When fats go wrong: how lipid metabolism drives Alzheimer’s disease

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is rapidly becoming one of the defining health challenges of an aging world. Characterized by memory loss, cognitive decline, and behavioral changes, it affects tens of millions globally. Despite years of targeting amyloid-β (Aβ) and tau proteins directly, most treatments have failed to halt the disease. Meanwhile, the brain—half of its dry weight made of lipids—has a unique, tightly regulated lipid metabolism. Even slight disruptions can trigger cascading damage. Genetic and molecular studies now tie lipid-related genes, particularly APOE, to higher AD risk. Due to these challenges, it is vital to investigate lipid metabolism’s role in AD onset and progression.

A team from China Pharmaceutical University has brought lipid metabolism to the forefront of Alzheimer’s research in a review (DOI: 10.26599/AGR.2025.9340037) published April 30, 2025, in Aging Research. They describe how cholesterol handling, fatty acid storage, and lipid clearance—processes often overlooked in neurodegeneration—can directly influence hallmark AD features: Aβ buildup, tau spread, synaptic breakdown, and chronic inflammation. By weaving together findings from genetics, biochemistry, and cell biology, the review frames lipid metabolism not as a background process, but as a central stage for future Alzheimer’s therapies.

The review maps four critical intersections where lipid metabolism shapes Alzheimer’s pathology. Disruptions in cholesterol handling and fatty acid balance can impair the brain’s ability to break down Aβ, while promoting plaque formation. Key players such as ABCA7 and the immune receptor TREM2 regulate cholesterol transport in microglia, influencing Aβ clearance, and different APOE isoforms vary in their efficiency—APOE4 being linked to heavier plaque burdens. Lipid imbalances also drive tau seeding and spreading: cholesterol esters and lipid droplet accumulation in neurons and glia can increase tau phosphorylation and aggregation, with astrocytic APOE4 particularly potent in elevating neuronal p-tau levels. Synaptic health, dependent on astrocyte-supplied cholesterol, suffers when regulators like SREBP and ATAD3A are dysregulated, leading to reduced synaptic protein production, weakened neurotransmission, and diminished plasticity. Furthermore, neuroinflammation is fueled when lipid metabolism falters, as imbalances can weaken the blood–brain barrier, activate glial cells, and trigger inflammatory cascades through complement proteins (C3) and oxysterols (25-HC). In APOE4 carriers, specific APOE–Aβ aggregates amplify these inflammatory signals. Collectively, the evidence positions lipid homeostasis as a master switch in AD, capable of influencing toxic protein buildup, synaptic resilience, and immune activation simultaneously.

“Alzheimer’s is often portrayed as a battle between proteins, but our work reveals the silent influence of lipids,” said lead author Jienian Zhang. “Lipid metabolism doesn’t just accompany the disease—it actively shapes its trajectory, from plaque formation to synapse loss. By targeting how the brain handles fats, we may open the door to therapies that strike at several disease pathways simultaneously. This could redefine how we think about preventing and treating Alzheimer’s.”

By reframing lipid metabolism as a core driver of Alzheimer’s, the review opens new therapeutic possibilities. Future treatments might boost microglial lipid clearance, stabilize cholesterol transport, or fine-tune fatty acid storage—all with the aim of reducing toxic protein buildup, protecting synapses, and calming harmful inflammation in one sweep. Advances in lipidomics and neuron–glia interaction models will accelerate this work, while genetically engineered systems that mimic human risk factors like APOE4 could refine drug testing. Cracking the brain’s “lipid code” may ultimately yield multi-target therapies that succeed where single-focus approaches have failed.

About Aging Research

Aging Research is an Open Access publication addressing the biology and medicine issues of aging and aging-related diseases. Aging Research publishes original research results that are of unusual significance or broad conceptual or technical advances in all areas of aging, longevity and aging related health issues. The journal focuses on the following research: to explore the process, mechanism, biomarkers, anti-aging strategies or drugs at the population, individual, system, organ, tissue, cell and subcellular levels; to study the epidemiological characteristics, pathogenesis, pathophysiological processes, diagnostic criteria, clinical experiments and translational research of age-related diseases.