Evaluation of the Effects of a Nutritional Intervention of Ketogenic Medium-chain Triglycerides and B-vitamins on Cognitive Functioning in Older Adults With Mild Cognitive Impairment (COGNIKET-MCI)

Inclusion Criteria:

1. Have read, understood, and signed the informed consent form (ICF).

2. Be aged ≥60 years at the time of screening.

3. Presence of acquired memory complaints with a duration of >3 months. Here we referto memory/cognitive complaints in a broader sense that can involve other cognitivedomains other than memory. (As reported by the participant or reliable trialinformant. Trial informants can be a relative, spouse or domestic partner, or closefriend who interacts closely enough with the participant to be able to respond toassessments/questionnaires as needed.)

4. Have a clinical diagnosis of MCI (with a clinical phenotype compatible with AD,insidious SVD [ie, no post-stroke cognitive impairment], or mixed AD/SVD) accordingto the participating site, or referring center, aligned with international/nationalstandards for MCI diagnosis, and additionally informed by a minimum of one of thefollowing objective criteria as assessed by components of the Consortium toEstablish a Registry for Alzheimer's Disease neuropsychological battery (CERAD NB):

5. Word list memory task: ≤19,

6. Word list recall: ≤5,

7. Fifteen-item subset of the Boston Naming Test (BNT): ≤13,

8. Constructional praxis recall: ≤7, or

9. Total CERAD score: ≤70.

10. Full autonomy for daily living based on the Instrumental Activities of Daily Living (IADL)-Lawton scale:

11. Score for women: 8 or

12. Score for men: 5.

13. Participants must have an available trial informant willing and able to attend thefollowing 3 clinic visits with the participant: V1/randomization, V3/12-month visit,and V4/18-month visit.

14. Participants must have a trial informant who in the opinion of the investigator, hascontact with the trial participant for a sufficient number of hours per week (atleast 2 hours per day and a minimum of 4 times per week).

15. Participants and their trial informants have an adequate ability to read and write,as well as adequate vision and hearing for neuropsychological testing according tothe investigator's judgment (corrective aids are allowed).

16. CDR global score of 0 to 0.5 at screening.

17. Sexually active females of childbearing potential (defined in further detail inAppendix 1 of the protocol) must practice 2 different highly effective methods ofcontraception with their heterosexual partner or remain abstinent during the trialand for 30 days after the last dose of nutritional formulation. If employingcontraception, the highly effective methods of contraception detailed in Appendix 1of the protocol must be followed.

18. Females of childbearing potential must have a negative highly sensitive urinepregnancy test before randomization; a positive urine pregnancy test result mustimmediately be confirmed using a serum test.

19. Participants able to satisfactorily comply with the protocol requirements.

20. Participants willing and able to discontinue all prohibited concomitant medicationsto meet any protocol-required washout periods before and during the trial period (Section 9.6.1 of the protocol provides more details).

Exclusion Criteria:

1. Diagnosis of a major neurocognitive disorder according to the 5th Edition of theDiagnostic and Statistical Manual of Mental Disorders (DSM-5), or dementia accordingto the DSM-IV and the National Institute of Neurological and Communicative Diseasesand Stroke/Alzheimer's Disease and Related Disorders Association criteria at thetime of enrollment.

2. MCI related to past or recent concussion, COVID-19, or other specific etiologies (including neurodegenerative disease like Parkinson's disease, multiple sclerosis,Huntington's disease, Lewy-body disease, fronto temporal dementia), or associatedwith medication/substance use, per the investigator's judgment.

3. A history of COVID-19 ≤120 days before screening or completion of a vaccinationcourse against severe acute respiratory syndrome coronavirus 2 ≤14 days beforescreening. The vaccine received must have been authorized for emergency use orapproved by the US Food and Drug Administration.

4. Newly introduced, or change in dose, within the last 2 months before randomization,of physician-prescribed interventions or medications affecting cognition or AD (eg,acetylcholinesterase inhibitors, memantine, anti-amyloid-beta agents), or plannedintroduction of such medications during the trial.

5. Participants who will likely require prohibited concomitant therapy during the trialbased on the investigator's judgment.

6. Known history of or ongoing alcohol or substance use disorder, based on medicalhistory, that in the opinion of the investigator may conflict with the participant'sparticipation.

7. Participants who, in the opinion of the investigator, medical monitor, or sponsorshould not participate in the trial.

8. Symptoms suggestive of depression or anxiety according to the Hospital Anxiety andDepression Scale (HADS):

9. HADS-D ≥8 or

10. HADS-A ≥8.

11. Known active HIV infection, COVID, hepatitis B, or hepatitis C based on medicalhistory.

12. Participants with epilepsy or a history of seizures, except for a single childhoodfebrile seizure, post-traumatic seizure, or alcohol withdrawal seizure.

13. Participants considered to be in poor general health based on the investigator'sjudgment. Examples include participants who have recent clinically significantweight loss, chronic dehydration or hypovolemia, poor fluid or nutritional intake,or a recent clinically significant infection, as per the investigator's judgment.

14. Cancer diagnosis in the past 2 years excluding select skin conditions considered tobe fully treated (basal cell or squamous cell carcinomas of the skin) or early-stagecancer with excellent prognosis (eg, some prostate cancer conditions) according tothe investigator's judgment.

15. Renal disease (estimated glomerular filtration rate <30 ml/min/1.73m2) based on theinvestigator's assessment and historical data.

16. Uncontrolled hypertension (systolic blood pressure >160 mm Hg, and/or diastolicblood pressure >100 mm Hg).

17. Significant and uncontrolled thyroid disease according to the investigator'sjudgment.

18. Any surgery or procedure requiring general anesthesia ≥3 hours, planned, or in theprevious 3 months.

19. Poorly regulated type 2 diabetes (HbA1c >9.0%), or type 2 diabetes that is currentlytreated with insulin, glucagon-like peptide-1 receptor analog (GLP-1 RA), or asodium-glucose cotransporter-2 (SGLT-2) inhibitor, or type 1 diabetes.

20. Vitamin B12 deficiency per the investigator's judgment, or current use of B-vitaminsupplementation >200% daily recommended value according to national standards.

21. Very high or severe hypertriglyceridemia (≥886 mg/dL or 10.0 mmol/L).

22. Participants who are unable to comply with protocol procedures in the opinion of theinvestigator (if an individual develops a major neurocognitive disorder during thecourse of the trial, the appropriateness for the individual to continue will bebased on the investigator's judgment).

23. Have a personal or hierarchical link with the research team members.

24. Participant who is a shift worker that involves night shifts.

25. Ongoing/planned pregnancy or breastfeeding at screening (female participants whohave a positive pregnancy test result before receiving nutritional formulation willbe excluded).

26. Participants who follow a ketogenic diet or other diet that is intended to influenceketone levels (eg, prolonged fasting, intermittent fasting, ketogenic mealreplacement product regimens), or take ketone-, kMCT-, or coconut oilsupplementation, or adhere to a diet that excludes milk product use (eg, vegandiet).

27. Cow's milk protein allergy or intolerance, or other allergy or intolerance to any ofthe ingredients of the nutritional formulation (eg, medium chain acyl-CoAdeficiency, or other fatty acid oxidation disorders).