive enhancement strategy, in breast and gynecologic cancer survivors with CRCI. Secondary analyses focused on whether improvements in performance on Neuroflex were associated with improvement in subjective cognitive complaints and objective cognitive performance measures. Results: Participants ( N = 21) completed an average of 7.42 hours of Neuroflex training per week, an average of 44.5 (±1.01) hours total, and had a 100% completion rate. Participants exhibited significant improvement in self-reported cognitive function as well as significant improvement on tasks of verbal learning and memory and auditory working memory. Participants also exhibited improvement in mood, as well as improvement on a disability assessment. Conclusions: Results demonstrate feasibility and that breast cancer survivors are capable of completing a lengthy and challenging cognitive training program. Secondly, Neuroflex may confer specific cognitive benefits to both self-reported and objective performance. Results strongly support further investigation of Neuroflex in a larger controlled trial to establish efficacy for CRCI symptoms. Further studies may also result in optimization of this digital intervention for women with CRCI.

Objective: Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self‐reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17β‐estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self‐reported (subjective) postmenopausal cognitive complaints.Methods: Forty postmenopausal women (aged 50–60 years) completed a 3‐month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC).Results: Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N‐back working memory task, regardless of whether they received estradiol treatment.Conclusions: The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks.