Diversity-sensitive brain clocks linked to biophysical mechanisms in aging and dementia

Carlos Coronel-Oliveros; Sebastian Moguilner; Hernan Hernandez; Josephine Cruzat; Sandra Baez; Vicente Medel; Jhosmary Cuadros; Hernando Santamaria-Garcia; Pedro A. Valdes-Sosa; Francisco Lopera; John Fredy Ochoa-Gómez; Alfredis González-Hernández; Jasmin Bonilla-Santos; Rodrigo A. Gonzalez-Montealegre; Tuba Aktürk; Ebru Yıldırım; Renato Anghinah; Agustina Legaz; Sol Fittipaldi; Görsev G. Yener; Javier Escudero; Claudio Babiloni; Susanna Lopez; Robert Whelan; Alberto Fernández; David Huepe; Gaetano Di Caterina; Marcio Soto-Añari; Raul Gonzalez-Gomez; Eduar Herrera; Daniel Abasolo; Kerry Kilborn; Nicolás Rubido; Ruaridh Clark; Rubén Herzog; Deniz Yerlikaya; Bahar Güntekin; Gustavo Deco; Pavel Prado; Mario A. Parra; Patricio Orio; Enzo Tagliazucchi; Brian Lawlor; Agustin Ibanez

doi:10.1038/s44220-025-00502-7

Diversity-sensitive brain clocks linked to biophysical mechanisms in aging and dementia

Carlos Coronel-Oliveros, Sebastian Moguilner, Hernan Hernandez, Josephine Cruzat, Sandra Baez, Vicente Medel, Jhosmary Cuadros, Hernando Santamaria-Garcia, Pedro A. Valdes-Sosa, Francisco Lopera, John Fredy Ochoa-Gómez, Alfredis González-Hernández, Jasmin Bonilla-Santos, Rodrigo A. Gonzalez-Montealegre, Tuba Aktürk, Ebru Yıldırım, Renato Anghinah, Agustina Legaz, Sol Fittipaldi, Görsev G. YenerJavier Escudero, Claudio Babiloni, Susanna Lopez, Robert Whelan, Alberto Fernández, David Huepe, Gaetano Di Caterina, Marcio Soto-Añari, Raul Gonzalez-Gomez, Eduar Herrera, Daniel Abasolo, Kerry Kilborn, Nicolás Rubido, Ruaridh Clark, Rubén Herzog, Deniz Yerlikaya, Bahar Güntekin, Gustavo Deco, Pavel Prado, Mario A. Parra, Patricio Orio, Enzo Tagliazucchi, Brian Lawlor, Agustin Ibanez

Research output: Contribution to journal › Article › peer-review

Abstract

Brain clocks track the deviations between predicted brain age and chronological age (brain age gaps, BAGs). These BAGs can be used to measure accelerated aging, monitoring deviations from the healthy brain trajectories associated with brain diseases and different cumulative burdens. However, the underlying biophysical mechanisms associated with BAGs in aging and dementia remain unclear. Here we combine source space connectivity (via electroencephalography) with generative brain modeling in healthy controls from the global south and north, alongside patients with Alzheimer’s disease and behavioral variant frontotemporal dementia (bvFTD) (N = 1,399). BAGs in aging were influenced by geography (south > north), income (low > high), sex (female > male) and education (low > high), with larger BAGs in patients, especially females, with Alzheimer’s disease. Biophysical modeling revealed BAGs related to hyperexcitability and structural disintegration in aging, while hypoexcitability and severe disintegration were linked to dementia. Our work sheds light on the biophysical mechanisms of accelerated aging and dementia in diverse populations.

Original language	English
Pages (from-to)	1214-1229
Journal	Nature Mental Health
Volume	3
Issue number	10
Early online date	18 Sept 2025
DOIs	https://doi.org/10.1038/s44220-025-00502-7
Publication status	Published - Oct 2025

Keywords / Materials (for Non-textual outputs)

brain clocks
biophysical modeling
E/I balance
structural disintegration
Global south
Dementia
Electroencephalography

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10.1038/s44220-025-00502-7

Merged_final-1Accepted author manuscript, 6.03 MBLicence: Creative Commons: Attribution (CC-BY)

https://www.nature.com/articles/s44220-025-00502-7

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Coronel-Oliveros, C., Moguilner, S., Hernandez, H., Cruzat, J., Baez, S., Medel, V., Cuadros, J., Santamaria-Garcia, H., Valdes-Sosa, P. A., Lopera, F., Ochoa-Gómez, J. F., González-Hernández, A., Bonilla-Santos, J., Gonzalez-Montealegre, R. A., Aktürk, T., Yıldırım, E., Anghinah, R., Legaz, A., Fittipaldi, S., ... Ibanez, A. (2025). Diversity-sensitive brain clocks linked to biophysical mechanisms in aging and dementia. Nature Mental Health, 3(10), 1214-1229. https://doi.org/10.1038/s44220-025-00502-7

