Prospective Research on Identification of Dementia in Early Stages (P.R.I.D.E)

### Scientific Background and Rationale

The PRIDE Study (Prospective Research on Identification of Dementia in Early Stages) is a multicenter, prospective, non-interventional observational study designed to investigate early cognitive decline in older adults reporting Subjective Memory Complaints (SMC).

Subjective memory complaints are frequently encountered in aging populations and may occur in the absence of objectively measurable cognitive impairment or represent an early manifestation of a neurocognitive disorder. Their clinical significance varies according to individual characteristics, comorbidities, neuropsychological profiles, and environmental and lifestyle-related factors.

Mild Cognitive Impairment (MCI) is characterized by objectively measurable cognitive impairment exceeding that expected for age and educational attainment, without substantial loss of independence in everyday activities. Identifying MCI among individuals reporting subjective memory difficulties may contribute to a better understanding of the earliest detectable stages of cognitive decline.

However, the progression from subjective complaints to objectively measurable impairment and subsequently to clinically diagnosed dementia is heterogeneous. A substantial proportion of individuals may remain cognitively stable, whereas others may experience progressive deterioration.

The PRIDE Study was developed to investigate this heterogeneity through standardized assessments and prospective longitudinal observation, with particular attention to the epidemiological distribution of MCI, cognitive trajectories, and factors associated with disease progression.

### Study Design and Organization

PRIDE is a multicenter, prospective observational cohort study conducted across participating healthcare institutions in Italy.

The study includes a single observational cohort. Participants are not randomized, assigned to experimental interventions, or allocated to different treatment or prevention strategies.

The study is designed to observe cognitive performance and its evolution without altering routine clinical management.

Recruitment will be consecutive and voluntary. Potential participants may be identified through participating healthcare facilities, specialist outpatient services, residential care settings, community-based healthcare services, and authorized awareness or screening initiatives.

A standardized recruitment process will be implemented across participating centers. This process will include preliminary identification, eligibility assessment, informed consent, baseline evaluation, and formal enrollment.

Each center will document the number of individuals approached, assessed for eligibility, excluded, declining participation, and definitively enrolled. These records will support assessment of recruitment performance, selection processes, and the interpretation of epidemiological estimates.

The multicenter structure is intended to increase the diversity of the study population, improve external validity, and permit assessment of potential differences in clinical and cognitive characteristics across participating settings.

### Clinical and Neuropsychological Assessment Procedures

Participants will undergo a standardized baseline assessment incorporating sociodemographic, clinical, functional, and neuropsychological information.

Clinical data collection will include medical history, comorbidities, concomitant medications, cardiovascular and metabolic risk factors, and relevant lifestyle characteristics.

Neuropsychological assessment will include standardized cognitive screening instruments, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and other tests specified in the study assessment battery.

Functional assessment will include measures of independence in basic and instrumental activities of daily living, including Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL).

Subjective memory difficulties will be assessed using the instruments specified in the protocol, including the Memory Complaint Questionnaire (MAC-Q).

The interpretation of cognitive findings will consider relevant clinical, functional, and educational characteristics.

A distinction will be maintained between a positive cognitive screening result, MCI classification according to the study protocol, specialist-confirmed MCI, and clinically diagnosed dementia.

A positive screening result will indicate possible cognitive impairment requiring further clinical assessment and will not independently constitute a diagnosis of dementia.

Formal clinical diagnoses established through routine specialist care will be documented separately from research-based cognitive classifications.

### Longitudinal Follow-up

Each enrolled participant will be followed for 60 months from the individual baseline assessment.

Follow-up evaluations will be scheduled annually at 12, 24, 36, 48, and 60 months, with an allowed visit window of 30 days before or after the scheduled date.

At follow-up visits, investigators will update relevant clinical information, concomitant treatments, comorbidities, cardiovascular and metabolic risk factors, functional status, and neuropsychological findings.

The study will document changes in cognitive performance, newly identified cognitive impairment, clinically confirmed diagnoses, and relevant clinical events.

The occurrence of clinically diagnosed dementia will be recorded only when supported by documentation obtained within routine healthcare pathways.

Participant retention, missed visits, withdrawals, and losses to follow-up will be systematically recorded.

The longitudinal design will permit investigation of cognitive trajectories and factors associated with progression while preserving the observational nature of the study.

