An international research team led by the Keck School of Medicine of USC analyzed fossil material from seven human ancestors ranging in age from roughly 1.5 million to 3.7 million years old, spanning two pivotal groups: Australopithecus and its descendants, the early members of the genus Homo. Rather than focusing on the outward shapes of bones, the researchers measured their strength, a property that changes during an individual’s lifetime in response to the mechanical forces placed upon them. This quality makes bone strength a living record of behavior, capturing how an animal actually moved through its world rather than simply what its skeleton was capable of doing.

The biological logic behind the approach is elegantly simple. Bones remodel themselves under load, becoming thicker and more resistant in response to repeated stress. Animals that spend more time climbing and moving through trees, such as modern apes, tend to develop relatively strong arm bones, because their upper limbs bear and absorb substantial forces. Humans, who walk upright on the ground, concentrate mechanical loading in their legs and consequently build stronger thigh bones. By comparing the relative strength of upper and lower limb bones within the same individuals, the team could reconstruct how each ancestor divided its activity between the trees and the ground.

To estimate bone strength, the researchers collected computed tomography scans, which use X-rays to generate a series of detailed cross-sectional images of the bones and their internal structure. From these images they calculated the thickness of the bone shafts, quantified their internal architecture, and estimated how resistant each bone would have been to bending and twisting forces. Crucially, they compared the strength of the upper arm, thigh, and shin bones within each individual, allowing a direct, body-by-body assessment of how mechanical demands were distributed across the skeleton during life.

The results revealed that Australopithecus, an early ancestor that lived roughly two to four million years ago, occupied a genuinely intermediate position that has no exact parallel among living species. These individuals possessed relatively strong arms compared with their thighs, a pattern resembling modern apes and indicating that they spent substantial time in trees. Yet when the researchers looked specifically within the legs, comparing the strength of the thigh and shin bones, they found a distinctly human-like pattern. The implication is striking: Australopithecus was already using its lower limbs for upright walking on the ground while still relying on its upper limbs for movement in the trees.

Australopithecus combined an ape-like upper limb strength with a human-like pattern in the legs, suggesting they had a unique movement strategy that has no modern comparison, said Kristian J. Carlson, a professor of clinical medical education at the Keck School of Medicine and the study’s lead author. This mosaic of traits complicates any simple narrative in which our ancestors descended from the trees in a single clean transition. Instead, the evidence points to a prolonged period in which climbing and bipedal walking coexisted within the same bodies, and likely within the same lifetimes.

The early Homo individuals in the sample, descendants of Australopithecus who lived about 1.8 to 2.3 million years ago, told a very different story. They had relatively strong leg bones and weaker arm bones, a pattern much more similar to that of modern humans. The findings suggest that the transition from Australopithecus to Homo included a major shift in how human ancestors moved and lived, one that appears to have been completed by roughly two million years ago. We’re proposing that relative limb strength is a threshold trait, a difference that marks an important and fundamental shift in behavior between Australopithecus and Homo, Carlson said.

The concept of a threshold trait is significant because it frames the change not as a slow, imperceptible drift but as a fundamental behavioral boundary. Below the threshold, ancestors like Australopithecus maintained a mixed strategy, retaining the capacity and habit of climbing even as they walked upright. Above it, early Homo had committed to a predominantly terrestrial existence, with skeletons shaped by the demands of walking long distances on the ground rather than hauling the body through branches. The relative strength of the limbs, in this view, serves as a reliable signal of that behavioral divide.

The findings also speak directly to a longstanding debate over how much time Australopithecus actually spent on the ground. Some researchers have argued that these early ancestors were already spending the majority of their time walking upright terrestrially, treating tree climbing as an occasional refuge. The new evidence suggests otherwise, indicating that Australopithecus continued to spend substantial time in trees, Carlson said. In this interpretation, the safety and resources of the canopy remained an important part of daily life for these hominins long after their legs had adopted a human-like walking pattern.

