Disease Modifying Potential of 5mg of Melatonin on Cognition and Brain Health in Aging

To address these broad aims, participants will be recruited from the Neuropsychology Clinic, community, Alzheimer's association local chapter events and support groups, senior citizen centers. Following fulfillment of several inclusionary and exclusionary criteria online/on the phone, participants will first complete a baseline visit with several tests designed to measure aspects of motor, affective, and cognitive function. The baseline visit will be briefer for those who do not fulfill in-person components of the inclusionary/exclusionary criteria (BMI\<35; MoCA\>=18; and CDR \<=.5).

Based on the information obtained during the baseline visit, participants' cognitive status will be categorized as either MCI+ or MCI-. The criteria adopted in this study for a determination of MCI is less stringent than typical clinical criteria. This information will be used to conduct stratified randomization of participants to placebo or active (5mg melatonin) arms. The schedule of randomization will be determined by University of Iowa Hospital \& Clinic's pharmacy so that study personnel and participants will not know which participant has been assigned to which study arm.

At the end of the baseline visit, participants will be given actigraphy watches to wear for a period of 8 weeks, a wash-out phase; phase#1. The watches monitor sleep and circadian rhythm in each participant's daily life. At the end of 8 weeks, participants will return to the lab to complete a brief battery of cognitive tests. At the end of the visit, they will be given freshly charged actigraphy watches to take home with them until week-16 as well as the first supply of study issued medications (beginning phase#2 of the study). They will receive a phone call at the beginning of week-9 to complete brief questionnaires regarding sleep quality, mood, and any physical symptoms that may be associated with study-issued medications. At the week-16 visit, the participants will return their actigraphy watches, complete brief cognitive testing, questionnaires on sleep quality, mood, physical symptoms that may be associated with study-issued medications, and complete the first LP and blood draw. They will also be given their supply of study-issued medications for the next 7-month period. They will receive a phone call around week-30 (midway between week-16 and the final study visit of week-44) to inquire about sleep quality, any physical symptoms that may be associated with study-issued medications, and mood. The final study visit will take place on week-44. The visit will be very similar to the baseline visit and will include comprehensive cognitive testing, questionnaires, and an LP. Participants will also receive a phone call the day after each LP to query them about any discomfort they may be experiencing and the adequacy of over-the-counter pain medications in addressing it.

In addition to these procedures, participants will be asked to consent to banking of CSF for assaying of future biomarkers during the two study LPs.

AS OF AUGUST 2024, THE LUMBAR PUNCTURE PROCEDURES FOR THIS CLINICAL TRIAL HAVE BEEN ELIMINATED. THAT IS, PARTICIPANTS ARE NO LONGER RECEIVING A LUMBER PUNCTURE. BUT ARE CONTINUING TO RECEIVE TWO SEPARATE BLOOD DRAWS AT WEEKS 8 AND 44 FOR BIOMARKER TESTING.

• Overall cognitive function [Time frame: Assessed at pre-treatment (week-8), and two post-treatment occasions: week-16 and week-44.]
• p-tau/Aβ42 ratio [Time frame: Assessed at pre-treatment (week-8) and one post-treatment occasion (week-44)]
• t-tau [Time frame: Assessed at pre-treatment (week-8) and one post-treatment occasion (week-44)]
• Sleep Efficiency [Time frame: Daily from actigraphy in the pre-treatment phase which lasts 8 weeks (phase#1) and daily from actigraphy in the post-treatment phase from week-9 to week-16 (phase#2).]
• Amplitude (Mesor) of rest-activity rhythm [Time frame: Daily from actigraphy in the pre-treatment phase which lasts 8 weeks (phase#1) and daily from actigraphy in the post-treatment phase from week-9 to week-16 (phase#2).]
• Acrophase of rest-activity rhythm [Time frame: Daily from actigraphy in the pre-treatment phase which lasts 8 weeks (phase#1) and daily from actigraphy in the post-treatment phase from week-9 to week-16 (phase#2).]