Emerging Alzheimer's disease therapeutics: promising insights from lipid metabolism and microglia-focused interventions

Abstract

More than 55 million people suffer from dementia, with this number projected to double every 20 years. In the United States, 1 in 3 aged individuals dies from Alzheimer's disease (AD) or another type of dementia and AD kills more individuals than breast cancer and prostate cancer combined. AD is a complex and multifactorial disease involving amyloid plaque and neurofibrillary tangle formation, glial cell dysfunction, and lipid droplet accumulation (among other pathologies), ultimately leading to neurodegeneration and neuronal death. Unfortunately, the current FDA-approved therapeutics do not reverse nor halt AD. While recently approved amyloid-targeting antibodies can slow AD progression to improve outcomes for some patients, they are associated with adverse side effects, may have a narrow therapeutic window, and are expensive. In this review, we evaluate current and emerging AD therapeutics in preclinical and clinical development and provide insight into emerging strategies that target brain lipid metabolism and microglial function - an approach that may synergistically target multiple mechanisms that drive AD neuropathogenesis. Overall, we evaluate whether these disease-modifying emerging therapeutics hold promise as interventions that may be able to reverse or halt AD progression.

Keywords: Alzheimer’s disease; amyloid; lipids; microglia; therapeutics.

Figure 1

Mechanism of action of Aducanumab, Lecanemab, and Donanemab. Aducanumab binds oligomeric and fibrillary amyloid aggregates, lecanemab binds soluble Aβ protofibrils, and donanemab binds N-terminally truncated pyroglutamate-modified Aβ (Aβ_pE), a type of Aβ only found in plaques in the brain and not in cerebrospinal fluid (CSF) nor plasma. Once each antibody binds its respective target, the Fc region of the antibody binds Fc gamma receptors (FCGRs) on phagocytes such as microglia and perivascular macrophages, which induces FCGR clustering, leading to FCGR-dependent phagocytosis, thereby enabling antibody clearance of Aβ from the brain. Information derived from Garapati (2012), Alawode et al. (2021), Lowe et al. (2021), Haddad et al. (2022), Söderberg et al. (2022), and van Dyck et al. (2023). Created with BioRender.com.

Figure 2

CT1812’s mechanism of action. The Aβ oligomer receptor complex consists of LilrB2 (leukocyte immunoglobulin-like receptor B2), the Nogo receptor, and PrP^C (cellular prion protein). The sigma-2 receptor complex consists of PGRMC1 (Progesterone Membrane Binding Component-1), the ligand binding site of the complex, TMEM97 (Transmembrane Protein 97), and the LDLR (Low-Density Lipoprotein Receptor). Aβ oligomers bind PrP^C on the oligomer receptor complex, which changes the function of the complex and increases the expression of the sigma-2 receptor complex. CT1812 binds PGRMC1, which allosterically regulates the sigma-2 receptor complex and destabilizes adjacent Aβ oligomer receptor binding sites, which stops Aβ oligomers from binding their receptors and allows for their eventual clearance into CSF. Figure adapted from Izzo et al. (2021). Information derived from Xu et al. (2011), Izzo et al. (2014a,, , Jarosz-Griffiths et al. (2016), Mroczko et al. (2018), and Riad et al. (2020). Created with BioRender.com.

Figure 3

ATV:TREM2 and AL002’s mechanism of action. Once each agonistic TREM2 antibody binds TREM2, the TREM2 signaling pathway is activated, which promotes microglial survival, function, proliferation, and phagocytosis of AD pathologies. Figure adapted from Alector, Inc (2021) and Shugart (2020). Information derived from Ward et al. (2021) and Shugart (2020). Created with BioRender.com.

Figure 4

CMS121’s mechanism of action. CMS121 has a variety of functions. It stops ROS (Reactive Oxygen Species) from peroxidizing PUFAs (Polyunsaturated Fatty Acids), which increases cell survival, decreases levels of the inflammatory markers 15LOX2 (a type of LOX enzyme) and GFAP (Glial Fibrillary Acidic Protein), prevents Aβ accumulation and subsequent aggregate formation, and inhibits FASN (Fatty Acid Synthase), which decreases fatty acid levels, thereby decreasing lipid peroxidation and LD (lipid droplet) accumulation in microglia. Information derived from Ates et al. (2020). Created with BioRender.com.

Figure 5

Summary figure. Agonistic TREM2 antibodies ATV:TREM2 and AL002 increase TREM2 signaling, sargramostim increases microglial proliferation, and CMS121 increases microglial function. These therapeutics collectively enhance microglial function and reduce AD pathology. Created with BioRender.com.