New Mega-Analysis Reveals Why Memory Declines With Age

A landmark international study that pooled brain scans and memory tests from thousands of adults has shed new light on how structural brain changes are tied to memory decline as people age.

The findings — based on more than 10,000 MRI scans and over 13,000 memory assessments from 3,700 cognitively healthy adults across 13 studies — show that the connection between shrinking brain tissue and declining memory is nonlinear, stronger in older adults, and not solely driven by known Alzheimer’s-associated genes like APOE ε4. This suggests that brain aging is more complex than previously thought, and that memory vulnerability reflects broad structural changes across multiple regions, not just isolated pathology.

Published in Nature Communications, the study, “Vulnerability to memory decline in aging revealed by a mega-analysis of structural brain change,” found that structural brain change associated with memory decline is widespread, rather than confined to a single region. While the hippocampus showed the strongest association between volume loss and declining memory performance, many other cortical and subcortical regions also demonstrated significant relationships. This suggests that cognitive decline in aging reflects a distributed macrostructural brain vulnerability, rather than deterioration in a few specific brain regions. The pattern across regions formed a gradient, with the hippocampus at the high end and progressively smaller but still meaningful effects across large portions of the brain.

Importantly, the relationship between regional brain atrophy and memory decline was not only variable across individuals but also highly nonlinear. Individuals with above-average rates of structural loss experienced disproportionately greater declines in memory, suggesting that once brain shrinkage reaches higher levels, cognitive consequences accelerate rather than progress evenly. This nonlinear pattern was consistent across multiple brain regions, reinforcing the conclusion that memory decline in cognitively healthy aging is linked to global and network-level structural changes, with the hippocampus playing a particularly sensitive role but not acting alone.

“By integrating data across dozens of research cohorts, we now have the most detailed picture yet of how structural changes in the brain unfold with age and how they relate to memory,” said Alvaro Pascual-Leone, MD, PhD, senior scientist at the Hinda and Arthur Marcus Institute for Aging Research and medical director at the Deanna and Sidney Wolk Center for Memory Health.

“Cognitive decline and memory loss are not simply the consequence of aging, but manifestations of individual predispositions and age-related processes enabling neurodegenerative processes and diseases. These results suggest that memory decline in aging is not just about one region or one gene — it reflects a broad biological vulnerability in brain structure that accumulates over decades. Understanding this can help researchers identify individuals at risk early, and develop more precise and personalized interventions that support cognitive health across the lifespan and prevent cognitive disability.”

In addition to Pascual-Leone, researchers were Didac Vidal-Piñeiro, PhD, professor of psychology, University of Oslo; Øystein Sørensen, PhD, research scientist, University of Oslo; Marie Strømstad, MSc, Researcher, University of Oslo; Inge K. Amlien, PhD, senior researcher, University of Oslo; William F.C. Baaré, PhD, senior researcher, Danish Research Centre for Magnetic Resonance; David Bartrés-Faz, PhD, professor, University of Barcelona; Andreas M. Brandmaier, PhD, senior researcher, Max Planck Institute for Human Development; Gabriele Cattaneo, PhD, researcher, University of Milan; Sandra Düzel,  Dr. rer. nat. (PhD), senior research scientist in the Center for Lifespan Psychology at the Max Planck Institute for Human Development; Paolo Ghisletta, PhD, professor, University of Geneva; Richard N. Henson, PhD, professor, University of Cambridge; Simone Kühn, PhD, senior scientist, Max Planck Institute for Human Development; Ulman Lindenberger, PhD, director, Max Planck Institute for Human Development; Athanasia M. Mowinckel, PhD, researcher, University of Oslo; Lars Nyberg, PhD, professor, Umeå University; James M. Roe, PhD, research scientist, University of Oslo; Javier Solana-Sánchez, PhD, postdoctoral fellow, University of Oslo; Cristina Solé-Padullés, PhD, researcher, University of Barcelona; Leiv Otto Watne, MD, PhD, neurologist, Oslo University Hospital; Thomas Wolfers, PhD, senior researcher, University of Oslo; Kristine B. Walhovd, PhD, professor, University of Oslo; and Anders M. Fjell, PhD, professor, University of Oslo.

About Hebrew SeniorLife
Hebrew SeniorLife, an affiliate of Harvard Medical School, is a national senior services leader uniquely dedicated to rethinking, researching, and redefining the possibilities of aging. Hebrew SeniorLife cares for more than 4,500 seniors a day across seven campuses throughout Greater Boston. Locations include: Hebrew Rehabilitation Center-Boston and Hebrew Rehabilitation Center-NewBridge in Dedham; NewBridge on the Charles, Dedham; Orchard Cove, Canton; Simon C. Fireman Community, Randolph; Center Communities of Brookline, Brookline; Jack Satter House, Revere; and Leyland Community, Dorchester. Founded in 1903, Hebrew SeniorLife also conducts influential research into aging at the Hinda and Arthur Marcus Institute for Aging Research, which has a portfolio of more than $87 million, making it one of the largest gerontological research facilities in the U.S. in a clinical setting. It also trains more than 500 geriatric care providers each year. For more information about Hebrew SeniorLife, follow us on our blog, Facebook, Instagram, and LinkedIn.

About the Hinda and Arthur Marcus Institute for Aging Research
Scientists at the Marcus Institute seek to transform the human experience of aging by conducting research that will ensure a life of health, dignity, and productivity into advanced age. The Marcus Institute carries out rigorous studies that discover the mechanisms of age-related disease and disability; lead to the prevention, treatment, and cure of disease; advance the standard of care for older people; and inform public decision-making.