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DISCOVERY OF 5 MOLECULAR SUBTYPES IN ALZHEIMER’S DISEASE BY UNSUPERVISED CEREBROSPINAL FLUID PROTEIN CLUSTERING
Abstract
Aims
Alzheimer’s disease (AD) pathophysiology is heterogenous. We studied if distinct subtypes could be detected with cerebrospinal fluid (CSF) proteomics.
Methods
We selected 419 AD individuals (with an abnormal amyloid biomarker) and 187 controls (with normal cognition and normal AD biomarkers) from Alzheimer center Amsterdam studies. With 16-plex TMT MS technology we detected 3987 proteins in CSF, of which 1310 proteins were observed in everyone and used for further analyses. We clustered 1059 proteins associated with AD (p<.05). Potential upstream drivers of molecular subtypes were identified with ENRICHR.
Results
We found 5 subtypes with distinct protein profiles: Compared to controls, 3 subtypes(1a, 1b, 1c) had high levels of neuronal plasticity proteins, and two(2a, 2b) had low levels of plasticity proteins. 137(32%) subjects had subtype 1a, with increased amyloid processing with high BACE1 and abeta40 levels. 560 subtype 1a proteins associated with REST and SUZ12 as potential upstream drivers. 124(30%) subjects had subtype 1b, with high levels of inflammation proteins and complement activation. 593 subtype 1b proteins converged on SOX2 as potential upstream driver. 24(6%) subjects had subtype 1c with high levels of 154 proteins converging on TCF3 as potential upstream driver. Subtypes 2a included 78(19%) individuals with high levels of 318 proteins expressed by the choroid plexus that converged on NFE2L2. Subtype 2b included 56(13%) subjects with high levels of 327 proteins associated with blood-brain barrier leakage, converging on ERG1.
Conclusions
We found three AD subtypes showing amyloid overproduction, and two with impaired amyloid clearance. This underlines the necessity of personalized treatment in AD.