Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals

Annika Öhrfelt; Andréa L Benedet; Nicholas J Ashton; Hlin Kvartsberg; Manu Vandijck; Michael W Weiner; John Q Trojanowski; Leslie M Shaw; Henrik Zetterberg; Kaj Blennow

doi:10.1212/WNL.0000000000201417

Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals

Annika Öhrfelt, Andréa L Benedet, Nicholas J Ashton, Hlin Kvartsberg, Manu Vandijck, Michael W Weiner, John Q Trojanowski, Leslie M Shaw, Henrik Zetterberg, Kaj Blennow

Old Age Psychiatry

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden [email protected].
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.; UK Dementia Research Institute at UCL, London, UK.; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
Fujirebio Europe NV, Ghent, Belgium.
Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA.; Department of Radiology, University of California, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, CA, USA.; Department of Psychiatry, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA.
Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.; UK Dementia Research Institute, London, United Kingdom.; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

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.

Original language	English
Pages (from-to)	E275-E285
Journal	Neurology
Volume	100
Issue number	3
Early online date	3 Oct 2022
DOIs	https://doi.org/10.1212/WNL.0000000000201417
Publication status	Published - 17 Jan 2023

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10.1212/WNL.0000000000201417

Cite this

@article{7353227cee724221a9e02779cb14995c,

title = "Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals",

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.",

author = "Annika {\"O}hrfelt and Benedet, {Andr{\'e}a L} and Ashton, {Nicholas J} and Hlin Kvartsberg and Manu Vandijck and Weiner, {Michael W} and Trojanowski, {John Q} and Shaw, {Leslie M} and Henrik Zetterberg and Kaj Blennow",

note = "Funding Information: Coauthor J.Q. Trojanowski, MD, PhD, died in February 2022. Data collection and sharing was funded by ADNI (NIH #U01 AG024904) and DOD ADNI (#W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH ( fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: Coauthor J.Q. Trojanowski, MD, PhD, died in February 2022. Data collection and sharing was funded by ADNI (NIH #U01 AG024904) and DOD ADNI (#W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH (fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: M.W. Weiner receives support for his research from the following funding sources: NIH: 5U19AG024904-14, 1R01AG053798-01A1, R01 MH098062, U24 AG057437-01, 1U2CA060426-01, 1R01AG058676-01A1, and 1RF1AG059009-01. Department of Defense (DOD): W81XWH-15-2-0070, 0W81XWH-12-2-0012, W81XWH-14-1-0462; and W81XWH-13-1-0259. Patient-Centered Outcomes Research Institute (PCORI): PPRN-1501-26817. California Department of Public Health (CDPH): 16-10054. University of Michigan: 18-PAF01312. Siemens: 444951-54249. Biogen: 174552; Hillblom Foundation: 2015-A-011-NET, Alzheimer's Association: BHR-16-459161. The State of California: 18-109929. He also receives support from Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI-BHR), The Stroke Foundation, and the Veterans Administration. H. Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), the AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C and ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen f{\"o}r Gamla Tj{\"a}narinnor, Hj{\"a}rnfonden, Sweden (FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. K. Blennow is supported by the Swedish Research Council (2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB-201809-2016615), the Swedish Alzheimer Foundation (AF-742881), Hj{\"a}rnfonden, Sweden (FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant 1R01AG068398-01), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495). A. {\"O}hrfelt is supported by grants from Demensfonden, Gun och Bertil Stohnes stiftelse, Stiftelsen gamla tj{\"a}narinnor, and {\AA}hl{\'e}n-stiftelsen. Industry-sponsored: Fujirebio supplied the antibodies for the in-house GAP43 assay. L. Shaw is supported by NIH grants: ADNI3 (U19 AG024904): PENN ADRC (P30 AG072979); R01MH117114 and a MJFox Fdn for Parkinson's Research grant 13637.01. Publisher Copyright: {\textcopyright} American Academy of Neurology.",

year = "2023",

month = jan,

day = "17",

doi = "10.1212/WNL.0000000000201417",

language = "English",

volume = "100",

pages = "E275--E285",

journal = "Neurology",

issn = "0028-3878",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "3",

}

TY - JOUR

T1 - Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals

AU - Öhrfelt, Annika

AU - Benedet, Andréa L

AU - Ashton, Nicholas J

AU - Kvartsberg, Hlin

AU - Vandijck, Manu

AU - Weiner, Michael W

AU - Trojanowski, John Q

AU - Shaw, Leslie M

AU - Zetterberg, Henrik

AU - Blennow, Kaj

N1 - Funding Information: Coauthor J.Q. Trojanowski, MD, PhD, died in February 2022. Data collection and sharing was funded by ADNI (NIH #U01 AG024904) and DOD ADNI (#W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH ( fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: Coauthor J.Q. Trojanowski, MD, PhD, died in February 2022. Data collection and sharing was funded by ADNI (NIH #U01 AG024904) and DOD ADNI (#W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH (fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: M.W. Weiner receives support for his research from the following funding sources: NIH: 5U19AG024904-14, 1R01AG053798-01A1, R01 MH098062, U24 AG057437-01, 1U2CA060426-01, 1R01AG058676-01A1, and 1RF1AG059009-01. Department of Defense (DOD): W81XWH-15-2-0070, 0W81XWH-12-2-0012, W81XWH-14-1-0462; and W81XWH-13-1-0259. Patient-Centered Outcomes Research Institute (PCORI): PPRN-1501-26817. California Department of Public Health (CDPH): 16-10054. University of Michigan: 18-PAF01312. Siemens: 444951-54249. Biogen: 174552; Hillblom Foundation: 2015-A-011-NET, Alzheimer's Association: BHR-16-459161. The State of California: 18-109929. He also receives support from Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI-BHR), The Stroke Foundation, and the Veterans Administration. H. Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), the AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C and ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. K. Blennow is supported by the Swedish Research Council (2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB-201809-2016615), the Swedish Alzheimer Foundation (AF-742881), Hjärnfonden, Sweden (FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant 1R01AG068398-01), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495). A. Öhrfelt is supported by grants from Demensfonden, Gun och Bertil Stohnes stiftelse, Stiftelsen gamla tjänarinnor, and Åhlén-stiftelsen. Industry-sponsored: Fujirebio supplied the antibodies for the in-house GAP43 assay. L. Shaw is supported by NIH grants: ADNI3 (U19 AG024904): PENN ADRC (P30 AG072979); R01MH117114 and a MJFox Fdn for Parkinson's Research grant 13637.01. Publisher Copyright: © American Academy of Neurology.

PY - 2023/1/17

Y1 - 2023/1/17

N2 - 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.

AB - 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.

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U2 - 10.1212/WNL.0000000000201417

DO - 10.1212/WNL.0000000000201417

M3 - Article

C2 - 36192174

SN - 0028-3878

VL - 100

SP - E275-E285

JO - Neurology

JF - Neurology

IS - 3

ER -

Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals

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