KAIST

<(Back row, from left) Professor Mi Hee Lim, Professor Mingeun Kim, Student Jimin Lee, Student Chanju Na, (Upper Right) Dr. Chul-Ho Lee, Dr Kyoung-Shim Kim> 

Conventional treatments of Alzheimer’s disease, one of the most common forms of dementia, have been largely focused on targeting individual pathological features. However, Alzheimer’s disease is a multifactorial disorder driven by multiple, tightly interconnected processes, rendering single-target therapeutic approaches inherently limited. Addressing this challenge, KAIST researchers propose a new strategy that enables the simultaneous regulation of multiple disease-inducing factors simply by rearranging the structural positions of drug candidate molecules without altering their chemical substituents.

KAIST (President Kwang Hyung Lee) announced on January 22 that a research team led by Professor Mi Hee Lim of the Department of Chemistry, in collaboration with Professor Mingeun Kim of Chonnam National University, Dr. Chul-Ho Lee of the Korea Research Institute of Bioscience and Biotechnology (KRIBB), and Dr. Kyoung-Shim Kim of the Laboratory Animal Resource Center, has elucidated at the molecular level how subtle differences in molecular arrangement, specifically positional isomerism, give rise to distinct modes of action against Alzheimer’s disease.

Using an Alzheimer’s disease mouse model (APP/PS1) harboring human dementia-associated genes, the research team demonstrated that these compounds also exert distinct therapeutic effects in vivo.

Alzheimer’s disease does not arise from a single cause. Rather, multiple pathological factors, including amyloid-b, metal ions, and reactive oxygen species, interact synergistically to exacerbate disease progression. In particular, metal ions bind to amyloid-b, modulating its aggregation and toxicity while promoting the generation of reactive oxygen species, which in turn accelerates neuronal damage. Effective control of Alzheimer’s disease therefore requires therapeutic strategies capable of simultaneously targeting multiple interrelated pathological processes.

< Alzheimer’s Disease – Chemical Approach Illustration (AI-generated image) >

The researchers focused on positional isomers, molecules composed of the same chemical elements but differing only in the positions at which those elements are connected. Remarkably, simple changes in molecular positioning resulted in pronounced differences in reactivity towards reactive oxygen species, as well as in interactions with amyloid-b and metal-bound amyloid-b.

To investigate these effects, the team compared the reactivities of three structurally similar molecules differing only in the positions of their functional groups. Their analyses revealed that even minimal structural rearrangements led to significant differences in antioxidant capacity and produced distinct modes of modulation of amyloid-b and metal-bound amyloid-b through different mechanisms, inducing peptide chemical modifications.

In other words, the study demonstrated that Alzheimer’s disease-related pathological factors can be regulated through mechanistically distinct pathways simply by altering molecular arrangement, without changing molecular composition.

Notably, a specific positional isomer capable of simultaneously modulating reactive oxygen species, amyloid-b, and metal-bound amyloid-b complexes also demonstrated therapeutic efficacy in an Alzheimer’s disease mouse model. In these experiments, the compound reduced oxidative stress in the hippocampus, the brain region critical for memory, and decreased amyloid plaque accumulation, resulting in significant improvements in memory deficits and cognitive impairment.

< In Vivo Efficacy Evaluation and Biological Outcomes According to Positional Isomers of Small-Molecule Compounds >

Professor Mi Hee Lim of KAIST stated, “This study demonstrates that multiple pathological factors associated with Alzheimer’s disease can be targeted simultaneously simply by adjusting molecular positioning, without altering the molecule’s core chemical framework.” She added, “These findings point to a new therapeutic strategy that may enable more precise control of complex, multifactorial diseases such as Alzheimer’s disease.”

This research was conducted with Chanju Na and Jimin Lee, integrated master’s-doctoral students in the Department of Chemistry at KAIST, who served as co-first authors. The results were published in the Journal of the American Chemical Society (Impact Factor: 15.7, top 5.0% in Chemistry) in Issue 1 dated January 14, 2026.

※ Paper title: “Positional Isomerism Tunes Molecular Reactivities and Mechanisms toward Pathological Targets in Dementia”

※ DOI: 10.1021/jacs.5c14323

This study was supported by the National Research Foundation (NRF) of Korea through the Basic Research Program (Creative Research Initiative and Global Science Research Center), the NRF Sejong Science Fellowship, the NRF Ph.D. Followship, and KRIBB Institutional Funding.