Long‐term nicotine treatment of mild cognitive impairment (The MIND Study): Baseline characteristics and study progress

Abstract

AbstractBackgroundCognitive decline in AD/MCI is related to loss of cholinergic neurons. However, inhibition of acetylcholine degradation has not slowed progression. Treatment directly targeting nicotinic cholinergic receptors may be more helpful. We have shown proof of concept in a 6‐month multicenter trial that transdermal nicotine provides significant improvement in attention, episodic memory, and global ratings of functioning with minimal side effects in MCI. A larger and longer (2‐year) trial is underway to determine the persistence of improvement and attenuation of cognitive decline.MethodMCI participants were randomized 1:1 to either transdermal nicotine, beginning at 3.5 mg/day, increasing to 21 mg/day or matching placebo by 5 weeks. Participants were assessed at 0, 3, 6, 12, 18, and 24 months, with a subset undergoing MRI scans at 0, 12, and 24 months, and CSF collection at 0 and 24 months. Primary cognitive outcomes included reaction time standard error change‐from‐baseline (Connors CPT) for attention and delayed word recall (Cogstate) for memory. Primary clinical outcome is the CGIC. Secondary clinical measures include behavioral/functional scales and the CDR‐SOB. An MRI substudy is examining possible neural mechanisms.ResultTo date, 663 participants were screened and 309 were randomized including 133 females (43%) and 176 males (57%). Mean age was 73.7±7.1, education 16±2.8 years. Mean MMSE was 27.4±1.8 and CDR Global was 0.5. Randomization of ethnoracial underrepresented populations (URPs) was 9.4% (Black/African‐American 4%, Asian 2%, Hispanic/Latinx 3%). Treatment/Study discontinuations were higher than expected at 29% due in part to pandemic‐related disruptions. There are 87 completers thus far. Baseline MRI scans are 59 and LPs are 37. Safety results show that treatment has been generally well tolerated with no SAEs definitively or probably tied to study participation or investigational product thus far.ConclusionIf the hypotheses are validated, this will support a novel, broadly available, and inexpensive repurposed intervention for MCI and would encourage early treatment to improve symptoms, attenuate progression of cognitive impairment, and lead to combined trials with agents that interact with Aβ, tau or other mechanisms. Low URP recruitment and higher dropout rate remain challenging and will be specifically addressed in recruitment/enrollment/retention efforts moving forward.