Kozlova A, Zhang S, Sudwarts A, Zhang H, Smirnou S, Byeon SK, Thapa C, Sun X, Stephenson K, Zhao X, Jamison B, Ponnusamy M, He X, Schneider JA, Pandey A, Bennett DA, Pang ZP, Sanders AR, Bellen HJ, Thinakaran G, Duan J. PICALM Alzheimer's risk allele causes aberrant lipid droplets in microglia. Nature. 2025 Sep 3; Epub 2025 Sep 3 PubMed.
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Vrije Universiteit Amsterdam
I’m very excited about the findings in this paper as they couple a genetic AD variant in an endocytic protein to changes in lipid metabolism. Overall, I find the results robust, and the IPSC gene-editing and rescue experiments very neatly done. The paper provides strong evidence that PICALM has a major role in lipid metabolism, which might be unexpected for a gene that primarily has been associated with regulation of the endocytic system. Combined with a novel way of defining risk variants, this is a very refreshing story.
The outcomes remind me of the publication by Priyanka Narayan, who, using completely different systems, yeast and induced astrocytes, found that PICALM overexpression can rescue detrimental ApoE4/4 effects (Naryan et al., 2020). While the mechanisms linking PICALM and lipid crosstalk need to be fleshed out, this paper contributes to a view of AD in which endosome-lipid interactions are key in shaping glial immune function and AD risk.
View all comments by Rik van der KantIcahn School of Medicine at Mount Sinai
Genome-wide association studies (GWAS) have identified dozens of common variants that modulate Alzheimer’s disease (AD) risk, but their mechanistic underpinnings are still only partially understood. In this elegant and comprehensive study, Kozlova and colleagues contribute to filling this gap by combining human genetics with functional genomics and experimental studies to reveal how a risk allele at the PICALM locus may modulate disease susceptibility.
Similar to prior work by our group and others, this study shows that risk alleles at AD GWAS loci can act not by altering protein sequence, but by tuning the expression of otherwise broadly expressed genes—such as the endolysosomal genes PICALM and BIN1—in a microglia-specific manner (Huang et al., 2017; Novikova et al., 2021; Nott et al., 2019). Here, the authors demonstrate that the rs10792832 risk allele reduces binding by the transcription factor, and AD risk gene, SPI1/PU.1, which in turn lowers PICALM expression, impairing microglial clearance of amyloid-β and myelin. This is accompanied by transcriptional activation of cholesterol biosynthesis genes, lipid droplet accumulation, and oxidative stress, tying PICALM to the dysfunctional lipid-droplet–accumulating microglia (LDAM) state previously described in aging and APOE4 carriers (Sep 2023 news; Jul 2025 news).
These findings reinforce a hypothesis we have recently proposed: that the three major pathways repeatedly implicated by AD GWAS—cholesterol metabolism, endocytosis/phagocytosis, and the innate immune response (Jones et al., 2010)—are not independent etiological processes, but rather components of a unitary pathogenic hub centered on efferocytosis (Romero-Molina et al., 2022). Efferocytosis is the process by which myeloid cells such as microglia and macrophages phagocytically clear apoptotic cells and other cholesterol-rich cellular debris, including myelin fragments and degenerating neurons. In this way, it represents a single cellular function that directly links cholesterol metabolism, endolysosomal clearance, and myeloid cells to AD risk. The next frontier will be to determine whether the other pathogenetic hallmark of AD, abnormal amyloidogenic processing of APP, integrates into this ensemble as well.
It is also worth recalling that abnormal lipid metabolism in microglia was prominently noted by Alois Alzheimer himself in his first description of the disease, but this observation was almost completely forgotten. Now, more than a century later, AD GWAS and post-GWAS studies like this one are bringing these early insights back to the forefront, positioning disordered lipid handling in microglia as a central driver of disease vulnerability.
View all comments by Edoardo MarcoraNational Institutes of Health
This study is a great example of how genomic and functional approaches can be combined to dig into the impact of non-coding SNPs. Using allele-specific open chromatin mapping across a large panel of iPSC-derived cell types, the authors pinpointed a PICALM risk allele that decreases expression by reducing PU.1 binding, with the strongest effects in microglia. In isogenic microglia, reduced PICALM expression impaired phagocytosis, drove lipid droplet accumulation, disrupted lysosomal function, and led to buildup of peroxidated lipids. These defects were rescued by restoring PICALM with CRISPRa and further linked to lipid state using triacsin C, a fatty acid acylation inhibitor.
What’s striking is how much this overlaps with APOE4 biology: impaired phagocytosis (Lin et al., 2018), cholesterol dysregulation (Feringa et al., 2024; Lee et al., 2023; Tcw et al., 2022), lipid peroxidation (Moulton et al., 2021; Windham et al., 2024), lysosomal stress (Gratuze et al., 2023; Guo et al., 2025; Nuriel et al., 2017), lipid droplet accumulation (Haney et al., 2024; Sienski et al., 2021; Stephenson et al., 2025; Victor et al., 2022), and disease-associated gene expression (Green et al., 2024; Keren-Shaul et al., 2017; Sun et al., 2023) all appear in both contexts. Similar signatures are emerging from other disease loci and models (Marschallinger et al., 2020; Podleśny-Drabiniok et al., 2024; Prakash et al., 2025), suggesting that diverse genetic factors may result in a shared microglial state associated with age or disease.
Our past work identified a functional link between APOE4 and PICALM around endocytosis (Narayan et al., 2020), but perhaps this relationship is much broader. Given PICALM’s role as a clathrin-mediated endocytosis adaptor, it’s worth considering whether some of these downstream phenotypes reflect new functions for PICALM or arise from altered trafficking of key substrates, such as cholesterol (via LDLR) or iron (via transferrin receptor). Perhaps perturbations in basic endocytic pathways could ripple into broader metabolic and lysosomal dysfunction.
The use of triacsin C to tie lipid droplets to microglial dysfunction is an important first step. Although it impacts multiple lipid pathways beyond lipid droplet biogenesis, it provides compelling initial evidence for a link between lipids and the many phenotypes discussed. More specific tools will help tease apart whether lipid droplets are causal or just one facet of broader lipidomic disruption.
Overall, this paper shows how a non-coding SNP can be connected to cellular dysfunction in a disease-relevant context and sparks fresh questions about the links between pathways that shape Alzheimer’s risk.
View all comments by Priyanka NarayanMake a Comment
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