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

Official title

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

Overview

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.

Interventions

• 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, multim

Primary outcome measures

• Predicting time (in months) to amyloid [¹⁸F]Flutemetamol (amyloid) PET negativity on a single scan [Time frame: baseline, 6 months, 12 months and 18 months]
• Predicting time (in months) to amyloid [¹⁸F]Flutemetamol (amyloid) PET negativity on two consecutive scans [Time frame: Baseline, 6 months, 12 months, 18 months]

Secondary outcome measures (12)

• Change in regional cerebral perfusion expressed in Standardized Uptake Volume Ratio (SUVR) [Time frame: 6 months, 12 months, 18 months]
• Change in global cerebral perfusion expressed in Standardized Uptake Volume Ratio (SUVR) [Time frame: 6 months, 12 months, 18 months]
• Longitudinal change in brain volume [Time frame: 6 months, 12 months, 18 months]
• Longitudinal change in white matter integrity via Neurite Orientation Dispersion and Density Imaging (NODDI) [Time frame: 6 months, 12 months, 18 months]
• Longitudinal change in brain connectivity via functional MRI [Time frame: 6 months, 12 months, 18 months]
• Change from baseline in plasma biomarkers Aβ42/Aβ40 [Time frame: 6 months, 12 months, 18 months]
• Change from baseline in plasma biomarkers pTau217 [Time frame: 6 months, 12 months, 18 months]
• Changes from baseline in plasma biomarkers pTau181 [Time frame: 6 months, 12 months, 18 months]
• Changes from baseline in plasma biomarkers NfL [Time frame: 6 months, 12 months, 18 months]
• Changes from baseline in plasma biomarkers GFAP [Time frame: 6 months, 12 months, 18 months]
• Change from baseline in Mini Mental Score examination (MMSE) [Time frame: 6 months, 12 months, 18 months]
• Change from baseline in Alzheimer's Disease Assessment Scale's cognitive score (ADAS-Cog) [Time frame: 6 months, 12 months, 18 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

Italy · 1 center

• San Raffaele Neurology Unit — Milan

Identifiers

NCT: NCT07456462 · AMYTRACK

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