Making Antibody Treatments More Effective in Early Alzheimer's Disease Using 3Tesla Magnetica Resonance

Precision Monitoring and Predictive Models for Optimizing Monoclonal Antibody Therapy in Early Alzheimer's Disease - A Prospective Monocenter Interventional Study on 3T MRI

Alzheimer's disease causes progressive memory and cognitive decline, driven in part by the buildup of a protein called β-amyloid in the brain. New antibody therapies - lecanemab and donanemab - can remove amyloid and slow down the disease in its early stages. However, it is still unclear how long each patient should continue treatment or when it is safe to stop, because amyloid is cleared at different rates across individuals.

Today, amyloid Positron Emission Tomography (PET) scans are used to measure whether amyloid has been removed from the brain, but these scans are expensive, not always available, and expose patients to radiation. Since repeated PET scans are not ideal, doctors need better ways to monitor treatment progress.

This study will use advanced brain Magnetic Resonance Imaging (MRI) and blood tests to create personalized prediction models. These models will simulate how amyloid spreads or clears in each person's brain and help identify when treatment is still needed. With this approach, monitoring becomes safer, more efficient, and more affordable - helping ensure that each patient receives the right treatment for the right amount of time.

This prospective monocenter study investigates the role of 3Tesla MRI-based predictive modeling in predicting treatment response to anti-amyloid monoclonal antibodies (lecanemab or donanemab administered as clinical practice) in 50 patients with early Alzheimer's disease (AD) at IRCCS Ospedale San Raffaele (Milan, Italy). Advanced MRI techniques, including high- resolution structural imaging for cortical thickness and volumetric atrophy, diffusion imaging for structural connectivity, and resting-state functional MRI for functional network analysis, will be acquired at baseline, 6, 12, and 18 months.

These multimodal MRI measures will be integrated into computational approaches, such as the Aggregation Network Diffusion (AND) model, to simulate individual disease trajectories and predict the probability of achieving negativity at amyloid PET under treatment.

While serial [¹⁸F]Flutemetamol PET will be performed as part of standard clinical practice to confirm amyloid removal, the focus of the study is on developing MRI- derived predictive biomarkers. The ultimate goal is to establish robust, non-invasive models capable of guiding individualized treatment monitoring and supporting evidence-based decisions on treatment discontinuation

Overall, the project aims to support more precise care for people with early Alzheimer's disease, while reducing unnecessary procedures and improving quality of life.

Study Overview

• Status: Not yet recruiting
• Conditions: Mild Cognitive Impairment (MCI); Alzheimer Dementia (AD)
• Intervention / Treatment: Other: MRI assessment and blood sample collection

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Federica FA Agosta, MD; Phone Number: 0226433051; Email: agosta.federica@hsr.it

Study Locations

• Italy
  • Milano
    • Milan, Milano, Italy, 20132
      • San Raffaele Neurology Unit
      • Contact: Federica Agosta, MD; Phone Number: 0226433051; Email: agosta.federica@hsr.it
      • Principal Investigator: Filippi Massimo, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1Participant is willing and able to give informed consent for participation in the study.

2. Participant is eligible for anti-amyloid therapy (AAT), i.e.:

• Participants aged 30-90.
• Diagnosis of early symptomatic AD, including MCI or mild dementia [2].
• Global Clinical Dementia Rating (CDR) score of 0.5 or 1.0

• Confirmed amyloid pathology through CSF or PET imaging. 3. Participant is willing to start Anti-amyloid therapy as part of his/her clinical-practice- therapeutic plan.

  4. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional four weeks after the end of study.

  5. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner.

Exclusion Criteria:

• 1. Contraindications to AAT, including:

  • Significant neurological diseases other than AD that could affect cognition or study participation (e.g., other dementias, serious brain infections, Parkinson's disease, multiple concussions, epilepsy with recurrent seizures).
  • Homozygous ApoE4 genotype.
  • Current use of anticoagulant therapy.
  • Vascular abnormalities: Presence of more than 4 microhemorrhages (defined as ≤10 mm in greatest diameter), a single macrohemorrhage >10 mm, superficial siderosis, evidence of vasogenic edema, multiple lacunar infarcts, or stroke involving a major vascular territory.
  • Amyloid-Related Imaging Abnormalities (ARIA): Evidence of ARIA, including cerebral amyloid angiopathy-related inflammation (CAA-ri) or amyloid beta-related angiitis (ABRA).
  • Bleeding disorders: History of bleeding disorders not under adequate control, including a platelet count <50,000 or international normalized ratio (INR) >1.5 for participants not on anticoagulant therapy.

  • Being currently under treatment with another AAT other than lecanemab/donanemab (e.g. as part of a Clinical Trial).

    2. Current serious or unstable illnesses, including:

  • Cardiovascular, hepatic, renal, gastrointestinal, respiratory, endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic diseases.
  • Conditions that, in the clinician's opinion, could interfere with study analyses or with a life expectancy of less than 24 months.

  • History of cancer within the last 5 years, except for non-metastatic basal and/or squamous cell carcinoma of the skin, in situ cervical cancer, non-progressive prostate cancer, or other cancers with low risk of recurrence.

