δ in Dementia Clinical Trials (δND)

The goal of this clinical trial is to demonstrate potential improvements in clinical trial methods relating to dementia and cognitive decline. The main questions it aims to answer are: Can an intervention's outcome be better assessed by a latent variable ("δ") integrating cognitive performance with functional status? Can latent biomarkers of δ guide the selection of an intervention that will modulate dementia severity? Can a latent variable, derived from information collected remotely from caregivers, preselect subjects most likely to respond to the intervention? Is the effect of the intervention in fact medicated by changes in the targeted biomarker? In this case, the biomarker will be a latent variable derived from several proteins measured in blood (i.e., so-called "adipokines"). The intervention will be donepezil, a medication approved for the treatment of Alzheimer's Disease, but only recently associated with adipokine changes. Participants with cognitive impairment and their caregivers will be interviewed by telephone and those with cognitive impairment will be treated for six-months with donepezil. On the basis of the caregiver's report, the cognitively impaired subjects will be assigned to two groups based on a prediction of their response to donepezil. Researchers will compare those groups to see if dementia severity, as measured by δ, improves in predicted responders, and whether the change in the d-score is mediated by changes in adipokines.

Title: "Novel Methods for Clinical rials in Dementia and Cognitive Decline" Study Description: This is a double-blind assignment open label clinical trial to test novel approaches to clinical trial methods. 1) The study team will pre-select cases most likely to benefit from adipokine modulation by a telephone assessment. 2) The study team will pre-select subjects with clinical and preclinical dementia most likely to respond to therapy. 3) The study team will test the drug donepezil's effect on dementia severity, in predicted responders and non-responders, as measured by a latent dementia phenotype "δ' and 4) test a latent Adipokines biomarker construct as a mediator of their association in the predicted responders. Objectives: Primary Objective: To test novel clinical trial methods relevant to dementia. Secondary Objectives: To test donepezil's effect on dementia severity as measured by δ. To test Adipokines as a mediator of donepezil's effect on δ. Endpoints: Primary Endpoint: Dementia severity as measured by the latent phenotype "δ" using the "dTEL" homolog. Secondary Endpoint: Change in Adipokines as a mediator of donepezil's effect on dTEL.

Group assignment determined by a response predictor algorithm derived from remotely acquired caregiver reports of cognitive performance.

Group assignment determined by a response predictor algorithm derived from remotely acquired caregiver reports of cognitive performance.

The frequency of dementia "reversion" defined as a final dTEL score > -0.40, i.e., the optimal d-score that discriminates subjects with AD from those with MCI in the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Inclusion Criteria: Ambulatory outpatient volunteers with competent informants Aged 65-100 years Clinical diagnosis of AD, or MCI Capacity to give informed consent Geriatric Depression Scale (GDS) (15 item) score ≤ 6 No significant visual or hearing impairments A standardized dECog score between 0.0 and -1.0 relative to ADNI's cohort Exclusion Criteria: A self-reported diagnosis of "Major Depression" (treatment with "antidepressants" not exclusionary) A history of psychosis, including visual hallucinations History or treatment for Parkinson's, or tremor, or Rapid Eye Movement (REM) behavior disorder History or treatment for atrial fibrillation Treatment for cancer in the last 5 years (excluding skin cancers) Major surgery in the last year Current treatment with acetylcholinesterase inhibitor (AChEI) (memantine is acceptable). -Potential subjects on an AChEI can washout for three months and be rescreened. Current treatment with anti-convulsants, mood stabilizers, neuroleptics, opiates, muscle relaxants, or systemic steroids

This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers 5 years after the completion of the primary endpoint by contacting royall@uthscsa.edu

Data from this study may be requested from other researchers 5 years after the completion of the primary endpoint by contacting royall@uthscsa.edu