### Sample Size Considerations

The sample size calculation was based on the primary epidemiological objective of estimating the prevalence of MCI among older adults with subjective memory complaints.

The protocol considers an expected MCI prevalence ranging approximately from 40% to 60% in this population, depending on demographic characteristics, diagnostic definitions, and assessment methods.

A conservative expected prevalence of 50% was selected for sample size calculations because it maximizes the variance of a proportion.

The calculation uses a 95% confidence level and a prespecified absolute precision.

The statistical section of the protocol specifies a target of 1,000 eligible participants completing baseline assessments. This sample size is intended to provide adequate precision for estimating MCI prevalence and to establish a cohort suitable for longitudinal analyses.

### Quality Assurance and Study Governance

The PRIDE Study incorporates a Quality Management System (QMS) based on risk-based quality management, standardized procedures, documented responsibilities, staff training, data integrity, and continuous quality improvement.

Scientific and operational oversight will be provided through a multicenter governance structure comprising the study sponsor, Scientific Coordinator, Scientific Committee, operational coordination functions, Data Management Unit, Biostatistics Unit, and local Principal Investigators.

Each participating center will designate responsible investigators and authorized research personnel.

Before study activities begin, participating personnel will receive training on the protocol, informed consent, clinical and neuropsychological assessments, data collection, documentation, and applicable data protection requirements.

The quality framework includes Standard Operating Procedures (SOPs), a monitoring plan, a risk management plan, a data management plan, staff training, internal audits, deviation management, and corrective and preventive actions (CAPA).

Monitoring intensity will be proportionate to the observational design and the risks identified.

### Data Collection and Validation

Study data will be recorded using standardized Case Report Forms (CRFs).

If an electronic data collection platform is used, the electronic Case Report Form (eCRF) will incorporate individual user authentication, controlled access, traceability of data modifications, and appropriate validation procedures.

Data collection will follow standardized definitions and coding procedures to promote consistency across participating centers.

Quality control activities will identify missing information, duplicate records, implausible values, inconsistencies between variables, and discrepancies between successive assessments.

Validation checks will be performed during data entry and through periodic review of the study database.

These checks will include assessment of data completeness, internal consistency, and conformity with predefined variable definitions and applicable reference ranges.

Detected discrepancies will be communicated to the relevant participating center for verification and documented correction.

Changes to study data will be traceable through the applicable documentation and audit-trail procedures.

### Source Data Verification and Monitoring

Data monitoring will be conducted through a combination of centralized database review, periodic document checks, and site visits when considered necessary.

Monitoring activities will assess adherence to the approved protocol, informed consent documentation, participant eligibility, completeness of study records, data quality, and compliance with applicable SOPs.

Where appropriate, recorded study data will be compared with original source documentation, including clinical records, neuropsychological assessment forms, and paper or electronic case report documents.

Source data verification will be directed toward assessing the accuracy, completeness, consistency, and traceability of information relevant to the study objectives.

The extent of verification and the need for on-site monitoring will be determined according to the study monitoring plan and risk-based quality management principles.

Internal audits may be conducted to evaluate procedural compliance and identify opportunities for corrective action.

### Data Management and Confidentiality

Each participant will be assigned a unique Study Identification Number.

Research data will be pseudonymized, and the correspondence between participant identity and study identification code will be stored separately from the research database, with access restricted to authorized personnel.

Study data will be managed according to applicable European and national data protection requirements, including Regulation (EU) 2016/679 (General Data Protection Regulation).

Access to study databases will be restricted according to assigned responsibilities.

Data transfers for authorized scientific collaboration will be subject to applicable institutional agreements, ethical requirements, and data protection safeguards.

Data management procedures will address secure storage, controlled access, traceability, backup, validation, and final archiving.

The study documentation includes standardized data collection instruments and operational definitions. The detailed variable specifications and coding conventions will be governed by the study's CRF and data management documentation.

### Protocol Deviations and Corrective Actions

Any deviation from approved study procedures will be documented, assessed, and classified according to its methodological and ethical relevance.

Deviation records will include the nature of the deviation, date, participating center, possible causes, impact on participant safety or data quality, and corrective measures undertaken.

Relevant deviations will be communicated to the Scientific Coordination Unit and, when required, to the Ethics Committee or competent authorities.

