Neuronal networks are differentially affected in mutation carriers versus non‐carriers in autosomal dominant Alzheimer’s disease

Abstract

AbstractBackgroundAutosomal dominant Alzheimer’s disease (AD) is caused by known genetic mutations which results in the biochemical consequences that underlie the pathological basis of the disease, and a disease process driven by amyloid accumulation. Mutation carriage is characterized by substantial amyloid accumulation, and dementia onset at or around the age of parental dementia onset. Dementia onset is likely due to neurodegeneration, including loss of neuronal networks, although changes to structural connectivity remain incompletely characterized. Here, we report preliminary connection‐wise analysis of neuronal networks based on mutation and cognitive status, as well as estimated years to symptom onset (EYO), in autosomal dominant AD.MethodCross‐sectional diffusion tensor imaging (DTI) data from participants in the Dominantly Inherited Alzheimer Network were analyzed. DTI pre‐processing was performed using FSL and MRtrix3. Network node regions were identified based on the IIT‐Desikan gray matter atlas. Threshold‐free network‐based statistics (TFNBS) method was applied to test the effect of group as well as the linear interaction effects of the EYO and group on neuronal networks. The groups examined were mutation carrying AD (AD:MC), cognitively unimpaired mutation carriers (CU:MC), and cognitively unimpaired non‐carriers (CU:NC). Age and sex were used as nuisance variables in the linear models.ResultSample characteristics are shown in Table 1. Group level effects are shown in Figure 1. EYO by group interaction effects are shown in Figure 2. The names of the corresponding gray matter regions are shown in Table 2. Threshold‐free network‐based ‐statistic matrices for the interaction effects are shown in Figure 3.ConclusionAD:MC and CU:MC groups had higher weighted totals (a proxy of intra‐axonal cross‐sectional area of fiber bundles) in most of the neuronal connections. In addition, a similar increase in the weighted totals was observed as CU:MC group approached EYO. Increased cross‐sectional area may reflect loosening and shortening of fiber bundles with disease progression. Characterizing these regions among cognitively unimpaired individuals may inform the specific disease pathophysiology that act upon brain structures and lead to dementia. Future studies will examine these patterns among individuals with late onset AD and assess longitudinal relationships.