Journal of lipid researchAug 6, 2025

How fat processing in brain immune cells relates to Alzheimer's disease and possible treatments

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

Alzheimer's disease is characterized by significant alterations in lipid composition, including reductions in phospholipids and sulfatides and increases in cholesterol and triglycerides.

Altered lipid metabolism in Alzheimer's disease may be linked to microglial dysfunction and the accumulation of pathological markers such as amyloid-beta and tau.
Genetic variants related to microglial lipid processing have been identified as strong risk factors for Alzheimer's disease.
Microglia exhibit dysfunction through lipid droplet accumulation and increased levels of cholesterol and triglycerides.
Strategies that inhibit lipid droplet accumulation and promote lipoprotein receptor activity in microglia may improve cellular functions and reduce Alzheimer's pathology.
The review highlights the potential of targeting microglial lipid metabolism for novel therapeutic interventions in Alzheimer's disease.

Simplified

Alzheimer's disease (AD) presents a significant challenge owing to its widespread prevalence and complex neuropathogenesis, affecting millions worldwide. Current therapeutic strategies that predominantly target amyloid-beta accumulation are insufficient, particularly for ApoE4 carriers. Alterations in lipid composition are well documented in AD, characterized by reductions in phospholipids and sulfatides, along with increases in cholesterol, cholesteryl esters, and triglycerides (TGs). Microglia, the brain's resident immune cells, link dysfunctional lipid processing to AD neuropathogenesis. For example, genetic studies have pointed to microglial lipid and lipoprotein processing gene variants as some of the strongest risk factors for AD. In addition, microglial dysfunction, characterized by lipid droplet accumulation, increased cholesterol and TG levels, and altered lipid transport, may exacerbate the pathological hallmarks of AD, such as amyloid-beta and tau accumulation. Conversely, emerging studies have shown that strategies aimed at inhibiting lipid droplet accumulation in microglia, reducing TG synthesis, and promoting the activity of lipoprotein receptors expressed by microglia can improve cell functions and markers of AD pathology. This review dissects the interplay between microglial lipid metabolism and AD, highlighting the significance of lipid transport and trafficking within the CNS. Given the intrinsic link between microglial metabolism and AD progression, emerging and potential therapeutic strategies aimed at restoring lipid handling and improving microglial function are explored. This review provides a comprehensive examination of the emerging literature, detailing the current state of knowledge on microglial lipid metabolism, its genetic underpinnings, and the potential for novel interventions targeting these mechanisms to ameliorate AD pathology.

Full Text

We can’t show the full text here under this license.

View Full Text ↗

Funding

Competing interests

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

PubMed

How fat processing in brain immune cells relates to Alzheimer's disease and possible treatments

Abstract

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief