The goal of this randomized clinical trial is to investigate whether low-dose whole-brain radiotherapy has a potential immunomodulatory effect that may influence disease progression in patients with early-stage Alzheimer's disease (ICD-10 diagnosed).
The main question(s) it aims to answer are:
Does low-dose radiotherapy have an effect on cognitive function and disease progression in early Alzheimer's disease? Is the intervention safe and feasible in this patient population under clinical trial conditions?
If there is a comparison group: Researchers will compare patients receiving low-dose whole-brain radiotherapy to a control group receiving a sham or non-active treatment, to assess potential differences in cognitive outcomes and disease-related parameters over time.
Participants will:
Undergo baseline diagnostic assessments including neuropsychological testing, MRI, EEG, and laboratory tests Be randomly assigned to one of two study groups Receive either low-dose whole-brain radiotherapy (6 sessions over 3 weeks) or a control condition Attend follow-up visits at 6 weeks, 3 months, and 6 months including repeated cognitive testing and clinical assessments
None
Prodromal Alzheimer's disease Mild cognitive impairment (MCI) Severe psychiatric disorders that could interfere with participation in the study Unstable or recently changed medication therapy Other neurodegenerative diseases or severe neurological disorders Uncontrolled chronic diseases that could increase the risk of complications Previous therapeutic brain irradiation Evidence of vascular cognitive impairment on MRI (Fazekas score >1 and Wahlund score ≥10/30) Oncological disease (except skin cancer), active or in remission for less than 5 years Evidence of substance abuse (alcohol and/or other drugs) with dependence within the last 12 months (DSM-IV criteria) Active or recent (within 3 months) cerebral infection or hemorrhage Immunocompromised status History of seizures Dermatological scalp disease Women who are pregnant, breastfeeding, or planning to become pregnant during the study period Patient has a history of cancer (except non-melanoma skin cancer) Patient is taking antiepileptic medication Patient and legally authorized representative are unable to provide informed consent Patient with a history of focal neurological deficits (except vibratory peripheral neuropathy)
Parallel
Low-Dose Whole-Brain Radiotherapy
RadiationParticipants receive low-dose whole-brain radiotherapy delivered using external beam photon radiation. The treatment is applied in a fractionated schedule over approximately three weeks (6 treatment sessions). A dedicated planning CT scan is performed prior to treatment for dose calculation and treatment planning purposes. Irradiation is performed according to institutional radiotherapy protocols under standard quality assurance procedures.
Control Condition (No Radiotherapy)
Other interventionParticipants in this arm do not receive radiotherapy or any study-specific therapeutic intervention. Instead, they undergo the same schedule of clinical and neuropsychological assessments as the intervention group, including baseline and follow-up visits over the same study period. This arm serves as a comparator to evaluate changes in clinical and cognitive outcomes over time in the absence of low-dose whole-brain radiotherapy.
Change in the CERAD-Plus score
The primary endpoint is the change in the CERAD-Plus score from baseline (t0) to 6 months, as well as from baseline to 3 months. This test assesses global cognitive performance, particularly with regard to memory and executive functions. Improvements at either of these time points indicate a positive effect of the intervention on cognitive performance and the course of Alzheimer's disease.
Change in the MADRS and BDI-II scores
The Montgomery-Åsberg Depression Rating Scale (MADRS) captures objective changes, while the Beck Depression Inventory II (BDI-II) assesses subjective changes in possible depressive symptoms and mood. A reduction in BDI-II scores at any time point indicates an improvement in mental health, which may correlate with cognitive recovery.
Change in the FWIT scores
The Color-Word Interference Test (FWIT) is used to measure changes in executive function and cognitive control. An increase in FWIT scores over these time periods indicates improved cognitive flexibility and inhibitory control.
Changes in EEG patterns
Electroencephalography (EEG) is used to monitor changes in brain-wave patterns in order to assess neuronal function and synaptic plasticity. Improvements in EEG activity over time, such as an increase in alpha-wave activity, may indicate cognitive and functional recovery.
Toxicity of radiotherapy according to CTCAE v5
Radiotherapy-related toxicity is assessed using the Common Terminology Criteria for Adverse Events (CTCAE). This endpoint includes documenting and evaluating any side effects caused by the radiotherapy.
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