Stable cerebrospinal fluid neurogranin and β-site amyloid precursor protein cleaving enzyme 1 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.

Comparative analysis of multimodal biomarkers for amyloid-beta positivity detection in Alzheimer's disease cohorts

“…The high AUCs obtained using non-amyloid CSF variables for the unimpaired and impaired groups implicate amyloid-related neurodegeneration both at early stages and during AD progression (Kirsebom et al, 2018 , 2022 ). Besides, our classification results were more favorable in the impaired cohorts, attributed to the presence of pronounced biomarker changes and cognitive impairment developments in these groups.…”

Costs of diagnosing early Alzheimer's disease in three European memory clinic settings: Results from the precision medicine in Alzheimer's disease project

“…The Precision Medicine Interventions in AD Consortium (PMI-AD) explores technologies and competencies to stratify early-stage AD patients using novel mechanistic pathways to therapeutic algorithms to develop costeffective, pathway-adapted diagnostics and early interventions to delay disease onset. 5 Two disease-modifying targets (DMTs) have shown statistically significant effects on cognition in randomized controlled trials: lecanemab and donanemab. 6,7 Lecanemab is approved by the Food and Drug Administration (FDA) in the US, in Japan and in China, and the process for its eventual approval has started by the European Medical Agency (EMA).…”

“…Genetic risks and disease pathways (mechanisms and cellular responses) differ between AD subgroups 3,4 and precision‐medicine (PM) approaches are required to develop successful interventions. The Precision Medicine Interventions in AD Consortium (PMI‐AD) explores technologies and competencies to stratify early‐stage AD patients using novel mechanistic pathways to therapeutic algorithms to develop cost‐effective, pathway‐adapted diagnostics and early interventions to delay disease onset 5 …”