This study aims to evaluate whether digital cognitive training and/or intensive lipid-lowering therapy with a PCSK9 inhibitor can improve cognitive function in patients with intracranial atherosclerosis (ICAS).

ICAS is a common cause of stroke and is also linked to thinking and memory problems. The study will enroll 420 adults aged 55-80 years who have 50-99% narrowing of an intracranial artery, subjective memory complaints, and LDL cholesterol ≥1.8 mmol/L, but who are not demented.

Participants will be randomly assigned to one of four groups in a 2×2 factorial design:

1. No cognitive training + standard statin therapy
2. Cognitive training + standard statin therapy
3. No cognitive training + intensive statin plus PCSK9 inhibitor
4. Cognitive training + intensive statin plus PCSK9 inhibitor

Cognitive training consists of 30 minutes of tablet-based exercises, 5 days per week for 12 weeks. The intensive lipid-lowering group receives a PCSK9 inhibitor (Recaticimab) injection at weeks 0, 4, and 12, on top of maximally tolerated statin.

The main outcome is change in a composite cognitive score from baseline to 24 weeks. Secondary outcomes include changes in specific cognitive domains, MRI markers of brain structure and function, and safety measures.

The study is multicenter, open-label with blinded outcome assessment, and is conducted under the approval of the ethics committee of Peking Union Medical College Hospital.

This is a national, multicenter, 2×2 factorial randomized controlled trial with a PROBE design (Prospective, Randomized, Open-label, Blinded Endpoint assessment). The study is conducted in China and is approved by the Institutional Review Board of Peking Union Medical College Hospital.

Background and Rationale:

Intracranial atherosclerotic stenosis (ICAS) is highly prevalent in Asian populations and is associated with both ischemic stroke and vascular cognitive impairment. Chronic hypoperfusion, microemboli, and white matter damage contribute to cognitive decline. While digital cognitive training has shown benefit in mild cognitive impairment, and PCSK9 inhibitors profoundly lower LDL-C and stabilize plaque, no trial has directly tested their combined effect on cognition in ICAS patients. This study aims to fill that gap.

Study Objectives:

• Primary: To evaluate the effect of digital cognitive training and intensive lipid-lowering (PCSK9 inhibitor) on change from baseline in a composite cognitive Z-score at 24 weeks.
• Secondary: To assess effects on MoCA, domain-specific cognitive scores (memory, attention, executive function, visuospatial, language), whole-brain atherosclerotic burden, and plaque burden at the most stenotic site.
• Exploratory: To test for interaction between the two interventions, and to evaluate changes in brain structure and function using advanced MRI.

Study Population:

Inclusion criteria: age 55-80 years, education ≥6 years, MRA/CTA/DSA-confirmed 50-99% intracranial arterial stenosis, no large (>3cm) brain infarct, baseline LDL-C ≥1.8 mmol/L, subjective cognitive decline, MMSE ≥24, ADL <18, no dementia, able to operate a tablet, pass a run-in period, agree to statin and PCSK9 inhibitor, and able to complete neuropsychological and MRI assessments.

Exclusion criteria: ≥50% extracranial stenosis, acute cerebrovascular event within 90 days, MRI contraindications, severe white matter disease (Fazekas 3), non-atherosclerotic stenosis, neurodegenerative disease, severe comorbidities, major psychiatric illness, prior PCSK9 inhibitor use, contraindications to statins or PCSK9 inhibitors, significant liver or muscle enzyme elevations, etc.

Sample Size:

A total of 420 participants will be enrolled (approximately 204 per marginal comparison after accounting for 20% dropout). Power calculation assumed a conservative effect size of Δμ=0.4 for the composite cognitive Z-score (σ=1), α=0.05 (two-sided), 1-β=0.80.

Randomization and Blinding:

Subjects are randomized 1:1:1:1 via an interactive web response system (IWRS), stratified by center and symptomatic ICAS status (prior stroke/TIA yes/no). Random block sizes are used. The study is open-label for the interventions, but outcome assessors (neuropsychological testers, MRI readers) are blinded to treatment allocation. Separate blinded and unblinded teams manage assessments and intervention delivery, respectively.

Interventions:

• Factor A (cognitive training):
• Intervention group: 12 weeks of adaptive, multi-domain digital cognitive training (processing speed, attention, perception, memory, language, executive function) delivered via tablet. Participants are asked to train 30 minutes/day, 5 days/week. Minimum dose: ≥3 days/week and ≥20 minutes/session or ≥60 minutes/week.
• Control group: Active control with low-difficulty standardized tasks (same device and contact time, no adaptive difficulty).
• Factor B (lipid-lowering):
• Both groups receive maximally tolerated statin (rosuvastatin 20mg or atorvastatin 40mg daily) with optional ezetimibe 10mg at investigator discretion.
• Intervention group additionally receives subcutaneous Recaticimab (PCSK9 inhibitor) at weeks 0 (150mg), 4 (300mg), and 12 (450mg).
• Control group receives no PCSK9 inhibitor.

Outcome Measures:

• Primary endpoint: Change in composite cognitive Z-score (average of memory, executive, visuospatial, attention, language domain Z-scores) from baseline to week 24.
• Secondary endpoints: Change in composite Z-score at week 12; change in MoCA total score at weeks 12 and 24; change in each cognitive domain Z-score; change in whole-brain atherosclerotic burden (11-segment MRA score) and plaque burden (HRMRI) at week 24.
• Exploratory endpoints: Interaction between training and lipid-lowering; changes in brain structure (DTI, 3D T1), function (resting-state fMRI), perfusion (ASL, optional), and lipid parameters (TC, non-HDL-C, Lp(a), TG, HDL-C).
• Safety endpoints: Adverse events related to cognitive training (headache, eye strain, fatigue, sleep disturbance, etc.) and to lipid-lowering (myalgia, liver enzyme elevation, CK elevation, injection site reactions, allergic reactions).

