Brain pathologies: CAA and amyloid-beta deposition

Among the brain pathologies, the most consistent and well-supported association between APOE genotype and pathology was observed in CAA, particularly in the context of ICH. CAA is characterized by the progressive deposition of Aβ, particularly the Aβ₄₀ isoform, within the walls of small and medium-sized blood vessels in the cerebral cortex and leptomeninges. ^{Reference Hu, Wan, Hu, Wang, Li and Zhang51–Reference Cozza, Amadori and Boccardi53} This vascular deposition compromises vessel integrity, which increases the risk of hemorrhage, specifically in lobar regions. ^{Reference Smith and Greenberg SM54,Reference Gatti, Tinelli and Scelzo55} One of the key biological functions of APOE is Aβ aggregation and clearance. ^{Reference Wisniewski and Drummond56} Aβ is cleared from the brain through multiple mechanisms including transport across the blood-brain barrier, enzymatic degradation, uptake and degradation by glial cells, perivascular drainage and glymphatic system draining. ^{Reference Hu, Wan, Hu, Wang, Li and Zhang51,Reference Qi and Ma52} However, in the context of CAA, Aβ is predominantly cleared via the perivascular drainage pathway. ^{Reference Van Veluw, Benveniste and Bakker57} Although the exact mechanisms by which APOE influences Aβ accumulation are still under investigation, it has been suggested that isoform-specific differences in binding affinity play a key role. ^{Reference Qi and Ma52} The APOE ϵ4–Aβ complex binds weakly to basement membrane laminin in the perivasculature compared to the APOE ϵ3–Aβ complex. ^{Reference Qi and Ma52} This reduced binding may disrupt the normal Aβ clearance, causing impaired drainage, increased aggregation and ultimately the development of CAA pathology. ^{Reference Qi and Ma52}

Although most studies included in this review supported the conclusion that APOE may play a moderating role in CAA, thereby increasing the risk of ICH, this association was not universally found across the studies. Wan et al. reported that CAA was not a significant predictor of progressive hemorrhagic injury in patients aged 55 years or older. ^{Reference Wan, Gan and You26} While this discrepancy may be attributed to differences in demographic characteristics, it underscores the need for further investigation. Specifically, future studies are needed to definitively determine the role of CAA in ICH and other stroke subtypes and to clarify the mechanistic pathways through which APOE genotype influences the development of CAA.

Aβ is not only a hallmark of CAA pathology but may also play a role in CTE. Stein et al. reported a significant association between Aβ deposition and the APOE ϵ4 allele in patients with CTE. ^{Reference Stein, Montenigro and Alvarez41} Their findings indicated that Aβ accumulation correlated with more severe tau pathology, increased Lewy body accumulation and poorer clinical outcomes independent of age. ^{Reference Stein, Montenigro and Alvarez41} When comparing the CTE group to a normative aging cohort, the authors noted a distinct pattern of Aβ distribution, suggesting that repetitive TBI may not only accelerate normal aging but also alter the typical trajectory of Aβ pathology. ^{Reference Stein, Montenigro and Alvarez41} Although Jordan et al. did not discuss Aβ deposition in their cohort of CTBI (allegedly similar to CTE), they did observe that individuals carrying the APOE ϵ4 allele were more susceptible to developing CTBI. While the study by Stein et al. is the only one in this review to explicitly explore the relationship between Aβ and CTE, a recent review by Murray et al. provided additional insights on that association. The authors concluded that Aβ plaque pathology, while likely an age-related comorbidity, is frequently present in CTE and may contribute to disease progression. ^{Reference Murray, Osterman, Bell, Vinnell and Curtis58} Although the mechanisms by which Aβ influences CTE pathology remain unclear, growing evidence suggests that APOE genotype plays a critical role in modulating Aβ deposition across multiple neurodegenerative and cerebrovascular conditions including CAA, Alzheimer’s disease and potentially CTE.

