Table 1.
Studies of genetic association with the apolipoprotein E (APOE) gene.
| Study | Participants | Genes | Interaction Impact on Disease | Possible Mechanisms Described by the Authors |
|---|---|---|---|---|
| Martinez et al., 2009 [70] | 223 MCI patients, 345 AD and 253 HC | COMT | COMT (Val158 Met) polymorphism is not an independent risk factor for AD or MCI, but shows a synergistic effect with APOE ε4 allele that proves greater in women with AD. | Lowering the estrogen levels of brain. |
| Wang et al., 2005 [75] | 66 AD and 86 HC | COMT | The COMT high-activity genotypes and APOEε4 allele had a synergistic effect on the risk of AD. | A high metabolism of estrogen by COMT may have reduced the protective effect of estrogen in AD. |
| Sapkota et al., 2017 [76] | 634 non-demented older adults | COMT BDNF | APOE ε4+ carriers with BDNF Met/Met genotype and increasing allelic risk in the COMT + BDNF risk panel had poorer executive function performance. | − |
| Ward et al., 2014 [71] | 433 older adults (50–79 years) | BDNF | In BDNF Val homozygotes, the cognitive consequences of APOE polymorphisms were minimal. However, in BDNF Met carriers, the hypothesized beneficial/detrimental effects of APOE polymorphisms were found. | Firstly, there is a biological interaction related to the systems or aging-related roles of the encoded proteins. Secondly, the additive effects of the polymorphisms caused the analyses to reach statistical significance. |
| Gomar et al., 2016 [72] | 175 healthy subjects and 222 with prodromal and established AD | BDNF | BDNF Met and APOE ε4 carriers had thinner posterior cingulate and precuneus cortices in healthy subjects, and longitudinal decline in entorhinal thickness in MCI and AD. | − |
| Persson et al., 2013 [73] | 888 non-demented adults (35–85 years) | BDNF | A joint effect on memory decline in BDNF × APOE × age, with the subjects carrying the Met allele, as well as at least one copy of the APOE ε4 allele showing magnified effect sizes with increasing age on memory decline, while the homozygote Val subjects carrying the ε4 allele showed a decreased slope. | − |
| Yu et al., 2007 [77] | 193 late-onset AD, 232 subjects with no cognitive impairment, and 125 individuals with other neurodegenerative disorders | TOMM40 | It showed intriguing linkage disequilibrium with the ε4 allele and was strongly associated with the risk for developing late onset AD. | − |
| Roses et al., 2009 [78] | 191 AD and 131 HC (mean age: about 75 years) | TOMM40 | Individuals with long poly-T repeats linked to APOE ε3 develop late onset AD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ε3. | It is possible that the rs10524523 polymorphism, alone or in conjunction with other single-nucleotide polymorphisms in TOMM40, acts at a distance to affect transcription of APOE. |
| Johnson et al., 2011 [80] | 117 healthy APOE ε3 homozygous adults (mean age: about 55 years) | TOMM40 | Those who were homozygous for very long poly-T lengths had poorer memory than those who were homozygous for short poly-T length in APOE ε3/3. | − |
| Yu et al., 2017 [81] | 1151 old people (mean age: about 78.5 years) | TOMM40 | It revealed an association of APOE ε3/3-TOMM40′523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory. | The TOMM40 variant is implicated in affecting the level of neurofilament light proteins in cerebrospinal fluid. |
| Louwersheimer et al., 2017 [82] | A family with 9 AD patients spanning 4 generations, with an inheritance pattern suggestive of autosomal dominant | SORL1 | All four affected family members carried a rare variant in the vacuolar protein sorting domain 10 domain of the SORL1 gene, associated with Aβ protein precursor processing and AD risk. | A combination of homozygous or heterozygous APOEε4 and dysfunctional SORL1 may lead to abnormal increases in extracellular Aβ loads. |
| Barral et al., 2012 [83] | 1365 subjects in the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study | CR1, BIN1, CLU, PICALM | Several genotype patterns influenced episodic memory performance. | − |
| Gharesouran et al., 2014 [84] | 160 patients with late-onset AD and in 163 HC | PICALM, BIN1 | The associations with PICALM and BIN1 were only significant among subjects without the APOE ε4 allele. | − |
