Large-coil Parietal Repetitive Transcranial Magnetic Stimulation (rTMS) for Alzheimer Disease (AD)

About

Brief Summary

The goal of this clinical trial is to learn if using large-coil (or "deep") repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus and surrounding areas is feasible, tolerable, and potentially efficacious for memory in Alzheimer's Disease. Previous work studying rTMS in Alzheimer's is mixed, but recent work studying rTMS of the precuneus is encouraging for both its short-term and long-term effects. The main questions this study aims to answer are:

Is deep rTMS of the precuneus feasible and tolerable in Alzheimer's?
Are there signs of positive brain changes in response to deep rTMS?
Is deep rTMS potentially efficacious for memory in Alzheimer's? Researchers will compare active stimulation to placebo stimulation while obtaining memory testing and measurements of the brain (imaging, scalp electrode measurements, bloodwork) to see if active treatment works to treat Mild Cognitive Impairment (MCI) and mild-to-moderate dementia due to Alzheimer's disease.

Participants will:

Engage with memory testing, brain scans, and bloodwork during a comprehensive assessment
Visit the clinic 3 times for 12 consolidated rTMS sessions, followed by 8 once weekly maintenance visits
Be offered a full open-label active treatment course after completing their treatment course if they are initially in the placebo group

Primary Purpose

Other

Study Type

Interventional

Phase

Phase 1/Phase 2

Eligibility

Gender

All

Healthy Volunteers

No

Minimum Age

55 Years

Maximum Age

100 Years

Inclusion Criteria:

Agreement to participate in study and able to complete informed consent process
Have a caregiver or study partner who can accompany them to all study visits
Have a known alternate surrogate decision-maker (in case needed) who can be present for informed consent
Established diagnosis of biomarker-positive (amyloid-PET, plasma or CSF amyloid ratio or phosphorylated tau) mild-moderate (clinical stages 3, 4, and 5) Alzheimer's Disease based on the 2024 Alzheimer's Association Framework
Age 55-100 at the start of the study.
Screening MOCA 12-25 (< 26, > 11)
Screening GDS score <6
Either 1) treated with memory-enhancing medication (cholinesterase inhibitor or other medications or treatments) for at least 2 months, 2) failed trial with no plan to re-trial, or 3) no trial planned during the course of the study for other reasons
No change in use of psychotropic medication (or other treatments) for the treatment of depression, anxiety, ADHD, or psychosis for 2 weeks prior to the study

Exclusion Criteria:

Unwilling or unable to provide informed consent as outlined below
Currently pregnant or potentially pregnant
Diagnosis of a dementia or cognitive disorder primarily or exclusively due to a cause other than Alzheimer's Disease
Diagnosis of severe Dementia (CDR > 2.0/ AA clinical stage 6) at the start of the study
History of substance use disorder currently not in sustained remission
Substance misuse within the past 6 months (excluding nicotine or caffeine)
History of stroke, traumatic brain injury with loss of consciousness, or other major neurologic disorder (e.g., epilepsy, Huntington's disease, Parkinson's disease)
History of seizure disorder or family history of seizure disorder in a first-degree relative
Poorly-controlled hypertension, cardiovascular disease, or cerebrovascular disease
History of any other major active medical, neurologic, or psychiatric illness affecting cognition (associated with cognitive impairment) or a participant's ability to safely and meaningfully participate in the study
Non-fluent in English (not native or functionally-native, specified here for cognitive testing purposes)
Contraindication to TMS or MRI including claustrophobia, MRI-incompatible or unknown metal in body (including facial tattoos with uknown or metallic inks), surgery within 60 days, certain implants (excluding dental fillings), or previous abnormal MRI results unrelated to a potential participant's dementia.
For the randomized stage only-has a history of prior TMS treatment (not TMS naïve)
Currently enrolled in an interventional memory-enhancement study
Alteration in cognitive-enhancement medication (or other treatment) dose within the past 2 months or active plans for dose alteration during the course of the study (previously unplanned changes that occur during the study will be examined on a case-by-case basis)
Has started treatment with lecanemab, donanemab, or any other monoclonal antibody for Alzheimer's Disease within the past 6 months OR has a history of treatment complicated by amyloid-related imaging abnormalities (ARIA)
Currently or within the past 2 weeks taking any of the following classes of medication:
- Anticholinergic (e.g., tolterodine, benztropine)
- Sedating antihistamines (e.g., diphenhydramine)
- any drug that has significant anticholinergic or antihistaminic side effects (e.g., tricyclic antidepressant medications, mirtazapine).
- Benzodiazepines. While not a strict rule out, this will be decided on a case-by-case basis
- Opioid. While not a strict rule out, this will be decided on a case-by-case basis
- Antiepileptic agents. While not a strict rule out, this will be decided on a case-by-case basis
- Antipsychotic agents. While not a strict rule out, this will be decided on a case-by-case basis