APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review

Abstract

Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer’s disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4−) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4− AD patients. On the other hand, APOE4− AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4− AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.

Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia

“…Regarding non-PET measures, hippocampal volume and most of the cognitive measures were not associated with the ε4 allele in our sample, although we observed a slightly lower memory performance in ε4 carriers. Although in earlier stages, this is in line with the results found in a recent meta-analysis including only AD patients showing that ε4 carriers present worse cognition than non-carriers only in the memory domain [ 66 ]. A review studying the effects of APOE on cognition also suggested that some of the cognitive deficits seen in ε4 carriers might be related to AD pathology [ 67 ].…”

Short leukocyte telomeres predict 25-year Alzheimer’s disease incidence in non-APOE ε4-carriers

“…Given that LTL is a non-specific biomarker associated with multiple processes in the body, such as oxidative stress, inflammation, immune function, cardiovascular function [7,8,54], any mechanistic proposals on the relationship between APOE ε4-carriage and LTL in AD etiology would be premature based on the present observational findings. With that said, evidence for potentially differential disease mechanisms for AD in APOE ε4-carriers and non-carriers has been reported [1,55,56], and it cannot be ruled out that LTL is associated with a different mechanistic pathway in non-carriers than in carriers. For instance, gene expression analyses have identified modules of genes related to immunological and cardiovascular pathways to be expressed in AD brain samples of APOE ε4 non-carriers [56], processes which have also been linked to LTL [7,8,54].…”

“…For instance, gene expression analyses have identified modules of genes related to immunological and cardiovascular pathways to be expressed in AD brain samples of APOE ε4 non-carriers [56], processes which have also been linked to LTL [7,8,54]. In contrast, LTL may be relatively less related to neuropathological processes shown to be accelerated in APOE ε4-carriers [1,4,55,57], such as neuronal amyloid-β and tau deposition, blood-brain barrier dysfunction, or neuronal atrophy (but see [58][59][60]). APOE ε4-carriers and non-carriers have also been shown to be differentially represented in identified subcategories of AD [61,62], reinforcing the notion of potentially differential disease mechanisms.…”

Memory precision of object-location binding is unimpaired in APOE ε4-carriers with spatial navigation deficits

“…This explanation is supported for short-term object-location memory (Zokaei et al ., 2017, 2020; Lu et al ., 2020). However, it may be less applicable in the case of our results in a task that is more reliant on long-term memory processes and the medial temporal lobe (Berteau-Pavy et al ., 2007; De Blasi et al ., 2009; Haley et al ., 2010; Wolk and Dickerson, 2010; Greenwood et al ., 2014; Emrani et al ., 2020). Large-scale studies and meta-analyses across the lifespan have called into question the antagonistic pleiotropy hypothesis in the case of long-term memory (Salvato, 2015; O’Donoghue et al ., 2018; Weissberger et al ., 2018; Henson et al ., 2020) (Salvato, 2015; Weissberger et al ., 2018; Henson et al ., 2020).…”