Low-Dose Radiotherapy for Alzheimer's Disease (LDRT-MIND)

Inclusion Criteria:

1. Age ≥50 years at time of enrollment
2. Externally confirmed diagnosis by a neurologist or geriatric psychiatrist (at Renaissance Institute, collaborating neurologist Dr. Sherif Makar, MD of Charis Neurology is available for diagnostic consultation) of one of the following: a. Alzheimer's disease (per NIA-AA 2011 or 2018 criteria) b. Frontotemporal dementia with documented inflammatory features c. Dementia with Lewy bodies with elevated inflammatory CSF markers d. Other neurodegenerative dementia with confirmed inflammatory component (elevated CSF IL-6, IL-1β, or TNF-α; or neuroimaging evidence of neuroinflammation)
3. MoCA score 10-25 at baseline screening (moderate-to-mild cognitive impairment range)
4. Karnofsky Performance Status (KPS) ≥60 or ECOG Performance Status ≤2
5. Medically stable and capable of receiving radiation therapy as assessed by the treating radiation oncologist
6. Reliable caregiver or informant able to accompany the patient to ≥80% of scheduled visits
7. Written informed consent from patient (if decision-making capacity is preserved) and/or legally authorized representative (LAR); caregiver co-consent required
8. Life expectancy ≥18 months in the opinion of the treating physician

9. Ability and willingness to comply with monthly clinic visits for the 12-month maintenance period

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Exclusion Criteria:

1. Prior whole brain or partial brain radiotherapy of any dose at any time
2. Active systemic malignancy requiring concurrent oncologic treatment
3. Implanted device contraindicated with radiation therapy (pacemaker, cochlear implant, deep brain stimulator, or equivalent)
4. Brain MRI demonstrating any of the following: (a) more than 4 cerebral microhemorrhages on susceptibility-weighted imaging (SWI) or gradient echo (GRE) sequences; (b) more than 1 area of superficial cortical siderosis; (c) severe white matter disease (Fazekas grade 3); or (d) any macrohemorrhage or hemosiderin-stained lesion >10 mm. These thresholds are adapted from established AD trial imaging exclusion criteria to minimize enrollment of patients with advanced cerebrovascular disease or pre-existing hemorrhagic risk factors.
5. Known active cerebral amyloid angiopathy-related inflammation (CAA-ri) or amyloid-related beta-angiitis (ABRA), whether confirmed by biopsy, CSF analysis, or neuroimaging features consistent with active leptomeningeal or parenchymal amyloid-related inflammation
6. Active autoimmune encephalitis in acute phase (patients in stable chronic phase are eligible)
7. Uncontrolled systemic infection or active sepsis at enrollment
8. Severe psychiatric comorbidity (active psychosis, active suicidal ideation) impairing protocol compliance or safety assessment
9. Concurrent enrollment in another interventional trial targeting cognitive decline or neuroinflammation
10. Pregnancy or lactation; women of childbearing potential must use adequate contraception
11. Inability to lie flat and still for radiation delivery (approximately 10-15 minutes per session)
12. MoCA <10 at baseline screening (severe dementia; insufficient cognitive range for endpoint assessment)