KAIST proposes a new dementia treatment strategy by repositioning molecules without changing their chemical composition
Peer-Reviewed Publication
In honor of Alzheimer's Awareness Month, we’re exploring the science and stories surrounding Alzheimer’s disease.
Updates every hour. Last Updated: 27-Jan-2026 14:11 ET (27-Jan-2026 19:11 GMT/UTC)
A multidisciplinary USC research team has identified new compounds that may target a key driver of brain inflammation linked to Alzheimer’s disease. Their research just published in the Nature publication npj Drug Discovery. The driver is an enzyme called “calcium-dependent phospholipase A2,” or cPLA2. The team discovered its role in brain inflammation by studying people who carry the APOE4 gene — the strongest genetic risk factor for Alzheimer’s disease. While many people who have the APOE4 gene don’t develop the disease, those with elevated levels of cPLA2 generally do. The problem is that cPLA2 is also essential for normal brain function, so any potential drug molecule would need to inhibit the enzyme’s activity without eliminating it. The molecular candidate would also need to be small enough to cross the blood brain barrier to be effective. Using large-scale computational screening, the team evaluated billions of potential molecules, prioritizing those predicted to be selective, brain-penetrant and active under biologically relevant conditions. A cPLA2 inhibitor that reduced pathological cPLA2 activation in human brain cells exposed to Alzheimer’s-related stressors became the prime candidate. In mouse models, the inhibitor penetrated the blood-brain barrier and modulated neuroinflammatory pathways. The study suggests that inhibiting cPLA2 could be a promising therapeutic approach for neurodegenerative diseases.
As individuals with Alzheimer’s disease (AD) move from the mild cognitive impairment stage to moderate and severe dementia, complex awareness deteriorates although lower-level sensory awareness is relatively maintained. Most conscious processes also become more impaired as AD progresses, including attention, working memory, episodic memory and executive function, while unconscious processes, such as procedural or muscle memory, operant conditioning (behavior controlled by consequences), and priming (where the experience of stimulus affects the processing of a similar stimulus) are relatively spared. However, as damage spreads across different cortical regions in dementias such as AD, corresponding aspects of conscious awareness becomes diminished and then lost.
One measure of brain complexity, the perturbation complexity index-state transitions (PCI-ST), can be calculated by recording EEG signals following a transcranial magnetic stimulation pulse. This measure has previously been used to determine when people are in coma versus in a minimally conscious state. A new study asks whether this same measure could be used to evaluate the integrity of conscious processing in people with AD.
According to researchers from Boston University Chobanian & Avedisian School of Medicine, the answer is yes. They found that brain complexity in response to magnetic stimulation was reduced in people with AD compared with people aging normally.