Prognostic Value of Plasma Glial Fibrillary Acidic Protein in Cognitively Unimpaired Older Adults: Results from the A4 Study

INTRODUCTION Plasma glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, has been linked to Alzheimer’s disease; however, its prognostic value in cognitively unimpaired (CU) individuals remains unclear.

We included 949 CU older adults from the A4 preclinical AD trial, and its companion LEARN cohort. Baseline plasma GFAP was measured, and longitudinal associations with cognitive decline, clinical dementia rating (CDR) progression, and imaging biomarkers were assessed over 240 weeks.

Baseline plasma GFAP was higher in females and in A4 (amyloid-positive) versus LEARN (amyloid-negative) participants. Cross-sectionally, elevated GFAP was associated with lower cognitive performance and greater amyloid burden. Longitudinally, higher GFAP predicted faster cognitive decline, increased risk of CDR progression, AD-related cortical atrophy, and amyloid conversion, with stronger effects in females.

Plasma GFAP is a prognostic biomarker in CU older adults, predicting cognitive and biological changes, with stronger associations observed in females, highlighting a possible sex-specific vulnerability. Competing Interest Statement Declaration of conflicting interests: Elham Ghanbarian, Tianchen Qian, Babak Khorsand, Lukai Zheng, S. Ahmad Sajjadi, Laura A. Rabin and Ali Ezzati declare no competing interests. Dr. Richard B. Lipton is the Edwin S. Lowe Professor of Neurology at the Albert Einstein College of Medicine in New York. He receives research support from the NIH: 2PO1 AG003949 (mPI), 1RF1 AG057531 (Site PI), 1UG3FD006795 (mPI), 1U24NS113847 (Investigator), U01 AT011005 (Investigator), 1R01 AG075758 (Investigator), 1R01 AG077639 (Investigator), 1RO1A1011875 (Investigator), 1RM1DA0055437 (Investigator), RO1AG080635 (Investigator), SG24988292 (Investigator), U19AGO76581 (Investigator), 1RO1NS123374 (Investigator), R61NS125153 (Investigator), and K23 NS107643 (Mentor). He also receives support from the Migraine Research Foundation and the National Headache Foundation and research grants from TEVA, Satsuma and Amgen. He serves on the editorial board of Neurology, senior advisor to Headache, and associate editor to Cephalalgia. He has reviewed for the NIA and NINDS, holds stock and stock options in Axon, Biohaven Holdings, CoolTech and Manistee; serves as consultant, advisory board member, or has received honoraria from: Abbvie (Allergan), American Academy of Neurology, American Headache Society, Amgen, Avanir, Axon, Axsome, Biohaven, Biovision, Boston Scientific, Dr. Reddyn (Promius), Electrocore, Eli Lilly, eNeura Therapeutics, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Manistee, Merck, Pernix, Pfizer, Satsuma, Supernus, Teva, Trigemina, Vector, Vedanta. He receives royalties from Wolff Headache 7th and 8th Edition, Oxford Press University, 2009, Wiley and Informa. Dr. Reisa Sperling reported consulting fees from AbbVie, AC Immune, Acumen, Alector, Apellis, Biohaven, Bristol Myers Squibb, Genentech, Janssen, Nervgen, Oligomerixg, Prothena, Roche, Vigil Neuroscience, Ionis, and Vaxxinity outside the submitted work. Funding Statement This study was supported in part by grants from the National Institute of Health (NIA K23 AG063993; R01 AG080635; R01AG095017); the Alzheimer Association (SG-24-988292 ISAVRAD); Cure Alzheimer Fund. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The data that support the findings of this study is openly available in https://www.a4studydata.org/. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability The data that support the findings of this study is openly available in https://www.a4studydata.org/.