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

Area of Science:

• Neuroscience
• Biomarkers
• Genetics

Background:

• Synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are CSF biomarkers for synaptic integrity.
• These biomarkers are elevated in symptomatic Alzheimer disease (AD).
• The relationship between these biomarkers and Apolipoprotein E (APOE) ε4 carrier status, a major AD genetic risk factor, is not well understood.

Purpose of the Study:

• To investigate the association between CSF SNAP-25 and Ng levels and APOE ε4 carrier status in cognitively normal individuals.
• To determine if APOE ε4 influences presynaptic and postsynaptic integrity markers independently of amyloid status.

Main Methods:

• Compared CSF SNAP-25 and Ng levels in cognitively normal APOE ε4 carriers and noncarriers (n=274).
• Analyzed CSF levels of total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL).
• Adjusted analyses for age, sex, education, and amyloid status.

Main Results:

• CSF SNAP-25 was significantly elevated in APOE ε4 carriers compared to noncarriers (p < 0.0001), independent of age, sex, education, and amyloid status.
• CSF Ng levels did not differ between APOE ε4 carriers and noncarriers.
• CSF t-tau, ptau181, and NfL levels did not vary by APOE ε4 status.

Conclusions:

• Elevated CSF SNAP-25 in APOE ε4 carriers suggests both amyloid-related and independent presynaptic disruption.
• Postsynaptic disruption, indicated by CSF Ng, is associated with amyloid status rather than APOE ε4 carrier status.