Scientists have creatively used large databases of existing FDA-approved drugs and electronic medical records to locate candidates that are potentially effective against Alzheimer’s [1].
New approaches needed
Many previously discovered drugs may be effective beyond their original indications, but it is challenging to match them to new ones. Thankfully, ever-growing computing power, new data, and novel analytical tools make repurposing drugs easier.
In a new study published in the journal Cell, scientists from the University of California San Francisco set out to find existing drugs that would be effective against Alzheimer’s disease. Billions of dollars have been poured into Alzheimer’s drug development, but successes are very rare. Even a handful of the particularly expensive drugs that have been approved only slightly delay the disease’s progression, which makes finding new therapeutic options a pressing need.
One problem is Alzheimer’s complex etiology. Scientists do not know the exact causes, but it seems to be an amalgam of many factors, such as the accumulation of amyloid-β and tau proteins along with neuroinflammation [2]. To complicate things further, various types of brain cells behave differently in this disease.
Different cells, different drugs
The researchers used data from three large, publicly available single-nucleus RNA sequencing (snRNA-seq) datasets from human post-mortem brain tissue to determine which proteins are expressed differently in Alzheimer’s-affected brains vs healthy brains. Gene expression changes in six major brain cell types were included in the analysis: excitatory neurons, inhibitory neurons, microglia, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells (OPCs).
The team found that each cell type had a unique Alzheimer’s-related gene expression signature, with some genes showing opposite changes in different cell types. For example, in people with Alzheimer’s, the well-known risk-related gene APOE was upregulated in microglia but downregulated in astrocytes and OPCs.
The next step was to find existing drugs that could reverse these changes. The researchers used the Connectivity Map (CMap), a database of gene expression changes in human cell lines caused by different drugs, to screen for potential therapeutic candidates. By looking for molecules that produced gene expression changes in opposition to the Alzheimer’s signatures for each cell type, they identified several potential hits.
25 repurposed drugs significantly reversed cell-type-specific Alzheimer’s-associated gene expression profiles in multiple cell types. The list included a wide variety of compounds, such as antibiotics, anti-inflammatories, and antipsychotics. The immunosuppressant rapamycin (sirolimus), known for its anti-aging properties, also made the cut.
The team then validated their findings using a large Electronic Medical Records (EMR) database from the University of California health system by assessing the risk of Alzheimer’s in patients who had been prescribed these drugs for other conditions, such as cancer, to a matched control group with similar demographic and health characteristics.
The researchers decided to move on with two compounds, letrozole and irinotecan, as a combination therapy. Letrozole is a hormone therapy used for breast cancer, while irinotecan is a chemotherapy drug.
Letrozole was chosen to target neuronal Alzheimer’s signatures, and irinotecan is for glial cell signatures. The EMR analysis revealed that both were associated with a significantly lower risk of Alzheimer’s. Letrozole showed a relative risk of 0.466, while irinotecan had a risk of 0.195, meaning that patients who took irinotecan had an 80.5% lower risk of being diagnosed with Alzheimer’s compared to their matched control group.
“Alzheimer’s is likely the result of numerous alterations in many genes and proteins that, together, disrupt brain health,” said Yadong Huang, MD, Ph.D., senior investigator and director of the Center for Translational Advancement at Gladstone, professor of neurology and pathology at UCSF, and co-senior author of the paper. “This makes it very challenging for drug development – which traditionally produces one drug for a single gene or protein that drives disease.”
Sex-specific effects in mice
For in vivo validation, the researchers used a mouse model (5xFAD/PS19) that develops both amyloid plaques and tau tangles, the two key pathologies of AD, to closely mimic the human condition. The mice were treated for three months with either letrozole, irinotecan, or their combination.
The team assessed the mice’s spatial learning and memory using the Morris water maze test. Only the mice on the combination therapy demonstrated a significant improvement in both short-term and long-term memory compared to controls. The single-drug treatments produced much less pronounced effects.
The effect was also sex-dependent, with female mice showing much less improvement in the tests. Interestingly, letrozole works by targeting the estrogen pathway, which might explain the disparity. It is also known that in humans, Alzheimer’s prevalence is much higher in women, although this might be due to their longer average life expectancy [3]. On the other hand, EMR analysis showed no sex differences in letrozole’s effect on Alzheimer’s prevalence. The authors caution, however, that this finding is inconclusive because the number of male patients taking letrozole was very small.
After the behavioral tests, the researchers examined the mice’s brains for Alzheimer’s-related pathologies. The combination therapy group showed significant reductions in hippocampal atrophy, amyloid-beta plaque load, phosphorylated tau (p-tau) pathology, neuroinflammation, and neuronal loss. The treatment also reversed the expression of many of the disease’s signature genes that were initially identified in humans.
“Alzheimer’s disease comes with complex changes to the brain, which has made it tough to study and treat, but our computational tools opened up the possibility of tackling the complexity directly,” said Marina Sirota, Ph.D., the interim director of the UCSF Bakar Computational Health Sciences Institute, professor of pediatrics, and co-senior author of the paper. “We’re excited that our computational approach led us to a potential combination therapy for Alzheimer’s based on existing FDA-approved medications.”
Literature
[1] Li, Y., Pereda Serras, C., Blumenfeld, J., Xie, M., Hao, Y., Deng, E., … Sirota, M. (n.d.). Cell-type-directed network-correcting combination therapy for Alzheimer’s disease. Cell.
[2] Breijyeh, Z., & Karaman, R. (2020). Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules, 25(24), 5789.
[3] Mielke, M. M. (2018). Sex and gender differences in Alzheimer’s disease dementia. The Psychiatric times, 35(11), 14.
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