SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes

Abstract INTRODUCTION We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aβ) and cognitive performance in healthy apolipoprotein E ( APOE ) ε4 carriers. METHODS Synaptic density was assessed in 46 individuals ( APOE ε4/ε4 n = 14; APOE ε3/ε4 n = 16; APOE ε3/ε3 n = 16) with 11 CUCB‐J‐PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal 11 CUCB‐J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among 11 CUCB‐J SUVR, Aβ, hippocampal volume, and cognitive variables were analyzed with Spearman correlation. RESULTS Hippocampal synaptic density was different among the APOE groups ( P ANOVA = 0.016): APOE ε4/ε4 carriers had lower 11 CUCB‐J SUVRs compared to APOE ε3/ε3 ( p = 0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho = −0.052, p = 0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho = 0.17, p = 0.28), or 11 CPiB uptake (rho = −0.10, p = 0.50). DISCUSSION Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high‐risk individuals. Highlights Synaptic density was studied in vivo in healthy older adults using 11 CUCB‐J positron emission tomography. Apolipoprotein E ( APOE ) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.