The role of IGFBP2 in pre‐symptomatic Alzheimer's disease: a multimodal longitudinal study of cognitively unaffected individuals with a family history of sporadic Alzheimer’s disease

Abstract

AbstractBackgroundInsulin‐like growth factors (IGF) play pivotal roles in neurogenesis, neuronal survival, synaptogenesis and compensatory repair mechanisms following injury. Insulin‐like growth factor binding proteins (IGFBP) bind to IGFs, and regulate interactions between IGFs and their cell surface receptors. In the brain, IGFBP2 is the most abundant IGFBP. Several studies have observed altered IGFBP2 levels in Alzheimer’s disease (AD) patients. However, the role of IGFBP2 during pre‐symptomatic AD remains unknown. Thus, we used longitudinal data acquired from the pre‐symptomatic PREVENT‐AD cohort to examine its possible contributions to AD pathophysiology.MethodFor initial cross‐sectional analyses, the Mini‐Mental State Examination was used to stage the participants (PREVENT‐AD, CCNA and Douglas cohorts) across the AD spectrum. Olink’s primer extension assay was used to measure cerebrospinal fluid (CSF) IGFBP2 levels. PREVENT‐AD participants were followed longitudinally for 6‐8 years. Annual visits included cognitive performance assessments, lumbar punctures and neuroimaging. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) evaluated five cognitive domains (immediate memory, delayed memory, attention, language and visuospatial abilities) and included a total summary score.ResultCSF IGFBP2 levels were significantly reduced in MCI (p < 0.001) and AD participants (p = 0.027 and p < 0.001 respectively), relative to controls (Figure 1). In the PREVENT‐AD cohort, baseline CSF IGFBP2 levels were negatively correlated with RBANS cognitive performance trajectory slopes estimated over the course of 6 to 8 years, for the delayed memory (p = 0.003), visuospatial (p = 0.008) and total scale indices (p = 0.021) (Figure 2). However, baseline CSF IGFBP2 levels were not associated with cognitive decline for the immediate memory (p = 0.162), attention (p = 0.890) and language (p = 0.841) indices (Figure 3). Finally, in the PREVENT‐AD cohort, baseline CSF IGFBP2 levels were negatively correlated with baseline left entorhinal cortex volume (p = 0.011), but were not correlated with right entorhinal cortex volume (p = 0.868)(Figure 4).ConclusionOur results suggest that IGFBP2 may exhibit a bi‐directional association with AD stage pathology. Our findings revealed that IGFBP2 is strongly correlated with early cognitive decline in the delayed memory and visuospatial domains, in pre‐symptomatic individuals.