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

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.

Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1.

SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) and altered lipid profiles. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1-null neurons but does not rescue APOE levels. Pathway analyses implicate transforming growth factor ß (TGF-ß)/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Taken together, these data provide a mechanistic link between strong genetic risk factors for AD.

Disparate genetic variants associated with distinct components of cowpea resistance to the seed beetle Callosobruchus maculatus.

KEY MESSAGE: Polygenic genome-wide association mapping identified two regions of the cowpea genome associated with different components of resistance to its major post-harvest pest, the seed beetle Callosobruchus maculatus. Cowpea (Vigna unguiculata) is an important grain and fodder crop in arid and semi-arid regions of Africa, Asia, and South America, where the cowpea seed beetle, Callosobruchus maculatus, is a serious post-harvest pest. Development of cultivars resistant to C. maculatus population growth in storage could increase grain yield and quality and reduce reliance on insecticides. Here, we use a MAGIC (multi-parent, advanced-generation intercross) population of cowpea consisting of 305 recombinant inbred lines (RILs) to identify genetic variants associated with resistance to seed beetles. Because inferences regarding the genetic basis of resistance may depend on the source of the pest or the assay protocol, we used two divergent geographic populations of C. maculatus and two complementary assays to measure several aspects of resistance. Using polygenic genome-wide association mapping models, we found that the cowpea RILs harbor substantial additive-genetic variation for most resistance measures. Variation in several components of resistance, including larval development time and survival, was largely explained by one or several linked loci on chromosome 5. A second region on chromosome 8 explained increased seed resistance via the induction of early-exiting larvae. Neither of these regions contained genes previously associated with resistance to insects that infest grain legumes. We found some evidence of gene-gene interactions affecting resistance, but epistasis did not contribute substantially to resistance variation in this mapping population. The combination of mostly high heritabilities and a relatively consistent and simple genetic architecture increases the feasibility of breeding for enhanced resistance to C. maculatus.

Colonization of Marginal Host Plants by Seed Beetles (Coleoptera: Chrysomelidae): Effects of Geographic Source and Genetic Admixture.

The ability to adapt to a novel host plant may vary among insect populations with different genetic histories, and colonization of a marginal host may be facilitated by genetic admixture of disparate populations. We assembled populations of the seed beetle, Callosobruchus maculatus (F.), from four continents, and compared their ability to infest two hosts, lentil and pea. We also formed two cross-continent hybrids (Africa × N.A. and Africa × S.A.). In pre-selection assays, survival was only ~3% in lentil and ~40% in pea. For three replicate populations per line, colonization success on lentil was measured as cumulative exit holes after 75-175 d. On pea, we estimated the change in larval survival after five generations of selection. Females in all lines laid few eggs on lentil, and survival of F1 larvae was uniformly <5%. Subsequently, however, the lines diverged considerably in population growth. Performance on lentil was highest in the Africa × N.A. hybrid, which produced far more adults (mean > 11,000) than either parental line. At the other extreme, Asian populations on lentil appeared to have gone extinct. The Africa × N.A. line also exhibited the highest survival on pea, and again performed better than either parent line. However, no line displayed a rapid increase in survival on pea, as is sometimes observed on lentil. Our results demonstrate that geographic populations can vary substantially in their responses to the same novel resource. In addition, genetic admixtures (potentially caused by long-distance transport of infested seeds) may facilitate colonization of an initially poor host.

Combining Experimental Evolution and Genomics to Understand How Seed Beetles Adapt to a Marginal Host Plant.

Genes that affect adaptive traits have been identified, but our knowledge of the genetic basis of adaptation in a more general sense (across multiple traits) remains limited. We combined population-genomic analyses of evolve-and-resequence experiments, genome-wide association mapping of performance traits, and analyses of gene expression to fill this knowledge gap and shed light on the genomics of adaptation to a marginal host (lentil) by the seed beetle Callosobruchus maculatus. Using population-genomic approaches, we detected modest parallelism in allele frequency change across replicate lines during adaptation to lentil. Mapping populations derived from each lentil-adapted line revealed a polygenic basis for two host-specific performance traits (weight and development time), which had low to modest heritabilities. We found less evidence of parallelism in genotype-phenotype associations across these lines than in allele frequency changes during the experiments. Differential gene expression caused by differences in recent evolutionary history exceeded that caused by immediate rearing host. Together, the three genomic datasets suggest that genes affecting traits other than weight and development time are likely to be the main causes of parallel evolution and that detoxification genes (especially cytochrome P450s and beta-glucosidase) could be especially important for colonization of lentil by C. maculatus.

Components of Cowpea Resistance to the Seed Beetle Callosobruchus maculatus (Coleoptera: Chrysomelidae: Bruchinae).

Cowpea, Vigna unguiculata (L.) Walp., serves as a major source of dietary protein in many tropical and subtropical regions around the world. To identify loci associated with agronomically desirable traits, eight elite cowpea cultivars were systematically inter-crossed for eight generations to yield 305 recombinant inbred lines. Here, we investigated whether these founder parents also possess resistance to the seed beetle Callosobruchus maculatus (F.), a highly destructive post-harvest pest. We estimated larval survival in seeds, egg-to-adult development time, adult mass at emergence, and seed acceptance for oviposition. Survival varied significantly among cowpea cultivars, but the pattern was complicated by an unexpected source of mortality; on three cultivars, mature larvae in a substantial fraction of seeds (20-36%) exited seeds prematurely, and consequently failed to molt into viable adults. Even if such seeds were eliminated from the analysis, survival in the remaining seeds varied from 49 to 92% across the eight parents. Development time and body mass also differed among hosts, with particularly slow larval development on three closely related cultivars. Egg-laying females readily accepted all cultivars except one with a moderately rugose seed coat. Overall, suitability ranks of the eight cultivars depended on beetle trait; a cultivar that received the most eggs (IT82E-18) also conferred low survival. However, one cultivar (IT93K-503-1) was a relatively poor host for all traits. Given the magnitude of variation among parental cultivars, future assays of genotyped recombinant progeny can identify genomic regions and candidate genes associated with resistance to seed beetles.

Variable Responses to Novel Hosts by Populations of the Seed Beetle Callosobruchus maculatus (Coleoptera: Chrysomelidae: Bruchinae).

Cosmopolitan pests can consist of geographic populations that differ in their current host ranges or in their ability to colonize a novel host. We compared the responses of cowpea-adapted, seed-beetle populations (Callosobruchus maculatus [F.] (Coleoptera: Chrysomelidae: Bruchinae)) from Africa, North America, and South America to four novel legumes: chickpea, lentil, mung bean, and pea. We also qualitatively compared these results to those obtained earlier for an Asian population. For each host, we measured larval survival to adult emergence and used both no-choice and choice tests to estimate host acceptance. The pattern of larval survival was similar among populations: high or moderately high survival on cowpea, mung bean, and chickpea, intermediate survival on pea, and very low survival on lentil. One exception was unusually high survival of African larvae on pea, and there was modest variation among populations for survival on lentil. The African population was also an outlier with respect to host acceptance; under no-choice conditions, African females showed a much greater propensity to accept the two least preferred hosts, chickpea and lentil. However, greater acceptance of these hosts by African females was not evident in choice tests. Inferences about population differences in host acceptance can thus strongly depend on experimental protocol. Future selection experiments can be used to determine whether the observed population differences in initial performance will affect the probability of producing self-sustaining populations on a marginal crop host.