Stable CSF neurogranin and BACE1 levels differentiate predementia Alzheimer’s disease patients

Abstract CSF BACE1 (β-site amyloid precursor protein cleaving enzyme 1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer’s disease. BACE1 is also a drug target. However, CSF levels may differ between early stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). It is unknown whether BACE1 and neurogranin levels are persistent traits or change with disease progression. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer’s disease cases (n=176) (including cases that progressed to dementia (n=10)) and controls (n=74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n=86) and late stage (A+/T+/N+, n=90) of the Alzheimer’s Disease continuum and controls with normal markers (A-/T-/N-, n=74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately two-year intervals up-to six years from baseline. Using Linear Mixed Models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n=12), from A+/T-/N- to A+/T or N+ (n=12), remained stable A+/T-/N- (n=26), remained stable A+/T+/N+ (n=28) compared to controls remaining stable A-/T-/N- (n=33). Lastly, associations between these markers and memory decline were assessed. Compared to A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (p<.0001). In contrast, BACE1 was lower in A+/T-/N- (p<.05) and higher in A+/T+/N+ (p<.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (p<.05) and A+/T+/N+ (p<.0001) groups as compared to A-/T-/N- healthy controls and more strongly associated with memory decline (b=-.29, p=.0006) than neurogranin (b=-.20, p=.002) and BACE1 (b=-.13, p=.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups, but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A+T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer’s Disease subgroups, putatively with different options for treatment.