Hallmarks of healthy cognitive aging: Inter-individual differences in aging trajectories

Djoher Nora Abrous, Nicolas Blin, Carl-Johan Boraxbekk, Gwenaelle Catheline, Carlos P. Fitzsimons, Markus Hilscher, Maël Lemoine, Luísa V. Lopes, Anne Maass, Mats Nilsson, Lars Nyberg, Lene Juel Rasmussen, Miguel Remondes, Magdalena Sauvage, Stefanie Schreiber, Thomas Wolbers
Ageing Research Reviews. 2026-07-01; 119: 103102
DOI: 10.1016/j.arr.2026.103102

Abrous DN(1), Blin N(2), Boraxbekk CJ(3), Catheline G(4), Fitzsimons CP(5), Hilscher M(6), Lemoine M(7), Lopes LV(8), Maass A(9), Nilsson M(6), Nyberg
L(10), Rasmussen LJ(11), Remondes M(12), Sauvage M(13), Schreiber S(14), Wolbers T(15).

Author information:
(1)Univ. Bordeaux, INSERM, Magendie, U1215, Neurogenesis and Pathophysiology
Group, Bordeaux F-3300, France. Electronic address: .
(2)Univ. Bordeaux, INSERM, Magendie, U1215, Neurogenesis and Pathophysiology
Group, Bordeaux F-3300, France.
(3)Institute of Sports Medicine Copenhagen (ISMC) and Department of Neurology,
Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark; Institute for
Clinical Medicine, Faculty of Medical and Health Sciences, University of
Copenhagen, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.
(4)Univ. Bordeaux, CNRS, EPHE-PSL, INCIA, UMR 5287, Sleep/Wake Aging
Neuroimaging Group, Bordeaux F-3300, France.
(5)Brain Plasticity Department, Swammerdam Institute for Life Sciences, Faculty
of Science, University of Amsterdam, Amsterdam 1098 XH, the Netherlands.
(6)Department of Biochemistry & Biophysics/ Science for Life Laboratory,
Stockholm University, Stockholm, Sweden.
(7)Univ. Bordeaux, CNRS, ImmunoConcept, UMR 5164, Conceptual Biology and
Medicine Group, Bordeaux F-33000, France.
(8)Gulbenkian Institute for Molecular Medicine (GIMM), Lisbon, Portugal;
Faculdade de Medicina de Lisboa, Portugal.
(9)German Center for Neurodegenerative Diseases (DZNE), Magdeburg 39120,
Germany.
(10)Department of Diagnostics and Intervention, Diagnostic Radiology, Umeå,
Sweden; Department of Medical and Translational Biology, Umeå University, Umeå,
Sweden; Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden.
(11)Center for Healthy Aging, Department of Cellular and Molecular Medicine,
University of Copenhagen, Copenhagen DK-2200, Denmark.
(12)Gulbenkian Institute for Molecular Medicine (GIMM), Lisbon, Portugal;
Faculdade de Medicina de Lisboa, Portugal; Aculdade de Medicina Veterinaria,
Universidade Lusofona, Portugal.
(13)FAM Department, Leibniz Institute for Neurobiology (LIN), Medical Faculty,
Otto-von-Guericke University, Magdeburg 39118, Germany.
(14)Department of Neurology, Otto-von-Guericke University, Magdeburg 39120,
Germany.
(15)German Center for Neurodegenerative Diseases (DZNE), Magdeburg 39120,
Germany. Electronic address: .

Cognitive aging is a highly heterogeneous process, with some individuals
preserving stable cognitive performance across the lifespan while others
exhibiting pronounced decline. This marked interindividual variability indicates
that chronological age alone is a poor predictor of cognitive health. Rather
than reflecting uniform degeneration, cognitive aging emerges from divergent
biological trajectories spanning molecular, cellular, and network levels. In
this review, we synthesize emerging biological hallmarks of healthy cognitive
aging, emphasizing studies that characterize longitudinal cognitive trajectories
in humans or distinguish aged individuals who retain learning capacity from
those who do not. We focus on the medial temporal lobe, a region critical for
episodic memory and spatial navigation, and examine how variability in its
integrity contributes to distinct cognitive outcomes. Across species, convergent
evidence suggests that cognitive decline is more closely linked to alterations
in network regulation and synaptic plasticity than to overt neuronal loss. We
identify key mechanisms shaping individual trajectories, including large-scale
network organization, excitation-inhibition balance, neuromodulatory tone, glial
and vascular regulation, adult hippocampal neurogenesis, and cellular
homeostasis. These processes operate within an interconnected system in which
disruptions in core regulatory mechanisms can propagate across levels of
organization. Together, this synthesis supports a system-level framework in
which cognitive resilience depends on the preservation of coordinated network
dynamics. We advocate for longitudinal, multidimensional approaches to identify
early shifts in regulatory balance and inform strategies to maintain cognitive
function across the lifespan.