Table 5.

Studies investigating the effects of APOE4 on neurofibrillary tangles in AD patients

Study	Study details	Participant details	Study results
No relationship between NFT deposition/distribution and APOE4 status
Petersen et al. [107]	94 AD autopsy cases enriched for atypical AD presentation were evaluated for patterns of regional NFT accumulation in six selected neocortical and hippocampal regions.	Age range at death for the entire group was 51–73 at age of onset and 63–86 at death (n = 94; 40% female). No ancestry information was provided.	No significant difference in regional NFT density was found between APOE4+ vs. APOE4− AD patients, although there was a trend (p = 0.0992) towards more APOE4− AD patients in the hippocampal-sparing group and more APOE+ AD patients in the limbic predominant group.
APOE4 associated with increased NFT deposition in the medial temporal lobe
Murray et al. [61]	889 AD autopsy cases were used to study regional density and distribution of NFTs. Cases were classified as hippocampal-sparing, typical, or limbic predominant based on their relative NFT distribution.	Average age at death for the hippocampal-sparing subtype was 73 (n = 97; 37% female), typical subtype was 79 (n = 665; 55% female), and limbic predominant subtype was 86 (n = 127; 69% female). No ancestry information was provided.	Significantly more APOE4+ AD patients were included in the late-onset (> 65 years old) limbic predominant group, while a trend towards fewer APOE4+ AD patients were included in the hippocampal-sparing group.
Ossenkoppele et al. [108]	20 cases with either MCI or probable AD, and 15 Aß-negative cognitively normal individuals were evaluated for 18F-AV-1451 tau PET ligand uptake, as well as PIB-PET and FDG-PET.	Mean age for PCA patients was 63 (n = 7; 42% female), lvPPA patients was 65 (n = 5; 80% female), amnestic AD patients was 67 (n = 5; 40% female), non-amnestic AD patients was 59 (n = 1; 0% female), behavioral/dysexecutive variant AD patients was 59 (n = 1; 0% female), and CBS patients was 60 (n = 1, 100% female). No ancestry information was provided.	APOE4+ AD patients exhibited increased 18F-AV-1451 uptake in the bilateral medial temporal and right temporoparietal cortex compared to APOE4− AD patients.
Whitwell et al. [109]	62 Aß-positive AD patients were evaluated for 18F-AV-1451 tau PET ligand uptake in the entorhinal cortex (EC) relative to whole cortex (C). Using K-median cluster analysis, cases were classified into three categories: ECLo/CLo, ECLo/CHi, and ECHi/CHi.	Mean age for the ECLo/CLo group was 76 (n = 21; 38% female), the ECLo/CHi group was 64 (n = 21; 57% female), and the ECHi/CHi group was 62 (n = 20; 65% female). No ancestry information was provided.	APOE4 frequency was found to be significantly lower in the ECLo/CHi group (48%) relative to the ECLo/CLo (84%) and ECHi/CHi (74%) groups. Thus, in the context of high cortical tau load (but not low cortical tau load), fewer APOE4+ AD patients possessed low tau load in the entorhinal cortex compared to APOE4− AD patients.
Mattsson et al. [90]	65 Aß-positive patients with either MCI or AD (BioFINDER cohort) were evaluated for 18F-AV-1451 tau PET ligand uptake and cortical thickness via MRI.	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 exhibited increased tau load in the entorhinal cortex relative to the whole cortex, and lower NFT load in the lateral parietal, medial parietal, occipital, and whole brain cortical areas compared to APOE4− AD patients.
APOE4 associated with increased NFT deposition in other brain regions
Al-Shaikh et al. [110]	1361 AD subtypes and 103 controls (FLAME cohort) were assessed for NFT accumulation and neuronal density differences between different AD subtypes (hippocampal-sparing, typical, or limbic predominant).	Mean age at death for the hippocampal-sparing subtype was 72 (n = 175; % female), the limbic predominant subtype was 86 (n = 172; 70% female), the typical subtype was 81 (n = 1014; 54% female), and controls was 73 (n = 103; 46% female). No ancestry information was provided.	Within the “typical” AD group, APOE4+ AD patients exhibited higher NFT pathology in their nucleus basalis of Meynert (nbM), located in the basal forebrain, compared to APOE4− AD patients.