Computerized olfactory adaptive training improves Preclinical Alzheimer's Cognitive Composite scores and gray matter volume in medial temporal brain regions of interest: A randomized feasibility clinical trial

Abstract INTRODUCTION Mild cognitive impairment (MCI) is a critical intervention window in patients with Alzheimer's disease and related dementias (ADRD). Early features of ADRD include memory, executive, and olfactory deficits, and structural changes in the medial temporal lobe (MTL), including hippocampus (HC) and entorhinal cortex (ERC). This study evaluates whether computerized olfactory adaptive training (COAT) is associated with changes in cognition and gray matter volume (GMV) in MCI. METHODS In this randomized, double‐blind, sham‐controlled feasibility trial, 70 MCI participants were randomly assigned to daily COAT intervention ( n = 36), a multimodal olfactory stimulation intervention, or sham ( n = 34), a single‐odor stimulation with air. Intervention was for 6 months, followed by 3 months of observation. Participants underwent cognitive and olfactory tests at baseline, 6 months, and 9 months, and 3 Tesla magnetic resonance imaging (MRI) scans at baseline and 9 months. The primary outcome measure was the change in Preclinical Alzheimer's Cognitive Composite (PACC) scores. The secondary endpoints were changes in ERC and HC GMV. RESULTS Of 70 participants, 31 (86%) in the COAT arm versus 29 (85%) in the control arm completed the study. COAT was associated with a 2.34‐unit increase in PACC scores (95% confidence interval [CI] 0.35–4.32; p = 0.02) compared with sham, independent of age and sex. In MRI‐eligible participants ( N = 31), COAT was significantly associated with an increase in right ERC ( P = 0.001), left ERC ( P = 0.013), and right HC ( P = 0.034) GMV, independent of age, education attainment, and sex differences. DISCUSSION This study suggests that daily COAT over 6 months was associated with improvements in cognition and GMV in populations with MCI. This pilot trial provides preliminary evidence for future large‐scale studies to determine whether COAT‐induced improvements in HC and ERC GMV could represent a viable disease‐modification strategy to attenuate brain atrophy early in ADRD. TRIAL REGISTRATION The Computerized Olfactory Training Trial was registered on clinicaltrials.gov as NCT05122598 on September 28, 2021. Highlights Computerized olfactory adaptive training (COAT) is a home‐based, noninvasive intervention that modifies traditional olfactory training. Six months of COAT improved Preclinical Alzheimer's Cognitive Composite (PACC) scores in individuals with mild cognitive impairment (MCI). COAT also increased entorhinal cortex (ERC) and hippocampal (HIP) gray matter volumes (GMVs). Cognitive and structural effects were independent of age, sex, and education. COAT may complement existing therapeutic interventions for Alzheimer's disease and related dementias (ADRD). The study cohort was predominantly African American/Black, a population that is historically underrepresented in AD research yet disproportionately affected by dementia.