The purpose of the proposed study is to determine the feasibility of brief brain stimulation, using a device called Low Intensity Focused Ultrasound Pulsation (LIFUP), for persons with mild cognitive impairment (MCI) or mild (early-stage) Alzheimer's disease (AD). As a secondary aim, the investigators will explore whether this brief intervention is associated with improvements in cognitive functioning immediately and one week following the intervention.

Subjects will be randomly assigned to one of two experimental groups: either the LIFUP administration will be designed to increase the activity of neurons in a certain part of the brain or decrease the activity of neurons.

The investigators will study up to 8 subjects with MCI or mild AD. Initially, subjects will undergo a screening assessment with a study physician to determine medical and psychiatric history, establish AD diagnosis, and undergo a blood draw, if standard recent labs for dementia and EKG are unavailable. Subjects that meet criteria and agree to participate in the study will undergo a follow-up visit. In the baseline measurement visit, participants will first undergo neuropsychological testing. Participants will be randomly assigned to one of two LIFUP pulsing paradigms. Participants will then be administered four successive LIFUP treatments while the participants are in a functional magnetic resonance imaging (MRI). Sixty minutes following the administration, participants will undergo a second neuropsychological test. A final follow-up assessment will be administered at one week.

Alzheimer disease (AD) is a neurodegenerative condition and the most common cause of dementia or a functional impairment in memory and other cognitive abilities. Prior to developing the functional impairment of dementia, patients develop mild cognitive impairment (MCI), which increases the risk for developing the functional impairment of dementia. Deep brain stimulation (DBS) is of interest as a potential therapeutic option for MCI and AD because it can directly target and modulate the activity of brain structures implicated in memory functioning.

Recently there have been multiple reports that DBS of different locations within the brain may be effective in improving symptoms characteristic of dementia (e.g., Heschman et al., 2013). For example, Laxton et al. (2010) performed DBS in the fornix/hypothalamus of six persons with AD in a phase I clinical trial. The investigators hypothesized that stimulation of the fornix would alter the activity of the medial temporal memory circuits, and thus delay and/or reverse memory loss. After 6-12 months, the investigators noted improvement or slowing in the progression of AD in some of the research participants, as measured by two commonly-used assessments of global cognitive function. In a recent literature review, Laxton et al. (2013) also described several additional studies demonstrating that DBS of the fornix or nucleus of Meynert or subthalamic nucleus influences the pathologic neurological circuits involved in AD.

Four separate groups recently have published reports concluding that ultrasound improves amyloid-β clearance in mouse models and restores memory (e.g., Leinenga & Götz, 2015). This finding raises the question of whether one method of DBS, Low Intensity Focused Ultrasound Pulse (LIFUP), could improve cognition in patients with AD, which is characterized by abnormal deposition of amyloid plaques in brain regions controlling memory and thinking. The use of LIFUP in animal models is well described (Bystritsky et al., 2014). LIFUP is able to penetrate the human skull and reach deep structures within the temporal therapeutic window. The structures that are reachable by LIFUP include the temporal cortices, hippocampus, thalamus, and subthalamic nuclei, all of which are implicated in the pathophysiology of AD. The Food and Drug Administration (FDA) recently approved an investigational device exemption (IDE) to begin a feasibility and safety trial of LIFUP for persons with refractory seizures.

Although symptomatic treatments are available for AD, their modest effects are temporary and there is a need for more effective interventions. In the current project, the investigators propose to use the FDA-approved protocol to:

1. Determine the feasibility of a brief LIFUP intervention (four stimulations of 30 seconds each, with 2-minute intervals between each treatment) for persons with MCI or mild (early-stage) AD.
2. As a secondary aim, the investigators will explore whether this brief LIFUP intervention is associated with improvements on neuropsychological measures of cognitive functioning immediately following the intervention.

To investigate these aims, subjects with MCI or mild AD will be enrolled. Subjects will be randomized using a single-blind design, to one of two LIFUP pulsing paradigms in which activity of neurons in a certain part of the brain are either increased. Subjects will then be administered four successive LIFUP treatments while the subjects are in a functional magnetic resonance imaging (MRI). Neuropsychological assessments will be performed at baseline, immediately after LIFUP is administered, and one week following the conclusion of the visit.

Inclusion Criteria:

• Mild cognitive impairment or mild (early-stage) AD diagnosis through medical record review
• Agreement to participate in a clinical and brain imaging study.
• Age 55 years or older.
• No significant cerebrovascular disease as determined by a modified Ischemic Score of ≤ 4.
• Availability of a study partner (next of kin, family member) to attend all visits and to provide surrogate consent should it be determined that the participant does not have capacity.
• Adequate visual and auditory acuity to allow neuropsychological testing.
• Screening laboratory tests and ECG without significant abnormalities that might interfere with the study.
• Use of cholinesterase inhibitors for AD (Aricept, Namenda, etc.) will be allowed as long as the participant has been on a stable dose for at least two months.
• There must be a family member or caregiver available to make sure the participant gives informed consent, and in case the participant develops cognitive impairment that interferes with independent study participation.

Exclusion Criteria:

• Evidence of any other major neurologic or other physical illness that could produce cognitive deterioration, except for mild cognitive impairment (MCI) and any history of stroke or diabetes.
• History of myocardial infarction within the previous year or unstable cardiac disease.
• Uncontrolled hypertension (systolic BP > 170 or diastolic BP > 100), history of significant liver disease, clinically significant pulmonary disease, diabetes, or cancer.
• Major psychiatric disorders, such as bipolar disorder or schizophrenia, or persons with current untreated major depression
• Current diagnosis or significant history of alcoholism or drug dependence.
• Participants taking medications known to influence cognitive functioning will be excluded. Medications that will be excluded include: centrally active beta-blockers, narcotics, clonidine, anti-Parkinsonian medications, benzodiazepines, systemic corticosteroids, and medications with significant anticholinergic effects, anti-convulsants, or warfarin. During the screening visit, physicians will review all medications and determine whether the type, dose, and interaction of medications are likely to impact cognition and determine exclusion based on these factors.
• Use of any investigational drugs within the previous month or longer, depending on the drug's half-life.
• Contraindication for fMRI scan (e.g. metal in body, claustrophobia).

Participants and the participants' caregivers will be blinded to arm assignment.