Apolipoprotein E and alternative genetic and molecular mechanisms

In addition to its role in Aβ deposition, APOE appears to be involved in other genetic mechanisms, particularly in the context of cerebral concussion, where a negative association with APOE was consistently reported. ^{Reference Dretsch, Silverberg and Gardner33–Reference Tierney, Mansell and Higgins37} However, other studies explored the relationship between APOE and other genetic mechanisms. Tierney et al. and Terrell et al. reported a significant association between the APOE G-291T promoter polymorphism and the risk of concussion. ^{Reference Terrell, Bostick and Abramson36,Reference Tierney, Mansell and Higgins37} Specifically, carriers of the ϵ2 or ϵ4 alleles in combination with the T allele in the APOE G-291T promoter were more likely to experience two or more cerebral concussions. ^{Reference Tierney, Mansell and Higgins37} This finding suggests that the interaction between APOE genotype and the G-291T polymorphism might influence the risk for cerebral concussion. ^{Reference Tierney, Mansell and Higgins37} In addition, Terrell et al. identified that the presence of the T allele in the APOE G-291T promoter was associated with increased cerebral concussion severity. ^{Reference Terrell, Bostick and Abramson36} This implies that the genetic variation within the APOE promoter could potentially impact not only the likelihood of the occurrence of cerebral concussion but also its severity. ^{Reference Terrell, Bostick and Abramson36}

The involvement of non-coding regulatory regions in the APOE gene modulating the risk for neurological injury or disease is further supported by findings from Kaushal et al., who found no association between APOE genotype and aSAH but reported a potential link between aSAH and the 5′-untranslated region of the APOE gene. ^{Reference Kaushal, Woo and Pal30} Although the pathologies of cerebral concussion and aSAH differ, these studies suggest that variation in APOE regulatory regions, rather than coding variants, may play a role in neurological injury or disease risk. ^{Reference Kaushal, Woo and Pal30,Reference Terrell, Bostick and Abramson36,Reference Tierney, Mansell and Higgins37} However, further research is needed to confirm this potential association.

Another alternative mechanism for APOE’s impact on aSAH is proposed by Liu et al., who reported that decreased plasma total cholesterol, high-density lipoprotein cholesterol (HDL) and APOA1 are linked to a higher risk of aSAH. ^{Reference Liu, Zhan, Wu, Wang, Yang and Ou31} The study proposed that these lipid markers may contribute to endothelial weakening of intracerebral arteries, thus increasing the risk of aneurysm rupture and ICH. ^{Reference Liu, Zhan, Wu, Wang, Yang and Ou31} However, additional research is needed to further elucidate the role of these lipid markers in the risk of aSAH and other nervous system diseases or injuries.

Spine pathologies

Both studies included in this review identified a positive association between DCM and the APOE gene; however, they differed in terms of which genotypes were implicated. Diptiranjan et al. documented that the APOE ϵ2 was a potential risk factor for DCM, ^{Reference Diptiranjan, Harshitha, Sibin, Arati, Chetan and Bhat6} and Setzer et al. reported that the APOE ϵ4 allele was associated with DCM. ^{Reference Setzer, Hermann, Seifert and Marquardt7} Although both studies found a link between APOE and DCM, the underlying mechanism by which APOE may contribute to increased risk remains unclear. Desimone et al. explored the role of APOE in postoperative recovery following decompression surgery for DCM, ^{Reference Desimone, Hong, Brockie, Yu, Laliberte and Fehlings59} but the reasons why APOE might contribute to the increased risk of developing DCM have not been extensively studied. The current understanding of the pathophysiology of DCM includes a vascular hypothesis where impaired spinal cord perfusion could result in the development of DCM in individuals with spinal cord compression. ^{Reference Badhiwala, Ahuja and Akbar60} In addition, blood–spinal cord barrier disruption leading to neuroinflammation and apoptosis has been considered as part of the pathophysiology of DCM. ^{Reference Badhiwala, Ahuja and Akbar60} Because APOE contributes to synaptogenesis, Aβ clearance and maintenance of the blood-brain barrier, one may speculate that APOE genotypes could be involved in changes in the structure and/or function of small vessels affecting spinal cord perfusion and/or blood–spinal cord barrier disruption. ^{Reference Yamazaki, Zhao, Caulfield, Liu and Bu2–Reference Setzer, Hermann, Seifert and Marquardt7} More specifically, the ϵ4 allele has been implicated in adverse lipid profiles and vascular diseases such as coronary artery disease. ^{Reference Lumsden, Mulugeta, Zhou and Hyppönen16} While a single ϵ2 allele has been considered a protective rare variant, prior studies reported the association of the APOE ϵ2/ϵ2 genotype with type III hyperlipoproteinemia, leading to atherosclerosis that increases the risk for the development of cardiovascular and peripheral vascular diseases. ^{Reference Lumsden, Mulugeta, Zhou and Hyppönen16} Nevertheless, this represents an important gap in the literature, especially given that DCM is the most common cause of nontraumatic spinal cord injury in adults. ^{Reference Nouri, Cheng, Davies, Kotter, Schaller and Tessitore61}

Diseases of the peripheral nervous system

While Zhou et al. reported that APOE ϵ4 was not a risk factor for sensory predominant neuropathy, they found an apparently lower distal leg epidermal nerve fiber density among ϵ4 carriers (p = 0.08). ^{Reference Zhou, Hoke, Cornblath, Griffin and Polydefkis50} This disparity may be attributed to the insensitivity of their chosen outcome measure, the Neuropathy Impairment Score, in detecting small fiber dysfunction. ^{Reference Zhou, Hoke, Cornblath, Griffin and Polydefkis50} Similarly, Satoh et al. did not find a correlation between APOE genotype and the development of familial amyloid polyneuropathy. ^{Reference Satoh, Tokuda and Ikeda49} Bekenova et al. also found no association between cardiac autonomic neuropathy and APOE genotype, even though patients with cardiac autonomic neuropathy had reduced HDL concentrations. ^{Reference Bekenova, Aitkaliyev, Vochshenkova, Kassiyeva and Benberin47} HDL levels may be influenced by lecithin cholesterol acyltransferase, an enzyme essential for reverse cholesterol transport that esterifies free cholesterol within HDL particles. ^{Reference Bekenova, Aitkaliyev, Vochshenkova, Kassiyeva and Benberin47,Reference Manthei, Patra and Wilson62} The results of experimental studies using mouse models suggested that APOE may play a role in activating lecithin cholesterol acyltransferase, which could ultimately influence HDL levels and contribute to the risk of cardiac autonomic neuropathy. ^{Reference Bekenova, Aitkaliyev, Vochshenkova, Kassiyeva and Benberin47,Reference Amaya-Montoya, Pinzón-Cortés and Silva-Bermúdez63}

On the other hand, Chou et al. documented that APOE ϵ4 and the ϵ3/ϵ4 genotype served as a susceptibility gene for nonarteritic anterior ischemic optic neuropathy. In addition, the authors found no association between APOE genotype and various comorbidities including hypertension, hyperlipidemia and diabetes, but this negative result could be attributed to a small sample size and warrants further investigation. ^{Reference Chou, Sun and Wang48}

Overall, the role of APOE in the injuries and diseases involving the peripheral nervous system represents a significant gap in the literature, as most existing research has focused on central nervous system (CNS)-related diseases or injuries. Further investigations are needed to clarify the contribution of APOE to the risk of peripheral nervous system conditions.

Study limitations

Although this systematic review is focused on the clinically relevant but relatively understudied role of APOE on the risk of injuries and diseases involving the nervous system beyond Alzheimer’s disease and other brain degenerative diseases, there are certain limitations that should be considered when interpreting and applying the results. Given the extensive body of literature on the relationship between APOE and dementias, our search strategy needed to strike a balance between being broad enough to capture relevant studies and specific enough to exclude research focused solely on APOE and dementias. In aiming to keep the screening process manageable, the search may have been overly restrictive, potentially resulting in the omission of some articles that would have otherwise met the inclusion criteria. Furthermore, many studies included relatively small sample sizes of participants, which represent a substantial risk for type II error in the data analyses. Finally, the studies captured in this systematic review analyzed the association between APOE and central and peripheral nervous system injuries or diseases beyond dementias, and hence, one cannot conclude a cause-and-effect relationship.