Cerebrospinal fluid proteomic profiles predict progression to dementia in prodromal AD

Abstract

AbstractBackgroundIndividuals with mild cognitive impairment (MCI) and abnormal amyloid are at increased risk to develop dementia and are considered to have prodromal Alzheimer’s disease (AD). Still, the precise pathophysiological processes that lead to dementia remain unclear. We studied in prodromal AD whether alterations can be detected in cerebrospinal fluid (CSF) proteomics that are related to progression to dementia.MethodWe selected from the Amsterdam Dementia Cohort 44 individuals with prodromal AD (67±7 years old, 22(44%) female), who had CSF proteomic data measured with Olink multiplex panels. Of 1010 proteins available, 501 (49%) were detected in at least 10 individuals per group and considered for further analyses. To aid interpretation, protein concentrations were Z transformed according to a normal control group (from the EMIF preclinAD study: 56 individuals with normal cognition and normal CSF amyloid and tau (68±6 years old, 28(50%) female) measured within the same experiment. Within prodromal AD, associations of protein levels with progression to dementia were tested with Cox proportional Hazard models, adjusting for p‐tau levels, age and sex. ClueGO was used for biological pathway enrichment analyses.ResultFourteen (33%) individuals with prodromal AD developed dementia over 2.6±1.4 years. In total 49 of the 501 proteins were associated with progression to dementia: for 90% of proteins a standard deviation lower concentration was associated with a 2 to 9‐fold increased risk to develop dementia (Figure 1a). Figure 1b shows a progression curve for individuals labelled according to tertiles of a protein summary score combining these proteins, with individuals having low concentrations showing an 4‐fold increased risk to progress to dementia compared to individuals with high concentrations (p<.01). Proteins associated with progression showed enrichment for several biological pathways that clustered together into 6 groups and were associated with regulation of MAPK cascade, angiogenesis, leukocyte activation in immune response, extracellular matrix organisation and regulation of neuronal death (Figure 1c; all pfdr <.05).ConclusionNeurodevelopmental pathways, angiogenesis and the leukocyte activation in immune response are involved in early AD pathophysiology and related to subsequent progression to dementia. Furthermore, CSF proteomics may have potential as a stratification tool to select fast decliners within prodromal AD.