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Abstract
Background and Objectives To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally.
Methods In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time.
Results This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (nCU– = 197); CU Aβ-positive (nCU+ = 55), mild cognitively impaired (MCI) Aβ-negative (nMCI– = 228), MCI Aβ-positive (nMCI+ = 193), and AD dementia Aβ-positive (nAD = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline (p = 0.01), worse brain atrophy (p = 8.8 × 10−27), and worse MMSE scores (p = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94–14.80, p = 1.5 × 10−14]). Despite the significant association with Aβ pathology (η2Aβ PET = 0.09, PAβ PET < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η2pTau-181 = 0.53, PpTau-181 < 0.001; η2tTau = 0.59, PtTau < 0.001).
Discussion High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.
Glossary
- AD=
- Alzheimer disease;
- ADNI=
- AD Neuroimaging Initiative;
- Aβ=
- amyloid beta;
- CDR=
- Clinical Dementia Rating;
- CU=
- cognitively unimpaired;
- CV=
- coefficients of variation;
- FDG=
- fluorodeoxyglucose;
- GAP43=
- growth-associated protein 43;
- HR=
- hazard ratios;
- LM=
- linear regression models;
- LME=
- linear mixed effect;
- QC=
- quality control;
- MCI=
- mild cognitive impairment;
- MMSE=
- Mini-Mental State Examination;
- NFT=
- neurofibrillary tangles;
- NINCDS-ADRDA=
- National Institute of Neurologic and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association;
- pTau=
- phosphorylated tau;
- SUVR=
- standardized uptake value ratio;
- tTau=
- total tau
Footnotes
Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found in Appendix 2 at links.lww.com/WNL/C409.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
Submitted and externally peer reviewed. The handling editor was Linda Hershey, MD, PhD, FAAN.
- Received December 21, 2021.
- Accepted in final form August 31, 2022.
- © 2022 American Academy of Neurology
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