Which FDA‑approved cancer drugs identified by UCSF have been tested in Alzheimer's models and what are their safety profiles for long‑term brain use?
Executive summary
UCSF and Gladstone researchers used computational screening of gene‑expression signatures and real‑world medical records to nominate two FDA‑approved cancer drugs—letrozole and irinotecan—and reported that the combination improved memory and reduced brain degeneration in mouse models of Alzheimer’s disease (AD) [1] [2] [3]. The public reporting highlights repurposing advantages and early preclinical efficacy, but the sources do not supply direct data on long‑term safety of these drugs in the human brain, and they caution that mouse results may not translate to people [4] [5].
1. What UCSF identified and how it was tested: two cancer drugs emerge from a big‑data search
UCSF and Gladstone scientists screened ~1,300 drugs against single‑cell Alzheimer’s gene‑expression signatures and narrowed candidates by cross‑referencing the Connectivity Map and electronic health records from 1.4 million people, ultimately focusing laboratory testing on two FDA‑approved cancer drugs, letrozole and irinotecan [6] [1] [2]. In mouse experiments that combined amyloid and tau model strains, treatment groups receiving the combination showed less brain degeneration and restored performance in memory assays compared with controls, while single‑agent dosing produced weaker effects on tau aggregates in the brain [7] [6] [3].
2. What was claimed about safety and the appeal of repurposing — and the limits of those claims
Multiple outlets and the UCSF press materials emphasize that repurposing FDA‑approved drugs accelerates the path to clinical trials because basic safety data already exist for human use, reducing development time and cost relative to de novo drugs [4] [3] [8]. However, the reporting itself acknowledges that these conclusions rest on preclinical mouse data and retrospective record associations rather than prospective human AD trials, and that the investigators propose clinical testing rather than claiming established safety or efficacy in people with Alzheimer’s [5] [1].
3. What the sources say — and do not say — about long‑term brain safety
None of the provided UCSF/Gladstone or news summaries present data on chronic central nervous system safety of letrozole or irinotecan in humans with Alzheimer’s or in long‑duration animal studies focused on neurotoxicity; the sources therefore do not establish whether either drug—or the proposed combination—is safe for long‑term use in the brain [6] [1] [2]. The coverage repeatedly notes the need for clinical trials to evaluate human safety and efficacy, which implicitly acknowledges that existing FDA approval for oncology use is not equivalent to documented long‑term brain safety in older adults or people with neurodegeneration [5] [3].
4. Context, caveats and precedent that matter for safety judgment
Reporting places the findings in a cautious frame: mouse successes often fail to translate to human benefit, and retrospective EHR associations can be confounded despite large sample sizes, so controlled clinical trials are required before declaring acceptable risk‑benefit for chronic brain use [5] [1]. The literature cited by the news coverage also contains cautionary precedents where cancer drugs proved intolerable in AD trials (for example, historically thalidomide produced prohibitive toxicities in AD testing), underscoring that oncology approval does not guarantee tolerability in older, non‑cancer populations [9]. The UCSF/Gladstone team and media emphasize promise and the logistical advantages of repurposing but stop short of asserting that long‑term cerebral safety is proven [4] [10].
5. Bottom line for decision‑makers and researchers
The only FDA‑approved cancer drugs specifically named and tested in the UCSF/Gladstone Alzheimer’s study are letrozole and irinotecan, and their combination produced beneficial effects in mice and correlated with lower AD incidence in retrospective records [6] [7] [2]. The available sources do not provide evidence that either drug is safe for long‑term use in the human brain; investigators call for clinical trials to resolve safety and efficacy questions, and prior examples of oncology agents causing unacceptable toxicities in AD trials counsel caution [5] [9] [3].