Cerebrospinal fluid neurogranin in non‐amnestic and amnestic Alzheimer’s disease

Abstract

AbstractBackgroundNeurogranin (Ng) is a postsynaptic protein involved in long‐term potentiation and is largely expressed in temporal, parietal, and limbic regions (Lista et al., 2017; Kvartsberg et al., 2019). Increased Ng in cerebrospinal fluid (CSF) follows synaptic dysfunction, and is thought to be a marker specific to Alzheimer’s disease (AD) pathology (Portelius et al., 2018; Clarke et al., 2019). Even so, non‐amnestic variants of AD (naAD) show altered CSF biomarker levels compared to amnestic AD (aAD) (Wellington et al., 2018; Cousins et al., 2020). Here, we compared CSF Ng across aAD, naAD, and frontotemporal dementia (FTD). Neuroimaging tested if Ng differences across naAD and aAD are in part due to regional differences in atrophy.MethodPatient inclusion criteria were available CSF Ng and Aβ1‐42, and either a non‐amnestic (naAD, FTD) or amnestic (aAD) clinical diagnosis. naAD patients (n=34) had likely AD pathology, determined by autopsy (n=3) or CSF Aβ1‐42≤192 pg/mL (Shaw et al., 2009). FTD patients (n=60) had likely non‐AD pathology, determined by autopsy (n=21) or CSF Aβ1‐42>192 pg/mL. aAD patients (n=62) had autopsy‐confirmed AD pathology and an amnestic phenotype. Neuroimaging was available for 29 aAD, 24 naAD, and 50 FTD. Mindboggle Atlas defined regions (Klein and Tourville, 2012) and grey matter volume (GMV) estimated atrophic severity. Regressions 1.) identified regions associated with Ng and 2.) compared atrophy across aAD and naAD; age at MRI, time between MRI and CSF, and sex were covariates. We report regions that were significant in both analyses (p<0.01).ResultAn ANCOVA (covarying for age at CSF and sex) showed that CSF Ng differed by group (p=4.5x106). Post‐hoc pairwise comparisons showed aAD had higher Ng than naAD (p=0.016) and FTD (p=2.6x106), with no difference between naAD and FTD (p=0.23). Neuroimaging showed increased Ng correlated with lower GMV in left fusiform (p=0.0062), precuneus (p=0.0076), and superior parietal lobule (p=0.0073), and naAD had higher GMV than aAD in these three regions (all p<0.0007).ConclusionDespite likely AD pathology, naAD patients had significantly lower Ng than aAD, which may be explained in part by regional expression of Ng and differences in disease distribution between naAD and aAD.