Corrective and preventive actions will be implemented where necessary to address identified deficiencies and reduce the likelihood of recurrence.

Protocol amendments and changes to study procedures will be managed through documented version-control and approval processes.

### Missing Data Management

Missing data may arise from incomplete assessments, unavailable clinical information, missed follow-up visits, participant withdrawal, or loss to follow-up.

The study will implement preventive procedures to minimize missing information through standardized assessments, staff training, timely data entry, periodic quality checks, and follow-up monitoring.

Missing or unavailable information will be documented, together with the reason for non-availability whenever ascertainable.

The statistical handling of missing data will follow the prespecified Statistical Analysis Plan.

Depending on the nature and extent of missingness, analyses may use complete-case approaches or appropriate imputation methods.

The choice of analytical strategy will consider the characteristics of the missing data, potential mechanisms of missingness, and the possible impact on the validity and interpretation of study findings.

Sensitivity analyses will be performed when appropriate to evaluate the robustness of results to alternative assumptions.

### Statistical Analysis Plan

Statistical analyses will be conducted according to a prespecified Statistical Analysis Plan using validated statistical software.

Continuous variables will be summarized using means and standard deviations or medians and interquartile ranges, as appropriate.

Categorical variables will be summarized using absolute and relative frequencies.

The primary analysis will estimate the prevalence of MCI at baseline among evaluable enrolled participants with subjective memory complaints. The estimate will be expressed as a percentage with a corresponding 95% confidence interval.

Associations between clinical, sociodemographic, cardiovascular, metabolic, neuropsychological, and lifestyle-related characteristics and cognitive impairment will be investigated using appropriate univariable and multivariable statistical models.

Logistic regression models will be used for binary outcomes, including the presence of MCI. Multivariable models will account for potential confounding factors, and mixed-effects models may be used to address variability between participating centers.

Longitudinal changes in cognitive and functional scores will be analyzed using methods appropriate for repeated measurements, including linear mixed-effects models.

The occurrence of new MCI cases during follow-up will be assessed among participants without MCI at baseline.

Progression to clinically diagnosed dementia will be investigated using time-to-event methods, including Kaplan-Meier estimation and Cox proportional hazards regression, where applicable.

Potential prognostic factors will include demographic characteristics, educational attainment, cardiovascular risk factors, depressive symptoms, lifestyle characteristics, and baseline cognitive performance.

Adjusted effect estimates will be reported with 95% confidence intervals.

Exploratory analyses may investigate heterogeneous cognitive trajectories and develop predictive models using prespecified clinical and neuropsychological variables.

Where prediction models are developed, their performance will be evaluated using appropriate discrimination and calibration measures and internal validation procedures.

The methodological substudy of the MAC-Q will assess its reliability and reproducibility using appropriate psychometric methods.

Sensitivity analyses may include stratification by educational attainment and exclusion of participants with clinically significant depressive symptoms or early events, as specified in the statistical analysis plan.

Statistical tests will generally be two-sided, with a significance threshold of p < 0.05.

### Ethical Considerations and Participant Safety

The study is designed as a non-interventional observational investigation and does not involve experimental drug administration or changes to prescribed treatments.

All participants will be informed about the purpose of the research, the procedures involved, the voluntary nature of participation, confidentiality safeguards, and the right to withdraw consent.

Research personnel will assess participants' ability to understand essential study information and provide valid informed consent.

Clinical findings suggesting previously unrecognized cognitive impairment will be managed through appropriate communication and referral within routine healthcare pathways, without substituting research screening for formal specialist diagnosis.

Study-related safety concerns and relevant adverse events, when applicable, will be documented and managed according to the protocol, institutional procedures, and applicable ethical requirements.

The study will be conducted in accordance with the approved protocol, relevant ethical principles, and applicable national and European regulations.

### Expected Scientific Contribution

The PRIDE Study is expected to provide multicenter epidemiological evidence on the prevalence of MCI among older adults reporting subjective memory complaints.

Its prospective design will contribute to the characterization of cognitive trajectories and the identification of clinical, neuropsychological, functional, and lifestyle-related factors associated with progression toward dementia.

The study may support the development of improved approaches to early recognition, risk stratification, and future preventive research, while providing information relevant to healthcare planning and the organization of services for older adults at risk of cognitive decline.