| Keenan et al., 2012 [85] | 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project | CR1 | A significant interaction between our candidate functional variant rs4844609 and the presence or absence of APOE ε4 on episodic memory decline. | − |
| Liao et al., 2014 [86] | 536 AD cases and 307 cognitive-intact elder controls | ABCA7 | The influence of ABCA7 was only evident in individuals without APOE ε4 alleles but absent in ε4 carriers. | − |
| Casati et al., 2018 [87] | 57 MCI, 50 AD, and 42 non-demented healthy subjects (mean age: about 78.5 years) | TREM2 | Higher TREM2 levels in allele ε4 of apolipoprotein E carriers than non-carriers in MCI and particularly in MCI-AD. | The upregulation of TREM2 could be a mechanism to counteract neuroinflammatory processes in MCI patients who progress to AD. |
| Espeseth et al., 2006 [157] | 230 healthy middle-aged (53–64 years) and older (65–75 years) adults | CHRNA4 | APOE-ε4 carriers who were also CHRNA4 TT homozygotes showed disproportionately slowed reaction time (RT) following invalid location cues. There was also a trend for individuals with combined APOE-ε4/CHRNA4 TT genotypes to show both lower white-matter volume and slower overall RT on the attention task. | It remains for further research to determine which of several underlying mechanisms—acetylcholine synthesis, cholinergic neuronal metabolism, synaptic availability of acetylcholine, the affinity of cholinergic receptors, or other factors—are responsible for the interactive effects of APOE and CHRNA4 on attention. |
| Morgen et al., 2014 [158] | 165 patients with early AD dementia | PICALM | There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on volume in prefrontal and performance on the Trail Making Test. | The APOE and PICALM risk genotypes may contribute to Aβ accumulation through different mechanisms, ultimately leading to synaptic dysfunction and loss. |
| Thambisetty et al., 2013 [159] | 57 non-demented older individuals (mean age: about 78.5 years) and 22 cognitively normal older individuals (mean age: about 77.1 years) | CR1 | Carrying a risk allele of the CR1 rs3818361 results in a reduced brain amyloid burden compared to non-carriers, but only in ε4 non-carriers. | The CR1 risk allele might modify the relationship between APOE genotype and brain amyloid deposition. |
| Liu et al., 2018 [160] | 710 individuals (mean age: about 65 years) | SPON1 | Significant SPON1 × APOE genotype interactions in working memory and executive function performances. The effects of ε4 allele on activation of right inferior frontal gyrus, triangular part were modulated by rs2618516 in a working memory task. | − |
| Shen et al., 2017 [161] | 287 healthy, young, right-handed subjects (mean age: 22.7 ± 2.4 years, ranging from 18 to 29 years) | SORL1 | Significant SORL1 × APOE non-additive interaction was found in negative resting state functional connectivity (rsFC) between the hippocampus and inferior frontal gyrus. Compared with subjects with TT genotype, SORL1 G-allele carriers had a stronger negative rsFC in APOE ε4 carriers, but a weaker negative rsFC in APOE non-ε4 carriers. | − |
| Zhang et al., 2017 [162] | 267 healthy young adults (mean age: about 22.8 years) | KIBRA | Epistatic effects showed APOE × KIBRA interaction in the functional connectivity density (FCD) of the dorsolateral prefrontal cortex (DLPFC). The FCD of the DLPFC showed APOE risk-allele-dependent reduction (ε2 > ε3 > ε4) in KIBRA TT homozygotes, but APOE risk-allele-dependent increase in KIBRA C-carriers. | One candidate explanation for the complex APOE–KIBRA interactions on brain FCD may be the differential effects of genetic variations in APOE and KIBRA on the long-term potentiation of memory-related brain regions. |
| Porter et al., 2018 [163] | 602 CN adults | KIBRA | In comparison to APOE ε4- individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline, and hippocampal atrophy were observed in individuals who were APOE ε4+ and did not carry the rs17070145-T allele. | Synaptic plasticity, which is altered in AD, is modulated by dendrin, which in turn binds to the protein that KIBRA encodes. |
HC, healthy control; CN, cognitive normal; MCI, mild cognitive impairment; AD, Alzheimer’s disease.