The influence of known pathogenic gene mutation and ApoEε4 on neuropsychological evaluation and imaging markers in preclinical stage of familial Alzheimer’s disease

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Abstract Background In the preclinical stage of familial Alzheimer's disease (FAD), there have been changes in multi‐dimensional indicators, such as pathology, neuropsychology and imaging. This study explored the effects of known pathogenic gene mutation and ApoE on neuropsychology and imaging markers before the appearance of FAD symptoms. Method 102 cases of asymptomatic mutation non‐carriers (26 cases of ApoEε4) and 38 cases of asymptomatic mutation carriers (17 APP, 21 PS1) in FAD families were assessed by a series of neuropsychological scales, including mini mental state scale (MMSE), auditory verbal learning test (AVLT), etc. MRI images were collected. The volume of representative brain regions was obtained, including subregions of striatum, hippocampus, rostral middle frontal gyrus (rMFG), and posterior cingulate cortex (PCC). Diffusion indices and functional connectivity (FC) of neural pathways (striatum subregions to rMFG, hippocampus to PCC) were also obtained. The neuropsychological scores and imaging indexes were compared between groups, and the imaging indexes with group differences were further correlated with neuropsychological scores. Result Compared with asymptomatic mutation non‐carriers, APP group showed a trend increase in delayed recall score in AVLT (P = 0.08), significantly increased cued recall score, and increased radial diffusivity (RD) of bilateral caudate‐rMFG pathway (fig 1, P's < 0.05). In asymptomatic mutation non‐carriers, compared with APOEε4 non‐carriers, APOEε4 carriers showed increased right hippocampal volume, decreased fractional anisotropy (FA) of bilateral hippocampus‐PCC pathway, and increased FC of left caudate‐rMFG pathway (fig 2, P's < 0.05). The RD of right caudate‐rMFG pathway in PS1 group was positively correlated with MMSE total score (r = 0.749). The FC of left caudate‐rMFG pathway was negatively correlated with MMSE total score (fig 3, r = ‐ 0.623, P’s < 0.05). Conclusion There are neuropsychological and imaging changes in the early stage of FAD, which are affected by the known pathogenic gene mutation and ApoEε4. APP mutation affected memory domain in cognitive function and the structural connectivity of fronto‐striatal pathway. ApoEε4 mainly affected the structural connectivity of hippocampus‐PCC pathway. The hippocampal volume and the functional connectivity of fronto‐striatal pathway increased compensatively. The overall cognitive function is differently related to the structural and functional connectivity of fronto‐striatal pathway in APP, PS1 and ApoEε4.

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