Dementia is a leading cause of death in the UK, and long waits for diagnosis can delay access to care and treatment. The SANDBOX study is a research study in NHS Memory Clinics investigating whether providing clinicians with additional test results could help them diagnose dementia earlier. Adults aged 50 or over who have been referred to a Memory Clinic by their GP may be invited to take part. Taking part is voluntary and will not affect a participant's care. Participation adds to their NHS care and does not replace or delay it. Participants complete three assessments: a blood test that measures two proteins which can indicate whether Alzheimer's-related changes may be happening in the brain (not currently available on the NHS); a genetic test for the APOE gene, which influences Alzheimer's risk; and a cognitive assessment of memory and thinking that includes a recorded speech task analysed for subtle language changes. All results are shared with the participant's clinician. This research will help determine whether this approach can support earlier dementia diagnosis and improve care for patients across the UK.
The SANDBOX study evaluates an approach to integrating blood-based biomarkers, APOE4 genetic testing, and digitally administered cognitive assessments into Memory Clinic diagnostic pathways. The primary aim is to assess whether this approach improves efficiency of dementia diagnosis and patient flow through Memory Clinic services. Participants will undergo baseline assessment including venous blood draw (42.5 mL) for analysis of plasma phosphorylated tau-217, epigenetic markers in cell-free DNA, and APOE4 genotyping. Dried blood spot samples will be collected via finger-prick. Digital cognitive testing will be conducted using CANTAB (Cambridge Neuropsychological Test Automated Battery) and recorded speech analysis. Blood biomarker and genetic results will be withheld from clinical teams until participants have a Memory Clinic appointment scheduled, to prevent bias in triage decisions. Results will then be shared with clinicians to support diagnostic assessment. All participants will be offered genetic counseling regarding APOE4 status. A follow-up assessment occurs at 12 months (repeat blood draws and cognitive testing). Psychological impact of genetic disclosure will be monitored using validated questionnaires (Health Anxiety Inventory, CES-D, EQ-5D-5L, IGT-AD Scale). Health economic analysis will evaluate cost-effectiveness of the triage system compared to standard UK practice. AI-based exploratory analyses will investigate relationships between biomarkers and dementia progression.
Study Type
OBSERVATIONAL
Enrollment
1,000
Imperial College Healthcare NHS Trust
London, Greater London, United Kingdom
RECRUITINGCentral and North West London NHS Foundation Trust
London, London, United Kingdom
RECRUITINGWest London NHS Trust
London, London, United Kingdom
RECRUITINGSurrey and Borders Partnership NHS Foundation Trust
London, Surrey, United Kingdom
RECRUITINGAneurin Bevan University Health Board Clinical Research Centre
Newport, Wales, United Kingdom
RECRUITINGBradford District Care Foundation Trust
Bradford, United Kingdom
RECRUITINGCwm Taf Morgannwg University Health Board
Bridgend, United Kingdom
RECRUITINGHywel Dda University Health Board
Llanelli, United Kingdom
ACTIVE_NOT_RECRUITINGCumbria, Northumberland, Tyne and Wear NHS Foundation Trust
Newcastle upon Tyne, United Kingdom
RECRUITINGCardiff and Vale University Health Board
Penarth, United Kingdom
RECRUITING...and 2 more locations
Memory Clinic Performance Metrics
Time from the date of referral to the participant's Memory Clinic to the date of their first clinical assessment appointment. Reported as the mean number of days from referral to assessment.
Time frame: From referral into the Memory Service through first Memory Clinic assessment (up to 12 months)
Usability and Acceptability of Biomarker Enabled Approach-Clinician Feedback
Clinician feedback on the usability and acceptability of the biomarker-enabled approach is assessed using a structured questionnaire. Responses are recorded using categorical Likert-type scales (e.g., Very satisfied to Very dissatisfied), scored from 1 to 5, with higher scores indicating greater satisfaction or perceived effectiveness of the triage system. We will aggregate scores into a composite overall acceptability score.
Time frame: Every 3 months throughout the study (up to 36 months)
Health-Related Quality of Life (EQ-5D-5L)
Health-related quality of life measured using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L). The instrument includes five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each scored on a 5-level scale ranging from 1 (no problems) to 5 (extreme problems). Domain responses are combined into a single EQ-5D-5L index score, where higher scores indicate better health-related quality of life.
Time frame: Baseline (Study Visit 1), 2 weeks after return of results (Study Visit 3), and 12 months (Study Visit 4)
Health-Related Quality of Life - Self Rated Overall Health (EQ VAS)
Self-reported health status measured using the visual analogue scale (VAS) of the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L). The VAS ranges from 0 to 100, where 0 represents the worst health imaginable and 100 represents the best health imaginable. Higher VAS scores indicate better self-reported health status.
Time frame: Baseline (Study Visit 1), 2 weeks after return of results (Study Visit 3), and 12 months (Study Visit 4)
Plasma Alzheimer's Disease Biomarkers (PrecivityAD2)
Plasma Alzheimer's disease biomarkers measured using the PrecivityAD2 blood test (C2N Diagnostics), including the amyloid beta 42/40 ratio (Aβ42/40), percent phosphorylated tau-217 (%p-tau217). The Amyloid Probability Score (APS2) is a composite algorithm score derived from these biomarkers and ranges from 0 to 100, correlated with clinical diagnosis and cognitive performance. Higher APS2 values indicate a greater likelihood of brain amyloid pathology consistent with Alzheimer's disease. APS2 values from 0-47 are interpreted as negative for brain amyloid plaques, while higher scores indicate increased probability of amyloid positivity.
Time frame: Baseline (Study Visit 1) and 12 months (Study Visit 4)
Epigenetic Biomarkers in Cell-Free DNA
Methylation biomarkers in cell-free DNA analyzed by our models for associations with dementia-related clinical variables, including diagnosis and cognitive performance.
