Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review

Abstract

Background: Alzheimer's disease (AD) is a debilitating neurodegenerative condition with few treatment options available. Drug repurposing studies have sought to identify existing drugs that could be repositioned to treat AD; however, the effectiveness of drug repurposing for AD remains unclear. This review systematically analyzes the progress made in drug repurposing for AD throughout the last decade, summarizing the suggested drug candidates and analyzing changes in the repurposing strategies used over time. We also examine the different types of data that have been leveraged to validate suggested drug repurposing candidates for AD, which to our knowledge has not been previous investigated, although this information may be especially useful in appraising the potential of suggested drug repurposing candidates. We ultimately hope to gain insight into the suggested drugs representing the most promising repurposing candidates for AD. Methods: We queried the PubMed database for AD drug repurposing studies published between 2012 and 2022. 124 articles were reviewed. We used RxNorm to standardize drug names across the reviewed studies, map drugs to their constituent ingredients, and identify prescribable drugs. We used the Anatomical Therapeutic Chemical (ATC) Classification System to group drugs. Results: 573 unique drugs were proposed for repurposing in AD over the last 10 years. These suggested repurposing candidates included drugs acting on the nervous system (17%), antineoplastic and immunomodulating agents (16%), and drugs acting on the cardiovascular system (12%). Clozapine, a second-generation antipsychotic medication, was the most frequently suggested repurposing candidate (N = 6). 61% (76/124) of the reviewed studies performed a validation, yet only 4% (5/124) used real-world data for validation. Conclusion: A large number of potential drug repurposing candidates for AD has accumulated over the last decade. However, among these drugs, no single drug has emerged as the top candidate, making it difficult to establish research priorities. Validation of drug repurposing hypotheses is inconsistently performed, and real-world data has been critically underutilized for validation. Given the urgent need for new AD therapies, the utility of real-world data in accelerating identification of high-priority candidates for AD repurposing warrants further investigation.

Keywords: Alzheimer’s disease; drug repurposing; electronic health records; real-world data; validation.

FIGURE 1

Flow diagram for literature review.

FIGURE 2

Breakdown of AD drug repurposing studies published between 2012 and 2022. The studies are colored by repurposing strategy (computational, experimental, or combination). Studies with validation are shown with hatching. The total number of studies published each year is shown in bold text, with the number of studies with validation provided in parentheses.

FIGURE 3

Number of unique studies supporting each drug repurposing candidate.

FIGURE 4

Original therapeutic indications of drugs suggested for repurposing in AD. Drug therapeutic indications are represented using their Level 1 ATC codes.

FIGURE 5

Further breakdown of unique prescribable drug candidates suggested for AD repurposing. (A) Proposed drugs acting on the nervous system (ATC code N). (B) Antineoplastic and immunomodulating repurposing candidates (ATC code L). (C) Repurposing candidates acting on the cardiovascular system (ATC code C). Drugs in classes accounting for less than 5% of the total drug count have been classified as “Other unspecified”.

FIGURE 6

Changes in the AD drug repurposing landscape over time. The outermost ring of the sunburst plot represents drugs suggested by studies published between 2012 and 2016, with the size of each drug slice weighted by the number of unique supporting studies published during that time period. The innermost ring cumulatively adds drugs suggested by studies published in the last 5 years (between 2017 and 2022), providing a comprehensive breakdown of the AD repurposing candidates suggested between 2012–2022 and their literature support. Drug candidates are colored by their Level 1 ATC classification as shown in the center pie chart; for the purposes of this figure, drugs with more than one possible ATC code were mapped to a single code chosen at random. The drug slices corresponding to clozapine and demecarium are labeled. A high-resolution version of Figure 6 with all drug slices labeled is available as Supplementary Figure S1.

FIGURE 7

(A) Sankey diagram showing the breakdown of the validations performed across the studies. Validation is classified as in vitro, in vivo, other, or none. In vivo validation is further subdivided into animal models, clinical trials, and patient data. Three studies used two different types of validation (counted separately in the figure). (B) Breakdown of repurposing strategy and validation for the six studies suggesting clozapine as a repurposing candidate for AD. Repurposing strategy is classified as experimental or computational. Validation is classified as in vitro, in vivo, or none.

FIGURE 8

Breakdown of validation data types (AD-specific and nonspecific). 76 studies performed a validation; one study used two different types of AD-specific validation (N = 77 for entire pie chart).