New directions for Alzheimer's disease research from the Jackson Laboratory Center for Alzheimer's and Dementia Research 2022 workshop

Abstract

Introduction: In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the Alzheimer's disease and related dementias (ADRD) field.

Methods: During the workshop, the participants brainstormed new directions to overcome current barriers to providing patients with effective ADRD therapeutics. The participants outlined specific areas of focus. Following the workshop, each group used standard literature search methods to provide background for each topic.

Results: The team of invited experts identified four key areas that can be collectively addressed to make a significant impact in the field: (1) Prioritize the diversification of disease targets, (2) enhance factors promoting resilience, (3) de-risk clinical pipeline, and (4) centralize data management.

Discussion: In this report, we review these four objectives and propose innovations to expedite ADRD therapeutic pipelines.

FIGURE 1

(A) The term resilience can be used unambiguously to refer to the set of individuals who, despite harboring a risk factor (which can be fixed, progressive, or acute), show better outcomes. (B) This definition allows for the operational use of the term resilience with different combinations of risk factors or stressors and outcome measures, thereby resolving ambiguities in the field when a commonly used outcome is studied as a risk factor as well. For example, neuropathology can be both a risk factor and an outcome.

FIGURE 2

Proteostasis regulation in LOAD patients. This figure shows changes in families of related biological processes associated with the AD endophenotypic area "proteostasis". We developed computational models for 19 endophenotypes associated with LOAD for large scale data integration. All the graphs in this figure are taken from analysis done utilizing the genes associated with proteostasis. In (A)–(C), we employ the cytoscape java/R application ClueGO to map genes that are AD risk associated and either up‐ or down‐regulated. In this manner, we can identify biological processes that are specifically associated with a unidirectional shift in AD. In (A), the network of linked terms are used to heatmap the network of processes that are either upregulated (red) or down‐regulated (blue). (B) The metrics associated with global patterns of up‐regulated biological processes are grouped together into related terms and represented by lead term in the pie chart. (C) The down‐regulated processes are aggregated and shown by lead term. In (D), a conceptual representation of opposing directions of linked processes are demonstrated within macromolecular synthesis, vesicle trafficking associated with protein maturation, protein homeostasis, and synaptic function. The regulation of processes suggests a direct and oppositional response within proteostatic subdomains indicative of counter‐regulation, potentially suggestive of hormesis. AD, Alzheimer's disease; LOAD, late‐onset AD.

FIGURE 3

Go/No Go pipeline to de‐risk preclinical trials. An example of a testing pipeline for prioritized targets. (A) Ideally, prioritized drug candidates would first be tested in vitro in a panel of genetically diverse, patient‐derived IPSCs. If toxicity were to consistently occur in any such stem cell population, further testing would not continue in relevant genetic contexts (no‐go). Similarly, lack of positive response in any stem cell line would end testing for this compound. (B) If any iPSC population exhibited promising responses, follow‐up in vivo experiments would be conducted using mice with appropriate genetic alignment. Lack of successful outcome measures in these mice would end further testing. (C) Successful treatment in at least one mouse model would warrant the establishment of an ADMET score. As an example, if we consider a screen for compounds to increase synaptic density (phenotype) in neurons (cells), any indication that the compound was toxic to neurons, or did not show an increase in synaptic density would not pass the go/no‐go gates. (A) If successful, however, the compound would go on to be tested in diverse mouse strains to represent the likely diverse responses that would be observed in the human population. If a compound showed increase in synaptic densities in vivo in at least one mouse model, (B) that compound would go on to ADMET scoring (C). ADMET, chemical absorption, distribution, metabolism, excretion, and toxicity; iPSC, induced pluripotent stem cells.