Neurology. 2025 Apr 8;104(7_Supplement_1):1757. doi: 10.1212/WNL.0000000000208728. Epub 2025 Apr 7.
ABSTRACT
OBJECTIVE: To develop methods for enriching Alzheimer’s disease (AD) treatment trials with individuals likely to show clinically meaningful cognitive decline (CMCD) if treated with placebo.
BACKGROUND: Up to 45% of participants in the placebo arm of AD trials show no CMCD over 80 weeks. Enriching trial populations for individuals likely to decline should increase the power to detect treatment effects.
DESIGN/METHODS: We utilized data from patients with mild AD dementia from the placebo arms of the EXPEDITION1 and EXPEDITION2 trials (N=1025) to develop predictive models. Participants were categorized as Cognitively Stable (CS, defined as an ADAS-Cog14 change of <4 at week 80) or as having CMCD, defined as an ADAS-Cog14 change of ≥4 at trial completion (week 80s) (N=459). Neural Networks, Support Vector Machine, Naïve Bayses, K Nearest Neighbors, and Random Forest were trained to distinguish between CS and CMCD participants using a combination of demographic data, clinical data including Clinical Dementia Rating test (CDR), Geriatric Depression Scale test (GDS), Mini-Mental State Examination test (MMSE), and biomarkers, including APOE4 genotype and volumetric MRI. The trained models were then applied to classify participants in an external validation sample from the EXPEDITION3 study (N=1072).
RESULTS: Eligible participants from the EXPEDITION3 trial (N=838) had an average age of 72.7 ± 7.8 years; 59% were female. CS status was observed in 44.9% of participants at the final visit while CMCD occurred in 55.1%. Highest performing model showed a sensitivity of 78%, specificity of 52%, and AUC of 61%. The positive predictive values (PPVs) were 9% higher than the base prevalence of CMCD observed at the end of the trial.
CONCLUSIONS: Our findings suggest that predictive models could enhance the design of Alzheimer’s Disease trials by allowing for selective exclusion of participants likely to show clinically meaningful cognitive decline over 80 weeks of follow-up. Disclosure: Dr. Khorsand has nothing to disclose. Dr. Ghanbarian has nothing to disclose. Bhargav Nallapu has nothing to disclose. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Allergan/Abbvie. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Amgen. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biohaven. Dr. Lipton has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Eli Lilly. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lundbeck. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GlaxoSmithKline. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vedanta. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Grifols. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Pfizer. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Axon. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Satsuma. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cool Tech. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BDSI. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Linpharma. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Axsome. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Clexio. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shiratronics. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergan/Abbvie. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Lipton has stock in Biohaven. Dr. Lipton has stock in Manistee. Dr. Lipton has stock in Axon. Dr. Lipton has stock in CoolTech. The institution of Dr. Lipton has received research support from Teva. The institution of Dr. Lipton has received research support from Amgen. The institution of Dr. Lipton has received research support from Allergan/Abbvie. The institution of Dr. Lipton has received research support from Gammacore. The institution of Dr. Lipton has received research support from Axsome. The institution of Dr. Lipton has received research support from Charleston Labs. The institution of Dr. Lipton has received research support from Eli Lilly. The institution of Dr. Lipton has received research support from Satsuma. The institution of Dr. Lipton has received research support from NIH . The institution of Dr. Lipton has received research support from Veterans Administration. Dr. Lipton has received publishing royalties from a publication relating to health care. Dr. Ezzati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Mist Research. Dr. Ezzati has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BioDelivery Sciences International (BDSI) . The institution of Dr. Ezzati has received research support from NIA. The institution of Dr. Ezzati has received research support from Alzheimer’s Association. The institution of Dr. Ezzati has received research support from Cure Alzheimer’s Fund. Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.
PMID:40194074 | DOI:10.1212/WNL.0000000000208728
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