    3. Inability to undergo MRI or PET imaging procedures (e.g. non-MRI safe pacemaker or devices, claustrophobia etc).

    4. Women of childbearing potential who are not using adequate contraception, as well as pregnant or breastfeeding women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Participants with Alzheimer's disease and Mild Cognitive Impairment (MCI); Participants with AD or MCI receiving monoclonal antibody therapy (lecanemab or donanemab) administered as clinical practice.

Other: MRI assessment and blood sample collection; Participants will undergo non-contrast-enhanced 3T MRI, including structural, diffusion, and functional sequences, to assess brain atrophy, connectivity, and other imaging markers relevant to disease progression and treatment response. Peripheral venous blood will be collected at scheduled study visits to measure plasma biomarkers associated with amyloid, tau, and neurodegeneration, providing complementary information on treatment effects through a minimally invasive method. Eventually, multimodal predictive models, using the Aggregation Network Diffusion (AND) model, based on baseline amyloid burden, structural and functional brain connectivity, and clinical, cognitive and plasma biomarkers will be developed to estimate the time to significant amyloid reduction in patients with MCI or mild AD treated with lecanemab or donanemab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predicting time (in months) to amyloid [¹⁸F]Flutemetamol (amyloid) PET negativity on a single scan	Predicting time (in months) to amyloid [¹⁸F]Flutemetamol (amyloid) PET negativity, defined as amyloid load <11 Centiloids on a single scan	baseline, 6 months, 12 months and 18 months
Predicting time (in months) to amyloid [¹⁸F]Flutemetamol (amyloid) PET negativity on two consecutive scans	Predicting time (in months) to amyloid [¹⁸F]Flutemetamol (amyloid) PET negativity, defined as amyloid load -<25 Centiloids on two consecutive scans	Baseline, 6 months, 12 months, 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in regional cerebral perfusion expressed in Standardized Uptake Volume Ratio (SUVR)	Change in regional cerebral perfusion expressed in SUVR (as a proxy from early-phase [¹⁸F]Flutemetamol - amyloid PET)	6 months, 12 months, 18 months
Change in global cerebral perfusion expressed in Standardized Uptake Volume Ratio (SUVR)	Change in global cerebral perfusion expressed in SUVR (as a proxy from early-phase [¹⁸F]Flutemetamol - amyloid PET)	6 months, 12 months, 18 months
Longitudinal change in brain volume	Evaluating brain volume changes over time	6 months, 12 months, 18 months
Longitudinal change in white matter integrity via Neurite Orientation Dispersion and Density Imaging (NODDI)	Evaluating structural white matter integrity over time	6 months, 12 months, 18 months
Longitudinal change in brain connectivity via functional MRI	Evaluating functional brain changes over time with whole brain statistics analysis	6 months, 12 months, 18 months
Change from baseline in plasma biomarkers Aβ42/Aβ40	Evaluating the correlation between plasma biomarkers with imaging-based measures of amyloid reduction and brain network alterations.	6 months, 12 months, 18 months
Change from baseline in plasma biomarkers pTau217	Evaluating the correlation between plasma biomarkers with imaging-based measures of amyloid reduction and brain network alterations.	6 months, 12 months, 18 months
Changes from baseline in plasma biomarkers pTau181	Evaluating the correlation between plasma biomarkers with imaging-based measures of amyloid reduction and brain network alterations.	6 months, 12 months, 18 months
Changes from baseline in plasma biomarkers NfL	Evaluating the correlation between plasma biomarkers with imaging-based measures of amyloid reduction and brain network alterations.	6 months, 12 months, 18 months
Changes from baseline in plasma biomarkers GFAP	Evaluating the correlation between plasma biomarkers with imaging-based measures of amyloid reduction and brain network alterations.	6 months, 12 months, 18 months
Change from baseline in Mini Mental Score examination (MMSE)	Neuropsychological assessment aimed at evaluating changes in cognitive performance and their association with neuroimaging and biomarker trajectories	6 months, 12 months, 18 months
Change from baseline in Alzheimer's Disease Assessment Scale's cognitive score (ADAS-Cog)	Change in ADAS-Cog's score and its association with neuroimaging and biomarker trajectories	6 months, 12 months, 18 months
Change from baseline in Clinical Dementia's Rating scale's cognitive score (CDR)	Change in CDR's score and its association with neuroimaging and biomarker trajectories	6 months, 12 months, 18 months
Change from baseline in Clinical Dementia Rating-Sum of Boxes' cognitive score (CDRsb)	Change in CDRsb's score and its association with neuroimaging and biomarker trajectories	6 months, 12 months, 18 months

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Investigators: Principal Investigator: Massimo Filippi, IRCCS San Raffaele

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: February 24, 2026
• First Submitted That Met QC Criteria: March 3, 2026
• First Posted (Actual): March 6, 2026

Study Record Updates

• Last Update Posted (Actual): March 6, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's disease; Precision medicine; Lecanemab; Amyloid; Monoclonal antibody therapy; Predictive modeling; Plasma biomarkers; Donanemab; 3 Tesla Magnetic Resonance; Amyloid Tomography Emission Positron (PET)
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Cognitive Dysfunction; Alzheimer Disease
• Other Study ID Numbers: AMYTRACK

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No