[P2–241]: CSF NEUROGRANIN IS INCREASED IN FAMILIAL ALZHEIMER's DISEASE

CSF neurogranin (Ng), a neuron specific post-synaptic protein, is a promising biomarker for synapse degeneration in pre-dementia (mild cognitive impairment) as well as dementia stages of Alzheimer's disease (AD). CSF Ng concentration is higher in patients with AD than in other neurodegenerative diseases or controls, with promising specificity and clinical utility. To date, it is unknown how early CSF Ng concentrations increase in the AD trajectory. Familial AD, where individuals at risk of dementia can be reliably determined provides an ideal paradigm for exploring biomarkers at very early disease stages. We therefore performed a pilot study exploring CSF Ng levels in both presymptomatic and symptomatic mutation carriers. We measured CSF Ng by ELISA in 23 subjects, including controls (n=8), presymptomatic (n=8) and symptomatic carriers (n=7). Ng concentrations between groups were compared using Kruskal-Wallis test and Dunn's pairwise comparisons. Spearman correlations were used to explore the association of Ng with estimated years from disease onset (EYO), calculated from parental age at onset, and other CSF biomarkers for different aspects of AD pathology (Aβ42, T-tau, P-tau and neurofilament light [NF-L]). There was some evidence that CSF Ng concentration was higher in presymptomatic carriers (281 [median], 188.2–322.2 [IQR] pg/ml) than in controls (159.6, 125–221.3 pg/ml, p=0.07). Concentrations in symptomatic carriers (664.9, 342–1236 pg/ml), were significantly higher than controls (p<0.001) and presymptomatic carriers (p=0.04). We found a positive correlation between Ng and EYO in mutation carriers (r=0.57, p=0.03), largely driven by the symptomatic group. Including all participants, positive correlations were found with NF-L and T-tau (r=0.80 and 0.86 respectively, both p<0.0001) and P-tau (r=0.83, p=0.0001). These preliminary findings suggest that increased concentrations of CSF Ng are seen in the pre-symptomatic stages of FAD. The highest concentrations were seen in symptomatic patients, and whilst this may in part be related to the age of the individuals, suggests that markers of synaptic pathology may reflect both AD pathology and disease severity: support for this comes from the correlations between CSF Ng and other biomarkers for AD-type neurodegeneration. These findings provide hypotheses that can be tested in larger studies of FAD and pre-symptomatic sporadic AD.