The Road to a Cure for Alzheimer's

Stanford Medicine’s “Rethinking Alzheimer’s” series highlights a shift away from viewing Alzheimer’s solely through the lens of amyloid plaque buildup and toward a more comprehensive understanding rooted in genetics, immunity, and metabolism. For decades, scientists focused on A-beta plaques that gather between neurons, assuming they were responsible for memory loss, yet clearing these plaques did little to help patients. This failure pushed researchers to explore deeper causes, including the APOE gene, especially the APOE4 variant carried by about one-fifth of the population and strongly linked to early-onset Alzheimer’s. APOE’s role in transporting fats throughout the brain and body has become central to rethinking how the disease develops and why APOE4 may increase risk more than the other three known versions of the gene.
The series also explains why “plaque-attack” treatments fall short by shifting attention to neurofibrillary tangles, which form inside neurons and strongly contribute to their degeneration. These tangles are made from tau, a protein normally responsible for stabilizing the cell’s internal structure, but chemical changes can cause it to clump into harmful aggregates. A key finding is that individuals carrying the HLA-DR4 variant may naturally block tau clumping because DR4 binds to specific modified regions of tau, opening the door to immune-based therapies that mimic this protective effect. At the same time, aging-related inflammation emerges as another driving factor. Macrophages in the body become more reactive with age, producing chronic inflammation that, according to Stanford neuroscientist Kati Andreasson, “fuels brain aging in general and Alzheimer’s in particular.” Her team found that high levels of the inflammatory molecule TREM1 increase Alzheimer’s risk, and in mice, removing TREM1 from macrophages protected cognition without reducing amyloid plaques, meaning changes in the body’s immune system can influence the brain.

The final article expands this immune-metabolic view by identifying a third major hallmark of Alzheimer’s: the accumulation of lipid droplets, or tiny balls of fat, inside microglia, the brain’s resident immune cells. These droplets were largely overlooked in older autopsy samples because standard preparation methods washed away most lipids. Microglia, which make up roughly 15% of brain cells, normally clear pathogens and support neuron health, but with age, and especially in individuals carrying APOE4, they begin to store excess fat and become more inflammatory. Stanford researchers found that microglia overloaded with lipid droplets were linked to more severe amyloid and tau pathology and worse cognitive outcomes, suggesting this fat buildup plays an active role in neuro degeneration. Together, these findings connect genetic risk (APOE4), tau toxicity, and immune dysfunction with altered lipid metabolism, offering a more integrated, and promising, direction for future Alzheimer’s treatments.

Linked below is a pdf of a more extensive analysis of the four articles included in the studies, it was much too long for a blog post but I found a lot of information through these articles.

The Road to a Cure for Alzheimer's pdf

Sources: 

Goldman, Bruce. “Rethinking Alzheimer’s: Why This Common Gene Variant Is Bad for Your Brain.” News Center, 25 Sept. 2025, med.stanford.edu/news/insights/2025/09/rethinking-alzheimers-gene-variant-apoe4.html. 

Goldman, Bruce. “Rethinking Alzheimer’s: Untangling the Sticky Truth about Tau.” News Center, 23 Sept. 2025, med.stanford.edu/news/insights/2025/09/rethinking-alzheimers-tau-protein.html.

Goldman, Bruce. “Rethinking Alzheimer’s: Could It Begin Outside the Brain?” News Center, 24 Sept. 2025, med.stanford.edu/news/insights/2025/09/rethinking-alzheimers-outside-brain-macrophages.html.

Goldman, Bruce. “Rethinking Alzheimer’s: How These Tiny Balls of Fat Factor In.” News Center, 25 Sept. 2025, med.stanford.edu/news/insights/2025/09/rethinking-alzheimers-tiny-balls-fat-microglia.html.