Abstract Details

Title CSF levels of proinflammatory and anti-inflammatory cytokines as predictors of cognitive decline across Alzheimer’s disease spectrum

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) N4 - Neuroscience in the Clinic: Alzheimer's Disease Biomarker Testing and Amyloid Monoclonals in Clinical Practice (2:35 PM-2:45 PM)

Poster/Presentation
Number 004

Background Increasing evidence suggests a prominent role of neuroinflammation in AD pathogenesis. Identifying key inflammatory cytokines that complement AD-specific biomarkers like amyloid-β (Aβ) and tau in predicting cognitive decline may enhance our understanding of AD pathogenesis and identify individuals at a higher risk of disease progression.

Objective

To identify distinctive CSF inflammatory biomarkers associated with clinically meaningful cognitive decline (CMCD) over a 1-year follow-up period.

Design/Methods Participants were 242 older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI): 65 cognitively normal (CN), 111 with mild cognitive impairment (MCI), and 66 with dementia. All had CSF biomarkers of Aβ, tau, inflammatory cytokines including TNF-α, TNFR1, TNFR2, TGF-β1, TGF-β2, TGF-β3, IL-6, IL-7, IL-10, IL-21, and ICAM-1. The primary outcome of interest was CMCD, defined as an increase of ≥4 on the Alzheimer’s Disease Assessment Scale Cognitive Subscore 11 (ADAS-11, scores 0-70, higher scores indicate worse cognition). Predictor variables included demographics (age, sex, and education), genetic information (APOE4 status), and CSF biomarkers of Aβ, phosphorylated tau181 (p-tau181), total-tau, and inflammation. Random forest machine learning models were used in conjunction with out-of-bag estimation to calculate predictor variable importance scores. Predictive performance was compared between models with and without including inflammatory biomarkers in the feature set.

Results At 1-year follow up, 25.6% of participants showed CMCD. When comparing models, those with added inflammatory biomarkers showed improved CMCD prediction: whole sample (AUC=0.79 vs AUC=0.75, p=0.022), CN (AUC=0.92 vs AUC=0.90, p=0.021), and MCI (AUC=0.83 vs AUC=0.73, p<0.001).The most important inflammatory predictors of CMCD, based on variable importance scores, were TGF-β3 (0.522), TNFR2 (0.411), IL-7 (0.227), ICAM-1 (0.179), and TNF-α (0.147).

Conclusions CSF inflammatory biomarkers, particularly TGF-β3 and TNFR2, are predictors of cognitive decline over a 1-year follow-up period. These biomarkers demonstrated added value in predicting cognitive decline in addition to the AD-specific biomarkers of Aβ and p-tau.

Authors/Disclosures
Ali Ezzati, MD (University of California, Irvine) PRESENTER	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.
Kellen Petersen (Albert Einstein College of Medicine)	No disclosure on file
Bhargav Nallapu	No disclosure on file
Richard B. Lipton, MD, FAAN (Albert Einstein College of Medicine)	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 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.