In Aging Cell, researchers have outlined the relationship between Alzheimer’s, increased pain sensitivity, and the enzyme LPCAT2.
Pain is among the earliest signs
The key characteristics of Alzheimer’s disease, such as cognitive decline and brain deterioration, are very well-known [1]. However, other symptoms, such as pain sensitivity, may precede these key manifestations, providing an early warning of its development [2].
Previous research has pinpointed lipid metabolism as a key aspect of the relationship between pain and Alzheimer’s [3]. Changes in these lipids have been found to be among the first signs of Alzheimer’s, and they contribute to damage and inflammation [4]. In particular, lysophosphatidylcholine (LPC) is strongly associated with pain [5] along with both neuroinflammation and the removal of protective myelin from axons (demyelination) [6].
However, there are confounding factors in this relationship. Previous work has found that the allele APOE4, which greatly increases sensitivity to Alzheimer’s, plays a role [7]. Alzheimer’s presentation and pain sensitivity also vary by sex [8].
The biological chain of causality between these facts, however, had not been examined. These researchers aimed to rectify that by taking a close look at LPC acyltransferase 2 (LPCAT2), a core part of lipid metabolism and brain inflammation.
Large databases help find a limited group
Because of the number of involved variables, the researchers needed to use multiple large databases: the Alzheimer’s Disease Neuroimaging Initiative, the ROSMAP database on memory and aging, a Mayo Clinic database on gene expression in the brain, and the Taiwan Biobank were all used as data sources along with human brain samples from the NIH.
The researchers discovered that pain sensitivity is increased with mild cognitive impairment in men that do not have APOE4. Women, and men with APOE4, did not have results that reached the level of statistical significance. In fact, women without APOE4 trended towards suffering less pain with cognitive decline as measured by the MMSE, a commonly used metric of cognitive ability.
A gene expression analysis found that this increase in pain sensitivity in non-APOE4 men was indeed related to LPCAT2, which was associated with both increased pain and with the onset of Alzheimer’s disease. Men who did not express increased levels of LPCAT2 were unlikely to experience dementia; men who did had a much greater risk.
These findings were corroborated with an analysis of brain tissue. Nearly every sample that was derived from a non-APOE4 man with Alzheimer’s disease contained elevated LPCAT2. This was even found to be true in mice; male mice that were modified to be susceptible to Alzheimer’s disease were considerably more likely to have elevated LPCAT2 in the hippocampus, although this finding did not extend to the cerebral cortex.
Genetic susceptibility
The researchers found that there is a genetic component. Eleven single-nucleotide polymorphisms (SNPs) were found to be associated with increased LPCAT2, pain sensitivity, and the risk of Alzheimer’s disease. Mendelian randomization, a statistical technique, was used to confirm that this relationship is causal; these mutations do indeed raise the risk of increased pain sensitivity and Alzheimer’s disease in non-APOE4 men.
The researchers offer some hypotheses as to why this might be the case. They note that APOE is directly related to circulating LPC levels [9] and microglial behavior [10] and that estrogen has been found to play a role in this area as well [11]. However, this study is observational and does not suggest any methods of modulating LPCAT2. Determining whether or not this is a druggable target will be the domain of future work.
Literature
[1] Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D., & Jones, E. (2011). Alzheimer’s disease. the Lancet, 377(9770), 1019-1031.
[2] Zhao, W., Zhao, L., Chang, X., Lu, X., & Tu, Y. (2023). Elevated dementia risk, cognitive decline, and hippocampal atrophy in multisite chronic pain. Proceedings of the National Academy of Sciences, 120(9), e2215192120.
[3] Yin, F. (2023). Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. The FEBS journal, 290(6), 1420-1453.
[4] Bazan, N. G., Colangelo, V., & Lukiw, W. J. (2002). Prostaglandins and other lipid mediators in Alzheimerβs disease. Prostaglandins & other lipid mediators, 68, 197-210.
[5] Ren, J., Lin, J., Yu, L., & Yan, M. (2022). Lysophosphatidylcholine: Potential target for the treatment of chronic pain. International Journal of Molecular Sciences, 23(15), 8274.
[6] Freeman, L., Guo, H., David, C. N., Brickey, W. J., Jha, S., & Ting, J. P. Y. (2017). NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. Journal of Experimental Medicine, 214(5), 1351-1370.
[7] Romano, R. R., Carter, M. A., Dietrich, M. S., Cowan, R. L., Bruehl, S. P., & Monroe, T. B. (2021). Could altered evoked pain responsiveness be a phenotypic biomarker for Alzheimerβs disease risk? A cross-sectional analysis of cognitively healthy individuals. Journal of Alzheimerβs Disease, 79(3), 1227-1233.
[8] Aggarwal, N. T., & Mielke, M. M. (2023). Sex differences in Alzheimerβs disease. Neurologic clinics, 41(2), 343.
[9] Law, S. H., Chan, H. C., Ke, G. M., Kamatam, S., Marathe, G. K., Ponnusamy, V. K., & Ke, L. Y. (2023). Untargeted lipidomic profiling reveals lysophosphatidylcholine and ceramide as atherosclerotic risk factors in apolipoprotein E knockout mice. International Journal of Molecular Sciences, 24(8), 6956.
[10] Yamamoto, S., Hashidate-Yoshida, T., Yoshinari, Y., Shimizu, T., & Shindou, H. (2024). Macrophage/microglia-producing transient increase of platelet-activating factor is involved in neuropathic pain. Iscience, 27(4).
[11] Karpuzoglu-Sahin, E., Zhi-Jun, Y., Lengi, A., Sriranganathan, N., & Ahmed, S. A. (2001). Effects of long-term estrogen treatment on IFN-Ξ³, IL-2 and IL-4 gene expression and protein synthesis in spleen and thymus of normal C57BL/6 mice. Cytokine, 14(4), 208-217.
