Restoring Vascular and Insulin Function To Augment Anti-Amyloid Therapy in Alzheimer's Disease

The proposed pilot study will evaluate the efficacy, safety and tolerability of two therapeutic approaches: treatment with intranasal insulin in combination with anti-amyloid targeting therapy (ATT) and treatment with the sodium-glucose cotransporter type 2 inhibitor empagliflozin in combination with ATT, to correct bioenergetic and vascular dysfunction in adults with mild cognitive impairment due to Alzheimer's disease or mild dementia due to Alzheimer's disease.

Inclusion criteria

• Fluent in English
• Diagnosis of mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease via previously documented clinical assessment
• Amyloid positive by PET or cerebrospinal fluid criteria
• Stable medical condition for 3 months prior to screening visit
• Stable medications for general medical conditions for 4 weeks prior to the screening and study visits (exceptions may be made on a case-by-case basis by study clinician)
• Stable on Anti-Amyloid Targeting Therapy (lecanemab or donanemab) for at least 8 weeks prior to Baseline Visit
• If receiving an acetylcholinesterase inhibitor (donepezil, rivastigmine, galantamine) or memantine or both, must be stable on a dose for at least 30 days prior to Baseline Visit
• Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the study clinician
• Participants must have a study partner who agrees to participate throughout the duration of the study. The study partner must have frequent and sufficient contact (approximately 10 hours per week) with the participant and be able to provide accurate information regarding the participant's cognitive and functional abilities.

Exclusion criteria

• A diagnosis of dementia other than Alzheimer's disease
• History of a clinically significant stroke, history of transient ischemic attack within 12 months, or any history of seizures
• Current evidence or history in past two years of head injury with loss of consciousness, any major psychiatric disorder including psychosis, unstable major depressive disorder, bipolar disorder
• Diabetes (type I or type II) insulin dependent and non-insulin dependent diabetes mellitus
• Current or past regular use of insulin or any other anti-diabetic medication within 2 months of screening visit
• Cancer within the past 2 years with the exception of non-melanoma skin cancers and non-metastatic prostate cancer that has been stable for at least 6 months
• Pregnancy or possible pregnancy
• Use of anticoagulants
• Residence in a skilled nursing facility at screening
• Use of an investigational agent within two months of screening visit
• Regular use of alcohol, narcotics, anticonvulsants, anti-Parkinsonian medications, or any other exclusionary medications (exceptions may be made on a case-by-case basis by study clinician)
• Any history of immunologic disease (e.g. lupus, rheumatoid arthritis, Crohn's disease) or systemic treatment with immunosuppressants, immunoglobulins, or monoclonal antibodies or their derivatives
• History of a bleeding disorder that is not under adequate control, including a platelet count less than 50,000 or INR greater than 1.5
• Contraindications for MRI, including claustrophobia or the presence of contraindicated metal implants/cardiac pacemaker
• Baseline MRI Findings: More than four microhemorrhages defined as 10mm or less at the greatest diameter; A single macro hemorrhage greater than 10mm at greatest diameter; An area of superficial siderosis; Evidence of vasogenic edema; More than two lacunar infarcts or stroke involving a major vascular territory; Severe subcortical hyperintensities consistent with Fazekas score of 3; Evidence of amyloid beta-related angiitis (ABRA); Cerebral amyloid angiopathy (CAA); Cerebral contusion, encephalomalacia, brain aneurysm or other vascular malformations, central nervous system infection, brain tumor, or other major intracranial pathology that may cause cognitive impairment