Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations

Abstract

Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.

The pattern of atrophy in familial Alzheimer disease

“…In light of previous observations regarding possible clinical, 34 imaging, 35 molecular, 36,37 and neuropathologic differences between individuals with APP and PSEN1 mutations, and among individuals with distinct PSEN1 mutations, 38 atrophy patterns may differ among these subgroups. Since this study predominantly contains PSEN1 mutation carriers, it is difficult to determine what differences might be present in FAD caused by APP , PSEN1 , or PSEN2 mutations.…”

Evolving brain structural changes in PSEN1 mutation carriers

“…In this regard, our study only included subjects with PSEN1 mutations, whereas most previous studies also included APP or PSEN2 mutations in different proportions. In this context, Scahill et al (2013) reported that effect maps were suggestive of APP mutation carriers having more medial temporal lobe atrophy and, conversely, PSEN1 subjects showing more neocortical loss. We cannot rule out specific effects of the PSEN1 mutations included here, although we did examine subjects with 9 different PSEN1 mutations.…”

Presymptomatic cortical thinning in familial Alzheimer disease

“…A degree of variability, in terms of both clinical phenotype and radiologic appearance, has been found between the different FAD mutations, both between genes and within the same gene, 29,30 meaning that our cohort is likely to be heterogeneous. While this diversity means it may be more difficult to identify a common pattern, the inclusion of different mutations and genes means that the composite cortical signature identified is likely to be more robust to interindividual variability.…”