The ultimate goal of this study is to develop non-invasive, painless repetitive transcranial magnetic stimulation (rTMS) protocols to prevent cognitive decline in patients with mild cognitive impairment (MCI) and cognitively normal individuals at high risk of developing Alzheimer's disease (AD). Currently, 1 in 9 adults over the age of 65 have AD, which currently totals more than 5 million Americans and this number is expected to rise as high as 16 million by 2050.

MCI is a clinical syndrome that represents the gray area between healthy aging and dementia. Those with amnestic MCI (aMCI) have memory problems more severe than normal for their age and education, but their symptoms are not as severe as those of people with AD. Patients with aMCI are at high risk for AD. Notably, roughly half of those with MCI will continue to progress and convert to clinical dementia within 3 years. Alternatively, it is also worthwhile to study cognitively healthy older adults who carry genes that may increase the risk of AD. The frequency of the human APOE gene ε4 allele increases in patients with AD and the ε4 allele is also associated with an earlier age of disease onset.

Currently, there are no known therapies that can effectively modify the progression and hallmark symptoms of AD. Therefore, it is crucial to provide an early intervention in patients with aMCI to delay or prevent the progression to AD.

More specifically, this project has two specific aims:

1. To plan personalized non-invasive brain stimulation location by brain Imaging with Magnetic Resonance Imaging (MRI) in Mild Cognitive Impairment (MCI)
2. To identify potential personalized cognitive enhancement strategy (such as dosage or patterns) of Transcranial Magnetic Stimulation (TMS) in MCI.

Techniques to artificially and precisely stimulate brain tissue are increasingly recognized as valuable tools both in clinical practice and in cognitive neuroscience studies among healthy individuals and people with clinical conditions. With these practices, researchers can safely stimulate specific regions of the brain to explore causal relationships that comprise the brain's circuitry and modulate behavior.

In total, 60 participants (50-85 years old) with MCI will be recruited to participate in this trial.

Participants will be asked to receive 30 intervention sessions for three different protocols (10 sessions for each). Before and after the interventions, MRI and Cognitive tasks will be utilized again as the outcome measurements. There is a one-month interval between each protocol. Each intervention will be around half hour to an hour and each outcome measurement will take another two hours.

Each block includes:

• MRI+ Memory pre-assessment (2 hours/session)
• TMS * 10 (10 sessions; 0.5 hours/session)
• MRI+ Memory post-assessment (2 hours/session) Participants will experience each of the three TMS protocols. The total time commitment across these sessions will be approximately 27 hours.

There will be another 2 testing sessions to evaluate intervention effects. They will be scheduled at the beginning, and 1 month after the end of the intervention sessions. All sessions will take place in the Biosciences Research Laboratories (BSLR) Building (1230 N. Cherry Ave., Tucson, AZ 85721). The schematic below outlines the components of the sessions.

The investigators will acquire the following data during components for primary outcome measures and secondary measures.

1) Brain imaging data 2) Neuropsychological data and demographic data 3) Cognitive tasks 4) Biological sample

Individuals with mild cognitive impairment (MCI Group)

Inclusion Criteria:

• Age 50-85 years
• MCI clinical criteria: (a) typical comprehensive criteria (at least one cognitive test <= -1.5 SD), or (b) Jak/Bondi criteria (2 tests within the same domain <= -1SD or 3 tests total <= -1SD)
• Right handed
• English speaking
• Able to attend daily intervention (Monday-Friday) for 4 weeks
• Not enrolled in another interventional study within 6 months prior to beginning this study

Exclusion Criteria:

• Contraindications to transcranial magnetic stimulation (TMS) or magnetic resonance imaging (MRI)
• Other neurological disorders (e.g. stroke, head injuries, or multiple sclerosis)
• Current cancer treatment or other medical problems that might independently affect cognitive function

Cognitively Normal Individuals:

Inclusion Criteria:

• Age 50-85 years
• Right handed
• English speaking
• Able to attend daily intervention (Monday-Friday) for 4 weeks
• Not enrolled in another interventional study within 6 months prior to beginning this study

Exclusion Criteria:

• Contraindications to transcranial magnetic stimulation (TMS) or magnetic resonance imaging (MRI)
• Other neurological disorders (e.g. stroke, head injuries, or multiple sclerosis)
• Current cancer treatment or other medical problems that might independently affect cognitive function
• No dementia or impaired cognitive functioning, assessed using the NACC battery.