Perhaps the most tantalizing dimension of the study is its suggested connection to another landmark event in human evolution: the dramatic expansion of brain size that began around the same period, roughly two million years ago. Scientists have proposed many explanations for that increase, including language, tool use, and changes in how human ancestors found food. Carlson and his colleagues speculate that the move toward walking greater distances on the ground may have contributed to both the shift in relative limb strength and the increase in brain size. The shift toward more walking may have placed new demands on the body and brain, which could help explain why these changes happened around the same time, Carlson said. While the researchers are careful to present this as a hypothesis rather than a conclusion, the temporal coincidence is difficult to ignore: at the very moment the skeleton committed to the ground, the brain began its remarkable growth. The study, which included co-authors from institutions including the University of the Witwatersrand, Johns Hopkins University, Harvard University, Pennsylvania State University, and the Georgian National Museum, adds a distinctive kind of evidence to the record of bipedalism. Where earlier work documented how skeletal features changed over many generations, this research shows how individuals used their limbs during their own lifetimes, and in doing so it captures evolution in motion, one step at a time.

Subject of Research: Limb bone strength as evidence of the evolutionary transition from arboreal climbing to habitual bipedalism in Australopithecus and early Homo

Article Title: Study of bone strength reveals new clues about human evolution

Article References: Study of bone strength reveals new clues about human evolution. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: human evolution, bipedalism, Australopithecus, early Homo, bone strength, paleoanthropology, fossils, computed tomography, arboreality, limb bones, Science Advances, Keck School of Medicine of USC

The AHEAD 3-45 trial is testing a deceptively simple question: whether treating people with an approved Alzheimer’s drug earlier, before any outward sign of decline, can produce better outcomes than waiting for symptoms to appear. The drug in question, lecanemab, works by clearing sticky aggregates of amyloid-beta protein that accumulate in the brain and are closely associated with the progression of Alzheimer’s disease. In patients who already show cognitive symptoms, the drug can slow the clinical progression of the disease by roughly 30 percent. But it is currently prescribed only for people who have already begun to decline, leaving open the tantalizing possibility that intervening earlier could do far more.

That possibility creates an enormous recruitment challenge. The AHEAD 3-45 trial specifically targets people with early amyloid-beta buildup, a process that can begin as much as twenty or thirty years before the first noticeable problems with memory or thinking. Yet only about 30 percent of cognitively healthy adults over the age of 65 carry amyloid levels high enough to qualify for a trial like AHEAD. Finding those individuals means screening large numbers of older adults who feel perfectly well and have no obvious symptoms, then confirming with certainty that the biological hallmarks of the disease are present before enrolling them in a study that will involve repeated assessments and, ultimately, treatment with an amyloid-clearing antibody.

Before blood plasma screening entered the picture, that confirmation depended almost entirely on PET imaging. Positron-emission tomography is considered the gold standard for visualizing amyloid in the living brain, but it is expensive, requires access to specialized scanners and radiotracers, and adds months to the enrollment timeline. Candidates for the AHEAD 3-45 trial once faced a screening process stretching up to three months from their first visit to enrollment, and after undergoing a PET scan, more than 70 percent would learn they were ineligible. In other words, for every participant enrolled, the trial was paying for and performing multiple scans that revealed nothing more than the absence of the very biology the study was hunting for.

“The screening part of an Alzheimer’s trial is usually one of the costliest parts of the clinical trial for study sites,” said corresponding author Oliver Langford, MS, modeling and simulation director at the USC Epstein Family Alzheimer’s Therapeutic Research Institute at the Keck School of Medicine. “We definitely helped reduce the burden for participating clinical sites and for patients by reducing the number of individuals having to undergo PET scans.” The savings cascade beyond trial budgets. Fewer scans mean fewer clinic visits, less exposure to radiation and needles for volunteers, and a faster path from first contact to enrollment for the people the trial most needs to reach.

The algorithmic tool at the heart of the study incorporated two blood plasma biomarkers that have risen rapidly to prominence in Alzheimer’s research. The first is the amyloid-beta ratio, an early signal of amyloid accumulation that reflects the gradual sequestration of the protein into plaques in the brain. The second is p-tau217, a recently discovered marker of a phosphorylated form of the tau protein that more reliably reflects the actual amyloid burden carried in an individual’s brain. Blood tests measuring these proteins have shown steadily improving accuracy in recent years, and their performance has fueled a broader shift toward making Alzheimer’s detection accessible in ordinary clinical settings rather than confined to specialized imaging centers.

