New Approaches Target Underexplored Pathways in Alzheimer's Disease Research
Research initiatives are identifying novel therapeutic targets for Alzheimer's disease beyond traditional approaches, with focus on TREM2 agonists, metabolic interventions, and multi-omic data integration to diversify treatment strategies.
Despite extensive investments in Alzheimer's disease therapeutic development, progress toward effective interventions remains modest. The Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) consortium has integrated systems-level data from large-scale studies profiling thousands of human brains, yielding target-specific risk scores that partition disease risk into discrete biological domains. The consortium compared clinical trial targets with top-ranked TREAT-AD targets and found limited overlap as well as differences in the biology emphasized by each set.
The current Alzheimer's disease therapeutic development landscape remains largely under the "streetlight" of familiar biology, while unbiased measures of disease risk point toward other disease-associated processes that remain comparatively underexplored. Risk-associated targets uniquely implicate mitochondrial, lipid, and other pathways. Clinical AD trials remain focused on well-characterized biology, and advancing "dark" targets is critical to diversify AD therapeutic strategies.
TREM2 has generated considerable attention as a potential target for Alzheimer's disease. This receptor serves multiple roles on microglia, with numerous native ligands triggering a variety of signaling pathways and cellular processes, including those involved in the classic pathologies of AD. TREM2 is a transmembrane receptor expressed primarily on microglia in the CNS; its ligands include a variety of polyanionic lipoproteins that mediate a variety of functions including phagocytosis of Aβ.
Accumulation of extracellular Aβ plaques and seeding of intracellular hyperphosphorylated tau tangles, the two predominant pathologies of AD, are both impacted by TREM2 function. Critical to the pathogenesis of AD is the ability of TREM2 to recognize and bind Aβ oligomers and promote the phagocytosis of these malignant macromolecules. Levels of sTREM2 in the CSF of AD patients are elevated relative to healthy adults, and it has been hypothesized that CSF levels of sTREM2 could be implemented as a surrogate biomarker for the progression of AD.
Several TREM2 agonizing antibodies have entered human trials for AD, but thus far, none have demonstrated efficacy in the clinic. VG-3927, the first small molecule agonist of TREM2 to enter the clinic, successfully completed Phase 1 trials in 2025 and was the centerpiece of Sanofi's $470M acquisition of Vigil Neuroscience that same year. Patent activity around small molecule TREM2 agonists has been on the rise, with companies large and small filing on scaffolds that parallel Vigil's architectures.
A study on the multifactorial character of early AD discovered a group of 12 cerebrospinal fluid proteins capable of detecting disease with high accuracy before amyloid pathology appears. These proteins were shown to be largely involved in immunological function, as well as processes associated to dopamine biosynthesis, lysosomal activity, and lipid transport, suggesting intriguing new targets for early detection and therapeutic intervention.
Another proteomics investigation on dementia found five important proteins with predictive significance. Enrichment analysis indicated their participation in immune system pathways, cancer-related processes, and insulin signaling, providing insights into dementia's complex biological foundations and demonstrating proteomics' ability to find novel mechanisms and inform therapeutic strategies.
Given the accumulating evidence that traditional cardiovascular risk factors increase the likelihood of cognitive impairment and dementia, a new meta-analysis investigated how a diverse set of plasma proteins connected to cardiovascular health are associated with cognitive features. The findings identified similar connections between cardiovascular disease (CVD) and cognitive reserve or cognitive decline, indicating possible treatment targets to reduce CVD-linked genetic risk.
A phase II clinical experiment revealed additional insights into the multifactorial etiology of Alzheimer's disease, demonstrating that addressing metabolic imbalances enhanced cognitive performance. This expands on preclinical research in which mixed metabolic activators (CMA) increased mitochondrial fatty acid oxidation while decreasing oxidative stress, demonstrating their therapeutic potential.
A new large-scale proteomic investigation of Parkinson's disease found that blood-based lipid biomarkers are dysregulated up to 15 years before diagnosis, with consistent decreases and links to prodromal symptoms and brain abnormalities. These findings identify lipid metabolism as a potential early detection target. Another investigation of putative Parkinson's disease diagnostic indicators found elevated levels of inflammatory markers, particularly in cognitively impaired patients, indicating a change toward innate immune activation with time.
In a similar PD trial, CMA medication resulted in cognitive gains and positive shifts in metabolic indicators, despite no changes in motor symptoms. Proteomic and metabolomic results showed that CMA improved brain energy metabolism and neuronal function. Synaptogenesis, inflammation, membrane transport, DNA repair, and protection from oxidative damage and protein aggregation were all impacted.
A study found that several inflammatory proteins may contribute to the advancement of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Further investigation revealed that ALS may alter the levels of other immune-related proteins, indicating a potential bidirectional inflammation-disease interaction. These findings highlight ALS's complicated inflammation processes and potential treatment targets.