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.

BackgroundGenetic studies suggest involvement of the immune system in Alzheimer’s disease (AD) development, and neuroinflammation has been suggested as a key driver of AD. We here employ cerebrospinal fluid (CSF) markers to study whether immune‐ and glial activation are primary features of early amyloid plaque deposition, or follow significant tau pathology as the disease progresses.MethodWe included n=267 non‐demented cases with repeated CSF samples (1‐6 years). The presence of amyloid pathology (A), tau‐tangle pathology (T) and neurodegeneration (N) using Aß42/40 ratio, p‐tau181 and total‐tau were determined at baseline and follow‐ups. We then selected participants (n=226) that remained stable A‐/T‐/N‐ (n=134), A+/T‐/N‐ (n=33) and A+/T+/N+ (n=34) over time and cases that progressed from A‐/T‐/N‐ to A+/T‐/N‐ (n=14) and A+/T‐/N‐ to A+/T or N+ (n=11). Other A/T/N categories (e.g. A‐/T or N+) were excluded. Mixed Linear Models (MLMs) were used to measure longitudinal changes in CSF sTREM2, YKL‐40, clusterin, fractalkine, MCP‐1, IFN‐γ, IL‐6, IL‐18 and IL‐10 between groups with stable A‐/T‐/N‐ group as the reference. All models included age, sex and number of APOEε4 alleles as covariates.ResultCompared to stable A‐/T‐/N‐, cases progressing from A‐/T‐/N‐ to A+/T‐/N‐ had lower sTREM2 levels (p=.022) over time, and both fractalkine (p=.053), IFN‐γ (p=.055) and clusterin levels (p=.068) showed trend levels towards lower levels. In stable A+/T‐/N‐ cases, YKL‐40 (p=.007) and fractalkine (p=.043) were lower than stable A‐/T‐/N‐ over time. A+/T+/N+ cases had markedly higher sTREM2, fractalkine and clusterin levels (all p<.001) that remained high over time. In this group the YKL‐40 levels were also higher at baseline (p<.001) and increased slightly over time (p=.032). There were no between‐group differences at neither baseline or over time in the CSF levels of MCP‐1, IL‐6, IL‐18 and IL‐10.ConclusionAmyloid pathology alone was not associated with increased immune and glial activation in our cohort, and several of the CSF immune markers were lower in both those progressing to A+/T‐/N‐ and the stable A+/T‐/N‐. An increase in activation markers was only shown in cases with tau‐pathology at baseline, or in cases that developed tau pathology during the follow‐up period, suggesting immune activation in response to tau pathology.

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