We utilize chemical biology to understand and modulate Alzheimer's disease. 

Alzheimer's Disease

Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disorder characterized by progressive memory loss combined with cognitive impairment. Abnormal accumulation of amyloid-β (Aβ) in the brain has been theorized to be a primary cause of AD pathogenesis since the amyloid hypothesis was formulated. Aβ is generated from the amyloid precursor protein (APP) through sequential cleavages by β-secretase followed by the γ-secretase complexes, and the amyloidogenic aggregation of Aβ leads to synaptic dysfunction, tau tangle formation, and neuronal loss in affected brain regions. Since Aβ accumulation in the brain is the earliest and critical event in AD, it has been utilized as a reliable diagnostic biomarker for AD and as a potential therapeutic target. 

Drug Discovery for AD

The current trend of AD drug discovery is heavily concentrated around immunotherapy proven by the significant difference in therapeutic candidates that advance to clinical trials. While chemical drug candidates rarely proceeded to phase III clinical trials lately, the number of immunotherapeutic drug candidates in phase III clinical trials was maintained throughout. Moreover, several immunotherapy drugs have recently received clinical approvals for AD treatment. Nonetheless, we suggest that chemical drugs should and can be developed intensively in parallel to immunotherapy as they have prominent advantages such as administration route, blood-brain barrier (BBB) permeability, structural stability, and cost.

Chemical drugs can be administered orally in general while injection or parenteral administration is used for most immunotherapies. Given that drugs targeting the central nervous system (CNS) generally have a low molecular weight to penetrate the BBB, small molecules are easily optimized by altering their chemical structure to meet 0.3–0.5 brain-to-plasma ratio, a sufficient value for transport into the brain. Compared to immunotherapy, chemical drugs exhibit superior structural stability, contributing to their longer shelf-life under various conditions of temperature, humidity, and acidity. Moreover, low production cost is one of the leading advantages of chemical drugs, as the AD patient demographic is concentrated on the retired elderly who are not financially stable to receive long-term administration.

Diagnostic Tool Development for AD

Deposition of amyloid-β (Aβ) is a key sign of Alzheimer's disease (AD). In the brain of AD patients, Aβ monomers are released from amyloid precursor protein by abnormal enzymatic cleavages and aggregate into neurotoxic soluble oligomers and insoluble plaques, which are the pathological processes leading to neurodegeneration. The alteration of Aβ levels in AD patients increased in the brain while concomitantly decreased in the cerebrospinal fluid (CSF) as the disease progresses, and Aβ can be detected by positron emission tomography (PET) and CSF tests. As Aβ deposition precedes the onset of AD symptoms by at least a decade, earlier diagnostic approaches, such as Aβ blood tests, are actively investigated, to screen at-risk subjects and patients in asymptomatic stages prior to radiotracer injection and lumbar puncture. However, Aβ blood tests suffer from two issues impeding the measurement and data interpretation: low concentration of Aβ in blood and unclear brain-blood correlation of Aβ. First, blood Aβ and its AD-related perturbation are found at pg mL−1 level, which is below the limit of detection (LOD) of conventional Aβ-targeting enzyme-linked immunosorbent assay (ELISA) kits. Secondly, it is unclear whether blood Aβ, and its concentration alterations during AD development, is mainly derived from the brain, the peripheral nervous systems, or both yet. Consequently, the manner in which blood Aβ concentration alters in AD patients and cognitively normal subjects vary depending on study sites; overall longitudinal changes of blood Aβ does not correlate with the increasing pattern of brain Aβ deposition nor the decreasing behavior of Aβ in CSF.