Building the model required data on a remarkable scale. The USC team developed the algorithm using information from 1,080 participants in the AHEAD study and then validated it in an independent dataset drawn from the Wisconsin Registry for Alzheimer’s Prevention, a long-running observational study of dementia risk. Beyond the two plasma biomarkers, the model incorporated age and APOE4 carrier status, two well-established factors that increase the likelihood of amyloid accumulation. Crucially, the algorithm was not frozen at birth. It was refined across three successive versions during active recruitment, which ran from 2020 to 2024, allowing the researchers to fold in lessons from real-world screening performance as the trial progressed.

The staged rollout demonstrated how quickly each refinement translated into efficiency. When first introduced in February 2022, the version of the algorithm built on the amyloid-beta ratio alone reduced the proportion of participants who received a PET scan but proved ineligible from 71 percent to 50 percent. In May 2023, a second version integrated p-tau217, and that figure fell further to 31 percent. The improvement enabled the trial to enroll participants with both intermediate and elevated amyloid levels far more efficiently, sparing more than half of the would-be scanned candidates an unnecessary imaging procedure. For a phase 3 study recruiting across dozens of sites internationally, the cumulative effect on cost, time and volunteer burden is substantial.

Central to the algorithm’s design is a statistical technique known as Mixture of Experts, or MoE, which allows the model to grapple with a biological reality that simpler tools ignore: amyloid does not accumulate uniformly across the population. Rather than forcing each person into a binary positive or negative category, the team built a model that estimates where an individual falls along a continuous spectrum of amyloid buildup. “When we look at amyloid levels at a population level, we see a peak where people are amyloid-negative and another peak for those with elevated amyloid plaque buildup,” Langford explained. “There is a region in the intermediate range that isn’t fully captured by the plasma marker alone. The Mixture of Experts approach helps model that uncertainty more effectively and is better suited to the type of data collected.” By explicitly modeling the murky middle of the distribution, the algorithm can flag borderline cases for confirmatory imaging while confidently routing clear-cut cases either into the trial or out of it.

The implications extend well beyond a single clinical trial. The results add to a growing body of evidence that blood tests can serve as a practical first-pass filter before more intensive and expensive diagnostics, a reordering of the diagnostic pipeline that could reshape both research and routine care. “It’s going to allow more people to access testing that can help determine whether they have Alzheimer’s disease pathology,” Langford said. “If you are able to go to your doctor and get a blood test done, you’ll be able to understand whether you have the disease earlier.” More efficient screening for trials like AHEAD 3-45 may also bring the field a step closer to its ultimate ambition: primary prevention of Alzheimer’s disease. “If we can intervene earlier,” Langford said, “we’ll have a larger effect and hopefully prevent people from having symptoms.” In addition to Langford, the study’s authors include Rema Raman, Paul Aisen, Doris Molina-Henry, Gustavo A. Jimenez-Maggiora, Robert A. Rissman and Michael C. Donohue of USC; Reisa Sperling, Keith Johnson, Colin Birkenbihl, Madison Cuppels and Rachel F. Buckley of Harvard Medical School, Brigham and Women’s Hospital and Massachusetts General Hospital; Pallavi Sachdev and David Li of Eisai Inc.; and Sterling C. Johnson of C2N Diagnostics. The AHEAD Study is conducted through the Alzheimer’s Clinical Trials Consortium, funded by the National Institute on Aging of the National Institutes of Health under award U24AG057437, and is a public-private partnership supported by the NIA, Eisai, the GHR Foundation, the Alzheimer’s Association and other philanthropic organizations.

Subject of Research: Development and validation of a blood-based biomarker screening algorithm to improve recruitment efficiency for a preclinical Alzheimer's disease clinical trial

Article Title: USC develops algorithmic tool to improve screening of patients for Alzheimer's clinical trial

Article References: USC develops algorithmic tool to improve screening of patients for Alzheimer's clinical trial. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: Alzheimer's disease, blood biomarkers, PET imaging, lecanemab, amyloid-beta, p-tau217, clinical trial recruitment, Mixture of Experts, AHEAD 3-45, Keck School of Medicine of USC, plasma screening, early detection