Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25

Omar H Butt; Justin M Long; Rachel L Henson; Elizabeth Herries; Courtney L Sutphen; Anne M Fagan; Carlos Cruchaga; Jack H Ladenson; David M Holtzman; John C Morris; Beau M Ances; Suzanne E Schindler; Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.neurobiolaging.2021.02.008

Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25

Neurobiol Aging. 2021 Jun:102:64-72. doi: 10.1016/j.neurobiolaging.2021.02.008. Epub 2021 Feb 11.

Affiliations

¹ Department of Neurology, Washington University, Saint Louis, MO, USA.
² Department of Neurology, Washington University, Saint Louis, MO, USA; Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University, St. Louis, MO, USA.
³ Department of Neurology, Washington University, Saint Louis, MO, USA; Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA.
⁴ Department of Psychiatry, Washington University, Saint Louis, MO, USA; Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University, St. Louis, MO, USA.
⁵ Department of Pathology and Immunology, Washington University, Saint Louis, MO, USA.
⁶ Department of Neurology, Washington University, Saint Louis, MO, USA; Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University, Saint Louis, MO, USA.
⁷ Department of Neurology, Washington University, Saint Louis, MO, USA; Department of Radiology, Washington University, Saint Louis, MO, USA; Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University, St. Louis, MO, USA.
⁸ Department of Neurology, Washington University, Saint Louis, MO, USA; Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA. Electronic address: schindler.s.e@wustl.edu.

PMID: 33765432
PMCID: PMC8793109
DOI: 10.1016/j.neurobiolaging.2021.02.008

Abstract

Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.

Keywords: APOE; Biomarker; CSF; Neurogranin; SNAP-25; Synapse.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Alzheimer Disease / diagnosis
Alzheimer Disease / genetics
Alzheimer Disease / psychology
Apolipoprotein E4 / genetics*
Biomarkers / cerebrospinal fluid
Cognition / physiology*
Female
Heterozygote*
Humans
Male
Middle Aged
Neurogranin / cerebrospinal fluid
Risk Factors
Synaptosomal-Associated Protein 25 / cerebrospinal fluid*

Substances

Apolipoprotein E4
Biomarkers
SNAP25 protein, human
Synaptosomal-Associated Protein 25
Neurogranin

Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding