Deciphering the role of APOE in cerebral amyloid angiopathy: from genetic insights to therapeutic horizons

Abstract

Cerebral amyloid angiopathy (CAA), characterized by the deposition of amyloid-β (Aβ) peptides in the walls of medium and small vessels of the brain and leptomeninges, is a major cause of lobar hemorrhage in elderly individuals. Among the genetic risk factors for CAA that continue to be recognized, the apolipoprotein E (APOE) gene is the most significant and prevalent, as its variants have been implicated in more than half of all patients with CAA. While the presence of the APOE ε4 allele markedly increases the risk of CAA, the ε2 allele confers a protective effect relative to the common ε3 allele. These allelic variants encode three APOE isoforms that differ at two amino acid positions. The primary physiological role of APOE is to mediate lipid transport in the brain and periphery; however, it has also been shown to be involved in a wide array of biological functions, particularly those involving Aβ, in which it plays a known role in processing, production, aggregation, and clearance. The challenges posed by the reliance on postmortem histological analyses and the current absence of an effective intervention underscore the urgency for innovative APOE-targeted strategies for diagnosing CAA. This review not only deepens our understanding of the impact of APOE on the pathogenesis of CAA but can also help guide the exploration of targeted therapies, inspiring further research into the therapeutic potential of APOE.

Keywords: Cerebral amyloid angiopathy; amyloid β; apolipoprotein E; diagnosis; pathology; therapy.

Figure 1.

Mechanisms underlying Aβ fibril formation, aggregation, and APOE-mediated clearance in cerebral amyloid pathology. Aβ protein precursors generated in brain tissues polymerize to form Aβ, a process influenced by APOE. Aβ42 was the first peptide to be ‘seeded’ in brain tissues and blood vessel walls. Under the effects of APOE, Aβ40 aggregation and deposition processes are completed; Aβ40 gradually replaces Aβ42, ultimately causing structural damage to tissues. In the process of clearing Aβ, soluble Aβ can be directly degraded by extracellular proteases with the aid of APOE. In addition, Aβ can also form complexes with APOE and be cleared through the following pathways: (1) Through the perivascular and glial lymphatic system, which is composed of the brain interstitial space, astrocytes and microglia, Aβ is transported from the arterial side to the venous side and finally drained into venous blood vessels for clearance; this process is suppressed by APOE ε4. (2) Aβ is cleared through the drainage function of the IPAD pathway; the APOE ε4 genotype slows this clearance process, while APOE also participates in the drainage of nonfibrillar Aβ. (3) With the assistance of APOE, the complexes are absorbed by astrocytes and microglia through cell surface recognition receptors such as LRP-1 or are cleared into blood vessels and their anastomoses, which is jointly promoted by APOE and HDL. The clearance of APOE4–Aβ complexes is the slowest among the APOE subtypes. Abbreviations: Aβ: Amyloid β; APOE: Apolipoprotein E; AQP-4: Aquaporin-4; CSF: Cerebrospinal Fluid; CVSMCs: Cerebral Vascular Smooth Muscle Cells; HDL: High-Density Lipoprotein; IPAD: Intramedullary Periarterial Drainage; LRP-1: Low-density lipoprotein Receptor-related Protein-1

Figure 2.

Pathways for treating CAA by improving Aβ clearance. Current research on Aβ clearance includes the following directions: (1) promoting the interference and decomposition functions of enzymes such as neprilysin and IDE to promote decomposition and weaken the toxic effects of Aβ; (2) using receptor antagonists such as simvastatin and lovastatin to regulate vascular receptors by upregulating the vascular receptor LRP-1 and other methods to promote the clearance of Aβ; (3) using vasoactive agents to activate blood vessels, enhance arterial pulsation, or target low-frequency oscillations in sleep or the vascular BMs to improve its drainage function, among others, to promote blood vessel-mediated Aβ clearance via peripheral pathways; and (4) using other strategies such as drugs that reduces Aβ deposits (e.g. Memantine) or bind soluble Aβ (e.g. tramiprostate) to promote Aβ clearance. Abbreviations: CAA: Cerebral Amyloid Angiopathy; Aβ: Amyloid β; APOE: Apolipoprotein E; BMs: Basement Membranes; HDL: High-Density Lipoprotein; LRP-1: Low-density lipoprotein Receptor-related Protein-1; NEP: Neprylisin; IDE: Insulin-Degradation Enzyme; IPAD: Intramural Periarterial Drainage