Family history of Alzheimer's disease and hippocampal structure in healthy people

Abstract

Objective: Structural brain changes appear years before the onset of Alzheimer's disease, the leading cause of dementia late in life. Determining risk factors for such presymptomatic brain changes may assist in identifying candidates for future prevention treatment trials. In addition to the e4 allele of the apolipoprotein E gene (APOE-4), the major known genetic risk factor, a family history of Alzheimer's disease also increases the risk to develop the disease, reflecting yet unidentified genetic and, perhaps, nongenetic risks. The authors investigated the influence of APOE-4 genotype and family history risks on cortical thickness in medial temporal lobe subregions among volunteers without cognitive impairment.

Method: High-resolution magnetic resonance imaging (MRI) and a cortical unfolding method were performed on 26 subjects (APOE-4 carriers: N=13; noncarriers: N=13) with at least one first-degree relative with Alzheimer's disease and 25 subjects (APOE-4 carriers: N=12; noncarriers: N=13) without this risk factor. All subjects (mean age: 62.3 years [SD=10.7]; range=38-86 years) were cognitively healthy.

Results: Family history of Alzheimer's disease and APOE-4 status were associated with a thinner cortex in the entorhinal region, subiculum, and adjacent medial temporal lobe subfields. Although these associations were additive, family history of Alzheimer's disease explained a greater proportion of the unique variance in cortical thickness than APOE-4 carrier status.

Conclusions: APOE-4 carrier status and family history of Alzheimer's disease are independently associated with and contribute additively to hippocampal cortical thinning.

FIGURE 1. Cortical Unfolding of Gray Matter in Cognitively Healthy Subjects With and Without a First-Degree Relative With Alzheimer’s Disease^a

^a After manual segmentation of white matter and CSF (B), gray matter is computationally unfolded and flattened. Boundaries between subregions (as shown on one of the anterior [A] and one of the posterior [C] slices; fusiform cortex boundary depicts medial fusiform vertex) are projected onto the flat map (right side shown). Abbreviations: CADG=anterior cornu ammonis fields and dentate gyrus; 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.

FIGURE 2. Cortical Thickness According to APOE Genotype and Family History of Alzheimer’s Disease in Cognitively Healthy Subjects^a

^a Cortical thickness values for the possible APOE and family history risk factor combinations among subjects are depicted. Subjects with a family history of Alzheimer’s disease compared with subjects without this risk factor showed a significant thinner cortex averaged across all subregions (Global) and a thinner cortex in the cornu ammonis field 1, subiculum, entorhinal cortex, and parahippocampal cortex. APOE-4 allele carriers relative to noncarriers showed a significant thinner cortex averaged across all subregions and a thinner subiculum, entorhinal cortex, parahippocampal cortex, and fusiform cortex (mixed general linear model). Family history of Alzheimer’s disease was considered positive if at least one first-degree relative had been diagnosed with the disease using standard criteria. APOE-4=e4 allele of the apolipoprotein E gene; 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.