Evaluation of Blood-Based Biomarkers and Remote Cognitive Assessment for Dementia Triage (SANDBOX)

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.

Methylation biomarkers in cell-free DNA analyzed by our models for associations with dementia-related clinical variables, including diagnosis and cognitive performance.

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.

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.

Diagnosis, in-clinic cognitive test results, and demographic variables to characterise the study population and explore associations with dementia biomarkers.

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.

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.

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.

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.

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 from GP referral to clinical diagnosis in study participants compared to standard UK practice using Clinical Practice Research Datalink (CPRD) data as the comparator.

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.

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.

Results of probabilistic sensitivity analyses and scenario analyses to quantify the impact of data uncertainty and structural model assumptions on cost-effectiveness estimates.

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.