Family history and APOE-4 genetic risk in Alzheimer's disease

Abstract

Identifying risk factors for Alzheimer's disease, such as carrying the APOE-4 allele, and understanding their contributions to disease pathophysiology or clinical presentation is critical for establishing and improving diagnostic and therapeutic strategies. A first-degree family history of Alzheimer's disease represents a composite risk factor, which reflects the influence of known and unknown susceptibility genes and perhaps non-genetic risks. There is emerging evidence that investigating family history risk associated effects may contribute to advances in Alzheimer's disease research and ultimately clinical practice.

Fig. 1

Alzheimer’s disease and the ‘family history’ risk factor. Alzheimer’s disease has a high heritability, but the influence of environmental variables on disease development and clinical course is also substantial (Gatz et al. 2006). A first-degree family history of Alzheimer’s disease can be conceptualized as a composite risk factor, reflecting the influence of known and yet unknown genetic risks. Furthermore, specific environmental risk factors (such as low socioeconomic status; Borenstein et al. 2006) may contribute to the familial clustering of the disease as well, since these risks may be passed on to the next generation. Note: The individual size of a rectangle in the figure does not reflect an exact value

Fig. 2

Functional MRI (from Xu et al. 2009, The influence of parental history of Alzheimer’s disease and apolipoprotein E e4 on the BOLD signal during recognition memory, Brain, 2009, 132 (2):383–91, by permission of Oxford University Press). In a 2×2 ANCOVA analysis, the APOE4, FH and their interaction effects showed similar clusters with both PV and NV responses [P<0.05 (corrected for cluster size)]. a and d A larger response was observed in the -APOE4 group compared to the +APOE4 in the left anterior cingulate cortex to PV (a) or NV faces (d). b and e A larger response was observed in the -FH group compared to the +FH group in the left medial superior frontal gyrus (signal shown in the plot) and left cuneus. There is a clear declining trend in PV or NV response amplitude with the accumulation of Alzheimer’s disease risk factors (+FH and +APOE4). c and f The interaction between FH and APOE4 showed significance in the bilateral fusiform–parahippocampal gyrus with both PV (c) and NV faces (f)

Fig. 3

Structural MRI (from Donix et al. 2010a. Reprinted with permission from the American Journal of Psychiatry, (Copyright ©2010). American Psychiatric Association). The figure displays cortical thickness values for the possible APOE and family history risk factor combinations among cognitively healthy subjects. CA23DG cornu ammonis fields 2, 3 and dentate gyrus; CA1 cornu ammonis field 1; SUB subiculum; ERC entorhinal cortex; PRC perirhinal cortex; PHC parahippocampal cortex; FUS fusiform cortex; Global average cortical thickness across all medial temporal lobe subregions; FH family history; “+” = positive; “−” = negative

Fig. 4

PIB-PET (from Mosconi et al. 2010b. Reprinted with permission from the National Academy of Sciences). Statistical parametric maps showing higher Pittsburgh Compound B (PIB) retention in cognitively normal subjects with a maternal family history of Alzheimer’s disease than in subjects with a paternal or no family history (upper two rows), and in cognitively normal subjects with a paternal family history of Alzheimer’s disease than in subjects with no family (lower two rows). Areas with higher PIB retention are represented on color-coded scales, reflecting Z scores. All results remained significant after controlling for age, gender, education, and APOE status