Association of Accelerated Long-term Forgetting and Senescence-related Blood-borne Factors in Asymptomatic Individuals From Families With Autosomal Dominant Alzheimer’s Disease

Abstract Background: Accelerated long-term forgetting has been identified in preclinical Alzheimer’s disease (AD), and is attributed to a selective impairment of memory consolidation in which hippocampus plays a key role. As blood may contain multiple senescence-related factors that involved in neurogenesis and synaptic plasticity in the hippocampus, we tested whether there is an association between blood-borne factors and accelerated long-term forgetting in asymptomatic individuals from families with autosomal dominant AD (ADAD). Methods: We analyzed data of 39 asymptomatic participants (n=18 ADAD mutation carriers, n=21 non-carriers) from the Chinese Familial Alzheimer’s Disease Network (CFAN) study. Long-term forgetting rates were calculated based on recall or recognition of two materials (word list and complex figure) at three delays comprising immediate, 30 min and 7 days. Peripheral blood concentrations of candidate pro-aging factors (C-C motif ligand 11 [CCL11] and monocyte chemotactic protein 1 [MCP1]) and rejuvenation factors (growth differentiation factor 11 [GDF11], thrombospondin-4 [THBS4], and secreted protein acidic and rich in cysteine like 1 [SPARCL1]) were evaluated in all participants. Results: Despite normal performance on standard 30-min delayed testing, mutation carriers exhibited accelerated forgetting of verbal and visual material over 7 days in comparison with matched non-carriers. In the whole sample, lower plasma THBS4 was associated with accelerated long-term forgetting in list recall (β= -0.46, p=0.002), figure recall (β= -0.44, p=0.004) and list recognition (β= -0.37, p=0.010). Additionally, higher plasma GDF11 and CCL11 were both associated with accelerated long-term forgetting (GDF11 versus figure recall: β=0.39, p=0.007; CCL11 versus list recognition: β=0.44, p=0.002).Conclusions: Accelerated long-term forgetting is a cognitive feature of presymptomatic AD. Senescence-related blood-borne factors, especially THBS4, GDF11, and CCL11, may be promising biomarkers for the prediction of accelerated long-term forgetting.