Some brain regions are more vulnerable to Alzheimer’s disease than others. A new study suggests that this might be due to how they uptake cholesterol [1].
Why do some parts of the brain succumb earlier?
Despite decades of research and vast amounts of funding, scientists still have limited understanding of how Alzheimer’s disease develops and progresses. The field urgently needs new approaches, and a recent study from the University of California, San Francisco, published in Alzheimer’s and Dementia, is an example of one.
The researchers capitalized on the fact that some brain regions appear to be much more vulnerable to Alzheimer’s than others. To understand why, the authors analyzed 22 post-mortem brain samples from patients at various stages of the disease, focusing on two regions: the locus coeruleus (LC) and the substantia nigra (SN). The former is among the first regions to exhibit Alzheimer’s-related damage, while the latter remains relatively resilient.
“These two regions are remarkably similar despite their markedly different vulnerabilities to Alzheimer’s disease,” said study first author Alexander Ehrenberg, Ph.D., an investigator at the UCSF Memory and Aging Center and translational health fellow at the Innovative Genomics Institute.
Both are anatomically and neurochemically similar, and both are also similarly vulnerable to other neurodegenerative diseases like Parkinson’s. Given this, we reasoned that the differences between the brain regions at the beginning of the study would offer clues into the baseline selective vulnerability of the LC to Alzheimer’s disease.
Someone’s hungry for cholesterol!
The researchers analyzed gene expression in these two regions and found that some genes and pathways were expressed markedly differently in the LC versus the SN. These included inflammation-related pathways, which is expected given the known connection between neuroinflammation and Alzheimer’s; estrogen pathways; and, notably, significant differences in cholesterol-related genes.
Cholesterol has previously been linked to Alzheimer’s disease [2]. Importantly, the gene most strongly associated with sporadic Alzheimer’s, APOE, is involved in cholesterol transport. The brain contains about one-fifth of the body’s total cholesterol, mostly within neuronal membranes and the myelin sheaths that cover axons, the long, slender projections of neurons transmitting electrical impulses. Brain cholesterol is primarily produced by glial cells, especially astrocytes, and delivered to neurons through specialized transport mechanisms.
“One key difference between the brain regions had to do with cholesterol metabolism and homeostasis,” said Ehrenberg. “The LC neurons exhibit signatures suggesting that they are super cholesterol-hungry—these neurons are doing both their best to produce their own cholesterol and take in as much as possible. The SN, on the other hand, doesn’t have the same level of demands.”
The paper makes an interesting suggestion as to why the LC has a higher cholesterol demand: “The LC projects widely throughout the neocortex to regions with high metabolic demand, while the SN, comparatively, projects less diffusely.” Essentially, longer and more extensive projections might increase cholesterol requirements for maintaining neuronal membranes, supporting synaptic function, and, where present, sustaining myelin sheaths, although this is currently hypothetical.
Same receptors take up amyloid beta
The researchers identified significantly increased expression of the LDLR gene in the LC compared to the SN. This gene codes for part of the transmembrane receptor complex Sigma-2, which facilitates the uptake of extracellular lipoproteins, including the notorious LDL (low-density lipoprotein, or “bad cholesterol”) and apoE, produced by its namesake gene. However, Sigma-2 also takes in soluble oligomers (small clumps) of amyloid beta, the misfolded peptide central to Alzheimer’s pathology.
While amyloid beta is commonly associated with extracellular plaques, research suggests that its soluble oligomers that enter cells might also be harmful. It should be noted that in 2022, fraud was found in several influential studies dealing with amyloid beta oligomers, but these primarily involved a specific oligomer type (Aβ*56). Nonetheless, substantial unrelated evidence supports a role for amyloid beta oligomers in Alzheimer’s [3].
The study was limited by its small sample size and exploratory nature. Further experimental research is required to confirm this hypothesis. However, the authors’ comparative approach provides valuable insights into some of the mechanisms underlying Alzheimer’s. While focusing on cholesterol metabolism, the study also highlights other gene expression differences between these two brain regions, which are also potentially relevant to Alzheimer’s mechanisms.
“The study highlights how cholesterol regulation not only explains differences between people’s vulnerability to Alzheimer’s but also differences in vulnerability between brain regions at early disease stages,” said senior author Lea Grinberg, MD, Ph.D., the John Douglas French Alzheimer’s Foundation Endowed Professor at the UCSF Memory and Aging Center.
A deeper understanding of the causal factors underlying LC degeneration—and the development of strategies to mitigate its vulnerability—could have a profound impact on the treatment of Alzheimer’s. LC dysregulation impairs critical functions such as sleep regulation and neuroinflammatory control, both of which are recognized as key risk factors that can accelerate Alzheimer’s disease progression.
Literature
[1] Ehrenberg, A. J., Sant, C., Pereira, F. L., Li, S., Buxton, J., Langlois, S., Trinidad, M., Oh, I., Paraizo Leite, R. E., Diehl Rodriguez, R., Ribeiro Paes, V., Pasqualucci, C. A., Seeley, W. W., Spina, S., Suemoto, C. K., Temple, S., Kaufer, D., & Grinberg, L. T. (2025). Pathways underlying selective neuronal vulnerability in Alzheimer’s disease: Contrasting the vulnerable locus coeruleus to the resilient substantia nigra. Alzheimer’s & Dementia, 21, Article e70087.
[2] Feringa, F. M., & Van der Kant, R. (2021). Cholesterol and Alzheimer’s disease; from risk genes to pathological effects. Frontiers in Aging Neuroscience, 13, 690372.
[3] Jongbloed, W., Bruggink, K. A., Kester, M. I., Visser, P. J., Scheltens, P., Blankenstein, M. A., … & Veerhuis, R. (2015). Amyloid-β oligomers relate to cognitive decline in Alzheimer’s disease. Journal of Alzheimer’s disease, 45(1), 35-43.
View the article at lifespan.io
