This is a one-year, double-blind placebo-controlled randomized clinical trial that compares montelukast to placebo in individuals with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) dementia. The measures include cognitive function, cerebrospinal fluid (CSF) biomarkers and neuroimaging (cerebral perfusion and markers of vascular brain damage).

Participants will be treated with montelukast (escalating doses:10, 20 to 40 mg) or matched placebo.

Treatment options for Alzheimer's disease (AD) remain limited, especially treatments linking neurovascular and neuroinflammatory changes with clinical manifestations of the disease. Prior research studies have documented a positive effect of cysteinyl leukotriene type 1 (cysLT-1) receptor antagonist, particularly Montelukast, on inflammatory processes in the brain and on neuronal injury, blood-brain-barrier (BBB) integrity, and amyloid-β42 (Aβ) protein accumulation. Although montelukast is currently in use for the treatment of inflammatory diseases e.g. bronchial asthma and exercise-induced bronchospasm, its effects on memory and thinking abilities and on AD biomarkers are yet to be fully understood.

This is a single site randomized controlled trial at Emory University that compares the effects of montelukast vs. placebo on memory and thinking abilities, as well as on brain imaging and markers of brain degeneration. Each participant will undergo a screening process following informed consent to determine if they meet study eligibility criteria. Participants will be enrolled in the study for 1 year.

Inclusion Criteria:

1. Age: 50 years or older

2. MCI group will be defined based on:

   (i) Subjective memory concern;

   (ii) Abnormal memory function documented using the Logical Memory subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised (the maximum score is 25): [<11 for 16 or more years of education; <9 for 8-15 years of education; <6 for <7 years of education];

   (iii) Montreal Cognitive Assessment (MoCA) < 26;

   (iv) Clinical Dementia Rating (CDR) scale /Memory box score=0.5;

   (v) General functional performance sufficiently preserved (Functional Assessment Questionnaire ≤5).

3. Early AD dementia group will be defined based on:

   (i) Subjective memory concern;

(ii) Abnormal memory function documented using the Logical Memory subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised (the maximum score is 25): [<11 for 16 or more years of education; <9 for 8-15 years of education; <6 for <7 years of education];

(iii) Montreal Cognitive Assessment (MoCA) <26;

(iv) Clinical Dementia Rating scale/Memory box score 1 or 2;

(v) Early AD dementia defined as Functional Assessment Staging Test (FAST) of 4 or 5

Exclusion Criteria:

1. Intolerance to Montelukast;
2. Current diagnosis of bronchial asthma or exercise-induced bronchospasm and currently on Montelukast or other leukotriene receptor antagonists (Zafirlukast, Pranlukast);
3. Liver disease (elevated liver enzymes (>2x normal): Alanine aminotransferase (ALT), AST, alkaline phosphatase, total bilirubin);
4. Renal disease (Creatinine >2.0 mg/dl), platelets<50,000/μl, or INR>1.9;
5. Diagnosis of any neurological or psychiatric disorders that affects cognition such as uncontrolled depression, schizophrenia, Parkinson's disease or use of anti-Parkinsonian therapies (unless used for essential tremor), multiple sclerosis, or other active medical condition that in the judgment of the study physicians would affect the safety of the subject or scientific integrity of the study;
6. Other contributing factors to cognitive impairment such as uncontrolled hypothyroidism (TSH >10 mU/l) or untreated low vitamin B12 (<250 ng/mL);
7. Uncontrolled congestive heart failure reflected by poor exercise tolerance and shortness of breath at rest or with some exertion;
8. Actively undergoing chemotherapy or radiation therapy for cancer treatment;
9. History of stroke in the past 3 years;
10. Severely impaired cognition (MoCA ≤10, FAST >5 or CDR >2);
11. Inability to have MRI and LP e.g. for MRI, metal implants or cardiac pacemaker or for LP, bleeding diathesis from disease states or from use of anticoagulants such as warfarin, heparin and related products, Rivaroxaban or Xarelto, Apixaban or Eliquis, Edoxaban or Savaysa, Dabigatran or Pradaxa. Subjects who can have either one lumbar puncture (LP) or MRI will be enrolled;
12. Inability to have cognitive assessment due to hearing, vision, or language issues or due to severe impairment;
13. History of increased intracranial pressure (ICP);
14. In those who are unable to demonstrate that they understood the details of the study using the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) instrument modified for EMERALD (i.e. lack of decisional-capacity to consent), a study partner/surrogate who can sign on their behalf will be required; otherwise, they will be excluded;
15. Use of phenobarbital or rifampin due to drug interaction.

During follow up time, an average of 1 year

All participants on the Montelukast arm with reported AEs were safely escalated to 40 mg dose, and all their AEs resolved spontaneously with no sequelae. AE results were collected altogether (not dose based).

A limitation of the study is its relatively small sample size.