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

The HOPE study is a prospective, randomized, controlled clinical feasibility trial investigating the potential effects of low-dose whole-brain radiotherapy as a novel immunomodulatory intervention in patients with early-stage Alzheimer's disease. The study is based on emerging preclinical and early clinical evidence suggesting that neuroinflammatory processes may contribute to the pathophysiology and progression of Alzheimer's disease, and that very low-dose ionizing radiation may exert modulatory effects on microglial activation and neuroinflammation.

The study is designed as a two-arm randomized trial in which eligible participants are assigned in a 1:1 ratio to either an intervention group receiving low-dose whole-brain radiotherapy or to a control group receiving a non-active comparator condition. Randomization is performed after completion of baseline assessments.

The radiotherapy intervention consists of a very low total dose applied to the whole brain using external beam radiotherapy techniques in a standardized treatment schedule. Treatment is delivered over a short period of time in multiple fractions. Treatment planning is performed using a dedicated planning CT scan for dose calculation and treatment positioning. Radiation delivery is carried out under strict radiotherapy quality assurance procedures in accordance with institutional standards.

Participants undergo comprehensive baseline assessments prior to randomization, including neuropsychological testing, clinical evaluation, neuroimaging (MRI), electrophysiological assessment (EEG), and laboratory investigations. Additional optional diagnostic procedures may be performed if clinically indicated. These assessments are repeated at predefined follow-up time points in order to monitor changes in cognitive function, clinical status, and safety parameters over time.

The study duration for each participant is approximately seven months, including baseline evaluation, the treatment phase, and follow-up assessments. Follow-up visits are scheduled at multiple time points after completion of the intervention to evaluate both short-term and mid-term outcomes.

All study-related procedures are conducted in accordance with applicable national radiation protection legislation, Good Clinical Practice (GCP) guidelines, and institutional ethical standards. Prior to participation, all participants receive detailed verbal and written information about the study procedures, potential risks, and the voluntary nature of participation, and written informed consent is obtained.

Safety monitoring is an integral part of the study design. Adverse events are systematically recorded, evaluated, and reported according to regulatory requirements. Particular attention is given to neurological status, general clinical condition, and any potential radiation-related effects, although the applied radiation dose is substantially below conventional therapeutic levels.

The study is conducted in a multidisciplinary setting involving collaboration between departments of radiationtherapy and Neuropsychiatry and clinical research infrastructure units. Data collection is performed using standardized case report forms and secure electronic databases, ensuring data quality, traceability, and compliance with data protection regulations.

The HOPE study aims to generate feasibility data regarding study procedures, patient tolerability, and preliminary signals of clinical and cognitive effects of low-dose radiotherapy in Alzheimer's disease. The results are intended to inform the design of future larger-scale clinical trials in this field.

Inclusion Criteria:

Alzheimer's diagnosis according to ICD-10 Ability to understand the clinical study and provide informed consent Early-onset disease Age older than 50 years Stable treatment with anti-dementia medication for at least 3 months

Exclusion Criteria:

• 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)

Participants are blinded to treatment allocation. Treating physicians and radiotherapy staff are not blinded due to the nature of the intervention.