Table 3 Studies investigating the effects of APOE4 on brain atrophy in AD patients

Drzezga et al. [81]

32 moderate AD patients matched by demographics and level of cognitive impairment were evaluated for brain volume using cranial MRI and voxel-based morphometry (VBM).

Mean age for APOE4+ AD patients was 67 (n = 18; 50% female) and APOE4− AD patients was 68 (n = 14; 35% female). No ancestry information was provided.

Comparisons between APOE4+ vs. APOE4− AD patients showed similar levels and patterns of brain atrophy.

Jack et al. [82]

62 probable AD patients and 125 controls were evaluated for hippocampal volume using MRI.

Mean age for both the APOE4+ (n = 36) and APOE4− (n = 26) AD patients was 75, while APOE4+ control group (n = 30) was 80, and APOE4− control group (n = 95) was 78. No ancestry information was provided.

Although the authors noted that both the AD and control groups trended towards an APOE4 effect, there were no significant differences in hippocampal volume between APOE4+ vs. APOE4− AD patients

Wolk et al. [51]

91 mild AD cases (ADNI cohort) were evaluated for cortical volume using MRI morphometric measures.

Mean age for APOE4+ AD patients was 74 (n = 67; 43% female) and APOE4− AD patients was 74 (n = 24; 45% female). No ancestry information was provided.

APOE4+ AD patients demonstrated greater brain atrophy in the medial temporal lobe, but less fronto-parietal atrophy compared to APOE4− AD patients.

Hashimoto et al. [57]

138 probable AD patients were evaluated for regional brain volume in the hippocampal formation, amygdaloid complex, and whole brain using MRI-based volumetry techniques.

Mean age of all three groups, APOE3/3, APOE3/4, and APOE4/4, was 69 (n = 46; 65% female for each group). Participants were of Japanese ancestry.

AD patients demonstrated greater atrophy in the hippocampus and amygdala with increasing APOE4 alleles, whereas whole brain volume increased with increasing APOE4 alleles.

Kim et al. [58]

846 AD patients and 815 controls were divided into groups based on age (< 65, 65–74, ≥ 75 years old) to evaluate regional brain volume using MRI.

Mean age for the < 65 group was 58.1 (n = 184; 64% female), the 65–74 group was 66.4 (n = 252; 67% female), and the ≥ 75 group was 80.3 (n = 410; 70% female). Participants were of Korean ancestry.

In total AD patients, a higher number of APOE4 alleles were associated with cortical thinning in the bilateral medial temporal areas. Moreover, older (≥ 75 years old) APOE4+ AD patients had the most severe medial temporal atrophy, while young (< 65 years old) APOE4− AD patients had more severe frontal and perisylvian atrophy.

Mattsson et al. [90]

65 Aß-positive AD patients (BioFINDER cohort) were evaluated for tau load and cortical thickness using ¹⁸F-AV-1451 PET and MRI, respectively.

Mean age for APOE4+, AD patients was 72.4 (n = 46; 61% female) and APOE4− AD patients was 70.1 (n = 19; 53% female). No ancestry information was provided.

APOE4− AD patients demonstrated reduced thickness in the lateral and parietal areas compared to APOE4+ AD patients.

Filippini et al. [83]

83 AD cases were evaluated for regionally specific brain cortical volume using voxel-based morphometry (VBM).

Mean age of APOE4+ homozygotes was 75.5 (n = 15; 80% female), APOE4+ heterozygotes was 81.1 (n = 39; 53% female), and APOE4− was 75.8 (n = 29; 48% female). No ancestry information was provided.

Bilateral medial and anterior temporal lobes, including amygdala, hippocampal, and entorhinal cortex, and orbitofrontal gray matter volume decreased with increasing APOE4 allele load.

Juottonen et al. [84]

27 probable AD patients and 31 controls were evaluated for entorhinal cortex volume using MRI.

Mean age of APOE4+ AD patients was 70 (n = 16; 37% female), APOE4− AD patients was 69 (n = 11; 54% female), and control was 72 (n = 31; 64% female). No ancestry information was provided.

APOE4+ AD patients demonstrated greater atrophy in the entorhinal cortex, compared to APOE4− AD patients, with only the left entorhinal cortex reaching statistical significance.

Pievani et al. [85]

29 AD patients and 29 age- and sex-matched controls were evaluated for cortical volume using MRI.

Mean age of APOE4+ AD patients was 71 (n = 15; 93% female), APOE4− AD patients was 68 (n = 14; 50% female), and control was 69 (n = 29; 72% female). No ancestry information was provided.

APOE4+ AD patients demonstrated greater brain atrophy in the temporal cortex, right occipital pole, and, to a lesser less degree, in the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex compared to APOE4− AD patients.

Lehtovirta et al. [86]

58 probable AD patients and 34 age- and sex-matched controls were evaluated for hippocampal, amygdala, and frontal lobe volume, as well as cerebral blood flow, using MRI and SPECT, respectively.

Mean age of APOE4+ homozygotes was 66 (n = 13; 45% female), APOE4+ heterozygotes was 72 (n = 24; 46% female), APOE4− was 70 (n = 21; 52% female), and control group was 72 (n = 34; 58% female). No ancestry information was provided.

APOE4+ homozygous AD patients demonstrated greater brain atrophy in the medial temporal structures, hippocampus, and amygdala. However, the frontal lobe volume did not significantly differ between groups.

Lehtovirta et al. [87]

26 probable AD cases and 16 age- and sex-matched controls were evaluated for hippocampal, amygdala, and frontal lobe volume using MRI.

Mean age of APOE4/4 AD patients was 65 (n = 5; 60% female), APOE3/4 AD patients was 71 (n = 9; 44% female), APOE4− (APOE2/3 and APOE3/3) AD patients was 68 (n = 12; 41% female), while control was 70 (n = 16; 62% female). No ancestry information was provided.

APOE4/4 AD patients had the most prominent brain atrophy in the hippocampus and amygdala, and differed significantly from APOE3/4 and APOE4− AD patients in the volume of the right hippocampus and right amygdala. There were no significant differences between groups in the frontal lobe.

Tanaka et al. [88]

34 probable AD patients and 22 controls were evaluated for morphological and functional changes using CT, MRI, and SPECT.

Mean age of APOE4/4 AD patients was 80.8 (n = 4), APOE3/4 AD patients was 81 (n = 8), APOE4− (APOE3/3) AD patients was 84.6 (n = 22), while control was 82 (n = 22). No gender information was provided. Participants were of Japanese ancestry.

APOE4 allele dose did not affect overall brain volume during the course of the disease. However, the inferior temporal and infero-medial temporal areas were statistically lower in volume in APOE4+ AD patients, while the temporal horn was higher in volume in APOE4+ vs. APOE4− AD patients.

Geroldi et al. [89]

28 mild to moderate AD patients and 30 controls were evaluated for hippocampal, entorhinal cortex, anterior temporal, and frontal lobe volume using MRI.

Mean age for the AD patients was 73 (n = 28; 78% female) while control was 69 (n = 30; 67% female). No ancestry information was provided.

There was increasing atrophy in the hippocampus, entorhinal cortex, and anterior temporal lobes with increasing APOE4 dose. In contrast, larger volumes of the frontal lobes were observed with increasing APOE4 dose.