Time frame: Baseline (Study Visit 1), 6 months (Study Visit 4), and 12 months (Study Visit 5)
Digital Cognitive Testing Performance (CANTAB)
Cognitive performance measured by CANTAB (Cambridge Neuropsychological Test Automated Battery) across multiple domains including episodic memory, visuospatial working memory, attention, associative learning, decision-making, visual-constructional ability, planning, processing speed, and task switching. Performance is reported as standardized z-scores and percentiles relative to an age-matched reference population. Z-scores range from negative to positive values, where 0 represents average performance; positive values indicate above-average cognitive performance and negative values indicate below-average performance.
Time frame: Baseline (Study Visit 1), and 12 months (Study Visit 4)
Voice-Based Biomarkers from Free Speech Analysis
Speech parameters analysed from digitally recorded free speech tasks (narration of a complex scene with delayed repetition). Participants verbally describe the "cookie jar" scene and, after completing the CANTAB digital cognitive assessment, are asked to repeat the narration from memory. Speech recordings are analysed to derive quantitative speech parameters reflecting language production, including measures of fluency, lexical complexity, and acoustic features.These parameters are combined into a composite score reflecting evidence of dementia-related changes in speed, which is evaluated for associations with cognitive impairment.
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Time frame: Baseline (Study Visit 1), and 12 months (Study Visit 4)
Clinical and Demographic Data
Diagnosis, in-clinic cognitive test results, and demographic variables to characterise the study population and explore associations with dementia biomarkers.
Time frame: Study Visit 2, occurring at variable timepoints up to 12 months after baseline depending on clinic wait times
Acceptability and Feedback of Biomarker Enabled-Approach
Participant acceptability of the genetic risk disclosure and biomarker enabled approach assessed using a study-specific 8-item questionnaire. The questionnaire includes categorical response options such as Likert-type ratings (e.g., strongly disagree to strongly agree), ordinal satisfaction scales (e.g., very satisfied to very dissatisfied), binary responses, and open-ended feedback. Responses are analysed descriptively to assess participant perceptions of the genetic risk disclosure and diagnostic process.
Time frame: 2 weeks after return of results (Study Visit 3) and 12 months (Study Visit 4)
Psychological impact of genetic disclosure: Assessment of Anxiety Symptoms (Health Anxiety Inventory)
Health anxiety symptoms assessed using the Health Anxiety Inventory (HAI). The HAI consists of multiple items assessing concerns about health and illness, with responses scored on a Likert-type scale and summed to generate a total score. Total scores range from 0 to 54, with higher scores indicating greater health-related anxiety.
Time frame: Baseline (Study Visit 1), 2 weeks after return of results (Study Visit 3), and 12 months (Study Visit 4)
Psychological impact of genetic disclosure: Assessment of Depression Symptoms (CES-D)
Depressive symptoms assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D includes 20 items assessing symptoms of depression over the past week. Total scores range from 0 to 60, with higher scores indicating greater depressive symptom severity.
Time frame: Baseline (Study Visit 1), 2 weeks after return of results (Study Visit 3), and 12 months (Study Visit 4)
Genetic Risk Perception and Understanding (IGT-AD Scale)
Genetic risk perception and understanding assessed using the REVEAL Impact of Genetic Testing in Alzheimer's Disease (IGT-AD) Scale. The questionnaire includes multiple items rated on a 4-point Likert scale ranging from 0 (never) to 5 (often). Item scores are summed to produce a total score, with higher scores indicating greater psychological impact or concern related to receiving genetic testing results.
Time frame: 12 months (Study Visit 4)
Per-Patient Cost of Biomarker Enabled Approach Implementation
Cost estimates per patient derived from resource requirements for blood collection, phlebotomy services, dried blood spot kits, biomarker laboratory analysis (PrecivityAD2 and epigenetic markers), genetic testing, and remote cognitive testing infrastructure.
Time frame: Throughout study duration (up to 36 months), calculated from resource utilisation data
Diagnostic Efficiency Compared to Standard UK Practice
Time from GP referral to clinical diagnosis in study participants compared to standard UK practice using Clinical Practice Research Datalink (CPRD) data as the comparator.
Time frame: Measured from baseline through Memory Clinic diagnosis (up to 12 months); compared to CPRD data throughout study duration (up to 36 months)
Quality-Adjusted Life Years (QALYs) Gained
Incremental quality-adjusted life-years gained due to earlier diagnosis and access to pharmacological (e.g., donepezil) and non-pharmacological care (e.g., dementia support workers, caregiver support), calculated from EQ-5D-5L data using health economic modeling.
Time frame: Study duration (up to 36 months) with health economic modeling projecting outcomes over ≥10 years
Cost-Effectiveness by APOE4 Carrier Status (Subgroup Analysis)
Incremental cost-effectiveness results stratified by APOE4 carrier status (non-carrier, heterozygous carrier, homozygous carrier) to evaluate variability in outcomes and cost per QALY gained based on genetic risk category.
Time frame: Throughout study duration (up to 36 months), with health economic modeling
Health Economic Model Robustness
Results of probabilistic sensitivity analyses and scenario analyses to quantify the impact of data uncertainty and structural model assumptions on cost-effectiveness estimates.
Time frame: Throughout study duration (up to 36 months), with final analysis upon study completion
Healthcare Resource Utilisation
Healthcare resource utilisation following diagnostic evaluation, measured as the number of further investigations requested or avoided per participant (e.g., additional bloods, MRI, or other diagnostic tests), derived from a survey completed by the treating clinical team. The number of investigations are used to characterise healthcare resource use associated with the diagnostic pathway.
Time frame: Throughout study duration (up to 36 months)