Table 2 Studies investigating the effects of APOE4 on cognitive profiles in AD patients

Marra et al. [49]

30 early-onset (< 65 years old) and 41 late-onset (> 70 years old) AD patients were evaluated for the effects of APOE4 on the age at disease onset.

Mean age of early-onset APOE4+ AD patients was 58.8 (n = 20), early-onset APOE4− AD patients was 56 (n = 10), late-onset APOE4+ AD patients was 74.8 (n = 25), and late-onset APOE4− AD patients was 76.2 (n = 16). No gender or ancestry information was provided.

APOE4+ early-onset AD patients exhibited worse performance in measures of learning, long-term verbal memory, and general intelligence tasks. APOE4 status had no effect on cognitive impairment at onset in late-onset AD patients.

Snowden et al. [50]

523 AD patients were evaluated to explore the relationship between APOE status and family history.

Mean age of 60 (56% female). No ancestry information was provided.

APOE4+ AD patients had an older age of onset, a positive family history, and demonstrated greater amnestic deficits than APOE4− AD patients. In contrast, frontal lobe characteristics and posterior cortical presentations were not associated with APOE4 status. In addition, no association was found between reduced age of onset and APOE4 status.

Lehtovirta et al. [53]

58 probable AD patients and 16 controls were evaluated for the effects of age (< 65 or ≥ 65) and disease type (sporadic or familial) on cognitive decline across various measures.

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+ AD patients demonstrated greater amnestic deficits (immediate and delayed recall) with increasing allele load, and earlier age of onset compared to APOE4− AD patients.

Weintraub et al. [59]

The APOE genotype of 42 patients with primary progressive aphasia (PPA) and AD pathology (PPA/AD) was compared with 1418 patients with autopsy-confirmed AD and amnestic dementia of the Alzheimer type (DAT/AD).

Mean age of symptom onset for PPA/AD was 60.9 (42.9% APOE4+, 38.1% female) and DAT/AD was 68.2 (65.7% APOE4+, 45.8% female). No ancestry information was provided.

DAT/AD patients were found to be enriched for the APOE4 allele, while PPA/AD patients were not.

Scheltens et al. [48]

1982 probable AD patients across four large cohorts (Amsterdam Dementia Cohort, ADNI, German Dementia Competence Network, and UCSF Memory and Aging Center) were clustered using neuropsychological data and assigned to either a memory or a non-memory group.

Mean age was 71 (64% APOE4+, 54% female). No ancestry information was provided.

Across cohorts, AD patients in the non-memory clusters were less often APOE4 carriers and had less severe hippocampal atrophy and more severe posterior cortex atrophy compared to the memory group.

Smits et al. [54]

199 probable AD patients (Amsterdam Dementia Cohort) were evaluated using a neuropsychological battery to measure the effects of age of onset (≤ 65 years old or > 65 years old) and APOE4 status on cognitive decline.

Mean age of APOE4+ AD patients was 65 (46% female) and APOE4− AD patients was 65 (54% female). No ancestry information was provided.

APOE4− AD patients declined faster on language compared to APOE4+ AD patients. When taking age into account, early-onset APOE4− AD patients declined faster on language, attention, executive control, and visuospatial functioning compared to late-onset APOE4+ AD patients. There was no significant difference in decline on memory between groups.

Davidson et al. [55]

627 mild/moderate AD patients were evaluated using cognitive screening tools including the MMSE and the Dementia Rating Scale-2 (DRS-2) to identify cognitive subgroups using latent class analysis.

Mean age was 63.4 for males and 63.8 for females (52% of total subjects were female). All participants were Caucasian.

Four classes were generated (Mild, Attention/Construction, Severe, Memory). The Mild class was the most likely to include APOE4+ AD patients, while the Attention/Construction class was least likely to include APOE4+ AD patients.

Schott et al. [56]

39 AD patients were assessed using the MMSE, neuropsychological tests, and MRI imaging to investigate APOE4 frequency in the so-called biparietal AD, characterized as having “combinations of dyscalculia, dyspraxia, visuoperceptual, visuospatial, and spelling deficits with relatively spared memory.”

Mean age of the 10 “biparietal” AD patients was 56.1 (60% female). No ancestry information was provided.

10 “biparietal AD” patients were identified and were found more likely to be APOE4 non-carriers.

Hashimoto et al. [57]

138 probable AD patients were evaluated for cognitive abilities and regional brain volume using MRI-based 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.

No significant effects of APOE4 status were found on memory function, but there was an association between APOE4− AD patients and impairment on WMS-R attention/concentration subtests. Further, APOE4+ AD patients demonstrated increased WAIS-R performance and verbal IQ with increasing allele load compared to APOE4− AD patients.

Wolk et al. [51]

91 mild AD patients (ADNI cohort) were evaluated for phenotypic differences in cognition and regional cortical volume.

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 impairment on measures of memory retention, whereas APOE4− AD patients were more impaired on tests of working memory, executive control, and lexical access.

van der Vlies et al. [52]

229 probable AD patients were assessed for impairment in specific cognitive domains in relation to APOE4 status using numerous cognitive screening tools.

Mean age of APOE4 homozygotes was 66 (n = 32; 65% female), APOE4 heterozygotes was 66 (n = 132; 56% female), and APOE4− was 67 (n = 65; 51% female). No ancestry information was provided.

APOE4+ AD patients demonstrated greater overall amnestic deficits, while APOE4− AD patients were more impaired in domains of naming, executive function, and mental speed.

Kim et al. [58]

846 AD patients and 815 controls were divided into groups based on age (< 65, 65–74, ≥ 75 years) to evaluate regional brain volume and cognitive function in relation to APOE genotype.

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.

APOE4− AD patients under 75 years old and APOE3/4 AD patients under 75 years old performed worse on measures of language, visuospatial, and frontal function compared to APOE4/4 AD patients, while APOE4/4 AD patients over 75 years old performed worse on measures of memory compared to APOE4− AD patients.