Study Schedule:

• Screening/run-in (day -7 to 0): informed consent, medical history, physical exam, labs, MRI, neuropsychological assessment, and a run-in compliance check (3 simple tasks).
• Baseline (day 0): randomization, start interventions (PCSK9 injection, dispense training device if assigned).
• Follow-up visits: week 4 (±7 days), week 12 (±7 days), week 24 (±7 days). At each visit, labs, adverse event monitoring, and compliance assessment are performed. Full neuropsychological battery and MRI are repeated at week 24 (MRI also at baseline; cognitive battery also at week 12).
• Early termination: if a participant withdraws, an early termination visit includes the full set of outcome assessments.

Statistical Analysis:

Primary analysis will use a linear mixed-effects model (LMM) with subject as random effect, time as repeated measure, and fixed effects: factor A (training), factor B (PCSK9 inhibitor), time, A×B, A×time, B×time, and A×B×time. Baseline cognitive status and other prespecified covariates (center, age, education) will be adjusted. The primary inference is the marginal mean difference at week 24 with 95% CI. Intention-to-treat (ITT) analysis is primary; per-protocol and sensitivity analyses will be performed. Secondary outcomes will be analyzed similarly. Safety data will be summarized descriptively.

Data Monitoring and Quality:

The study will be monitored by independent clinical research associates. All serious adverse events (SAEs) will be reported within 24 hours to the sponsor and the ethics committee. Data will be collected using an electronic data capture (EDC) system. The database will be locked after data cleaning, and statistical analysis will follow a pre-specified SAP (Statistical Analysis Plan).

Ethics and Dissemination:

The protocol has been approved by the ethics committee of Peking Union Medical College Hospital (I-26PJ0926). Written informed consent will be obtained from all participants. Results will be submitted for publication in peer-reviewed journals, regardless of the outcome.

Inclusion Criteria:

1. Age 55-80 years old
2. The number of years of education is greater than or equal to 6 years
3. 50%-99% stenosis of the intracranial artery confirmed by MRA, CTA or DSA
4. Head CT or MRI confirmed that there were no infarct lesions/softening foci larger than 3 cm in the brain
5. LDL-C ≥ 1.8mmol/L at baseline
6. Decline in cognitive function of the complainant
7. MMSE ≥ 24 points; no severe impairment of daily living and social functioning, and the daily living ability scale (ADL, 14-item BADL and IADL combined version, total score range of 14-56 points) <=18; and the investigator's clinical assessment does not meet the diagnosis of dementia (DSM-V or NIA-AA diagnostic criteria)
8. Proficient in operating electronic products such as mobile phones and tablets
9. Complete the operation evaluation through the introduction period (see the definition of the introduction period)
10. Agree to receive maximally tolerated statin and PCSK9 inhibitor therapy during the study period
11. Able to cooperate with neuropsychological and multimodal magnetic resonance examinations

Exclusion Criteria:

1. Extracranial vascular stenosis ≥ 50%
2. Acute cerebrovascular events within 90 days
3. Contraindications to MRI (metal implants in the body, claustrophobia, etc.)
4. Visual and auditory impairments, as well as communication difficulties, that affect cognitive training
5. Clinically diagnosed vascular dementia
6. Neuroimaging showing significant white matter lesions (Fazekas grade 3) or multiple microbleeds
7. Non-atherosclerotic intracranial artery stenosis (such as vasculitis, moyamoya disease, dissection, etc.)
8. Neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.)
9. Severe comorbidities (tumors, multiple sclerosis, severe cardiopulmonary and renal diseases, intracranial aneurysms)
10. Other diseases that may affect cognition have been ruled out; severe anxiety, depression, or schizophrenia; a new stroke occurring within the 3 months prior to baseline; hereditary or inflammatory small vessel diseases; presence of any of the following clear sources of cardioembolic events: mitral stenosis, mechanical heart valves, endocarditis, intracardiac clots or vegetations, dilated cardiomyopathy, chronic or paroxysmal atrial fibrillation, ejection fraction less than 30%
11. Planning to use medications that may affect cognitive function within the past 3 months or in the following 24 weeks, including large amounts of sedatives, anti-anxiety drugs, cognitive enhancers, and cholinergic agents.(12) Previously treated with a PCSK9 inhibitor
12. Having a clear contraindication or severe intolerance to PCSK9 inhibitors or statins (such as a history of severe allergic reactions)
13. Presence of significant liver or muscle safety abnormalities at baseline, or the investigator deems the patient unsuitable for intensive lipid-lowering therapy (for example, significantly elevated ALT or AST, significantly elevated CK, etc.; the thresholds can be based on the reference ranges of each center's laboratory and specified in the protocol in advance)
14. Other circumstances deemed inappropriate for enrollment by the investigator

No plan to share IPD due to absence of consent for data sharing and institutional policies protecting participant confidentiality.

The study adopted a design featuring open-label intervention and blinded endpoint assessment (PROBE).

The blinded group investigator is only responsible for the evaluation and judgment related to the endpoint. The blinded group researchers did not obtain or ask the subjects about intervention allocation information during the entire study period, and did not participate in informed consent, random assignment, intervention implementation, adherence management, and medication adjustment.

The unblinded investigator is responsible for all study implementation except for endpoint assessment. Non-blind monitors are responsible for research process monitoring and quality control. The non-blind auditor is responsible for handling issues related to the digital cognitive intervention system, providing technical/process advice, and reviewing the monitoring report of the non-blinded monitor.