APP-derived peptides reflect neurodegeneration in frontotemporal dementia

Abstract

Objective: We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)-derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)-related syndromes, Alzheimer's disease (AD), and healthy controls.

Methods: We included 214 participants with CSF available recruited at two centers: 93 with FTLD-related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid β (Aβ)1-42, Aβ1-40, Aβ1-38, and soluble β fragment of APP (sAPPβ) were centrally analyzed. We compared CSF levels of APP-derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain-specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP-derived peptides, and regional gene expression profile using a brain-wide regional gene expression data in combination with gene set enrichment analysis.

Results: The CSF levels of Aβ1-40, Aβ1-38, and sAPPβ were lower in the FTLD-related syndromes group than in the AD and healthy controls group. CSF levels of all APP-derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD-related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP-derived peptides, we found a reduced expression of genes related to synaptic function.

Interpretation: APP-derived peptides in CSF may reflect FTLD-related neurodegeneration. This observation has important implications as Aβ1-42 levels are considered an indirect biomarker of cerebral amyloidosis.

Figure 1

Group comparison of CSF levels of APP‐derived peptides. CSF levels of (A) Aβ1‐42, (B) Aβ1‐40, (C) Aβ1‐38, (D) sAPPβ, (E) Aβ1‐42/Aβ1‐40 ratio, and (F) Aβ1‐42/Aβ1‐38 ratio across groups. Only statistically significant differences are displayed. We applied correction for multiple comparisons (Bonferroni’s post‐hoc test; *P < 0.001). The red‐dotted line represents our previously validated CSF cut‐point for Aβ1‐42. AD, Alzheimer’s disease; Aβ, amyloid β; FTLD‐S, frontotemporal lobar degeneration‐related syndromes; HC, healthy controls; sAPPβ, soluble β fragment of amyloid precursor protein; CSF, cerebrospinal fluid; APP, amyloid precursor protein.

Figure 2

Correlation of APP‐derived peptides with cortical thickness in the FTLD‐related syndromes group. Correlation of APP‐derived peptides with cortical thickness in the FTLD‐related syndromes group. Only clusters that survived family‐wise error correction P < 0.05 are shown. Only positive correlations were found (displayed in orange and red). Cortical thickness analyses were adjusted for age, sex, and MRI equipment. Aβ, Amyloid β; sAPPβ, soluble β fragment of amyloid precursor protein; APP, amyloid precursor protein; FTLD‐S, frontotemporal lobar degeneration‐related syndromes; MRI, magnetic resonance imaging.

Figure 3

Transcriptional architecture and gene set enrichment analysis. (A) Histogram representing the distribution of the effect size scores of the neuro‐related gene expressions between regions with and without a significant relationship with APP‐derived peptides in FTLD. The full list of genes with differential expression can be found in Table S2. (B) Bar graphs show the top FDR‐corrected (P < 0.0001) GO enrichment analyses of genes differential expression in the brain regions where correlations were observed. APP, amyloid precursor protein; FTLD‐S, frontotemporal lobar degeneration‐related syndromes; FDR, false discovery rate.