@article{6ee2a8fe20df449686bd7a1563070639,

title = "Diversity-sensitive brain clocks linked to biophysical mechanisms in aging and dementia",

abstract = "Brain clocks track the deviations between predicted brain age and chronological age (brain age gaps, BAGs). These BAGs can be used to measure accelerated aging, monitoring deviations from the healthy brain trajectories associated with brain diseases and different cumulative burdens. However, the underlying biophysical mechanisms associated with BAGs in aging and dementia remain unclear. Here we combine source space connectivity (via electroencephalography) with generative brain modeling in healthy controls from the global south and north, alongside patients with Alzheimer{\textquoteright}s disease and behavioral variant frontotemporal dementia (bvFTD) (N = 1,399). BAGs in aging were influenced by geography (south > north), income (low > high), sex (female > male) and education (low > high), with larger BAGs in patients, especially females, with Alzheimer{\textquoteright}s disease. Biophysical modeling revealed BAGs related to hyperexcitability and structural disintegration in aging, while hypoexcitability and severe disintegration were linked to dementia. Our work sheds light on the biophysical mechanisms of accelerated aging and dementia in diverse populations.",

keywords = "brain clocks, biophysical modeling, E/I balance, structural disintegration, Global south, Dementia, Electroencephalography",

author = "Carlos Coronel-Oliveros and Sebastian Moguilner and Hernan Hernandez and Josephine Cruzat and Sandra Baez and Vicente Medel and Jhosmary Cuadros and Hernando Santamaria-Garcia and Valdes-Sosa, \{Pedro A.\} and Francisco Lopera and Ochoa-G{\'o}mez, \{John Fredy\} and Alfredis Gonz{\'a}lez-Hern{\'a}ndez and Jasmin Bonilla-Santos and Gonzalez-Montealegre, \{Rodrigo A.\} and Tuba Akt{\"u}rk and Ebru Yıldırım and Renato Anghinah and Agustina Legaz and Sol Fittipaldi and Yener, \{G{\"o}rsev G.\} and Javier Escudero and Claudio Babiloni and Susanna Lopez and Robert Whelan and Alberto Fern{\'a}ndez and David Huepe and Caterina, \{Gaetano Di\} and Marcio Soto-A{\~n}ari and Raul Gonzalez-Gomez and Eduar Herrera and Daniel Abasolo and Kerry Kilborn and Nicol{\'a}s Rubido and Ruaridh Clark and Rub{\'e}n Herzog and Deniz Yerlikaya and Bahar G{\"u}ntekin and Gustavo Deco and Pavel Prado and Parra, \{Mario A.\} and Patricio Orio and Enzo Tagliazucchi and Brian Lawlor and Agustin Ibanez",

note = "Conceptualization was provided by A.I. and C.C.-O. Supervision was provided by A.I. Methodology and analyses were performed by C.C.-O., H.H. and J. Cruzat. Data were collated by R.G.-G., J. Cruzat and P.P. The original draft was written by C.C.-O. and A.I. Review and editing of the paper were carried out by C.C.-O., S.M., H.H., J. Cruzat, S.B., V.M., J. Cuadros, H.S.-G., P.A.V.-S., F.L., J.F.O.-G., A.G.-H., J.B.-S., R.A.G.-M., T.A., E.Y., R.A., A.L., S.F., G.G.Y., J.E., C.B., S.L., R.W., A.F., D.H., G.D.C., M.S.-A., R.G.-G., E.H., D.A., K.K., N.R., R.C., R.H., D.Y., B.G., G.D., P.P., M.A.P., P.O., E.T., B.L. and A.I.",

year = "2025",

month = oct,

doi = "10.1038/s44220-025-00502-7",

language = "English",

volume = "3",

pages = "1214--1229",

journal = "Nature Mental Health",

issn = "2731-6076",

publisher = "Springer Nature",

number = "10",

}

Coronel-Oliveros, C, Moguilner, S, Hernandez, H, Cruzat, J, Baez, S, Medel, V, Cuadros, J, Santamaria-Garcia, H, Valdes-Sosa, PA, Lopera, F, Ochoa-Gómez, JF, González-Hernández, A, Bonilla-Santos, J, Gonzalez-Montealegre, RA, Aktürk, T, Yıldırım, E, Anghinah, R, Legaz, A, Fittipaldi, S, Yener, GG, Escudero, J, Babiloni, C, Lopez, S, Whelan, R, Fernández, A, Huepe, D, Caterina, GD, Soto-Añari, M, Gonzalez-Gomez, R, Herrera, E, Abasolo, D, Kilborn, K, Rubido, N, Clark, R, Herzog, R, Yerlikaya, D, Güntekin, B, Deco, G, Prado, P, Parra, MA, Orio, P, Tagliazucchi, E, Lawlor, B & Ibanez, A 2025, 'Diversity-sensitive brain clocks linked to biophysical mechanisms in aging and dementia', Nature Mental Health, vol. 3, no. 10, pp. 1214-1229. https://doi.org/10.1038/s44220-025-00502-7

TY - JOUR

T1 - Diversity-sensitive brain clocks linked to biophysical mechanisms in aging and dementia

AU - Coronel-Oliveros, Carlos

AU - Moguilner, Sebastian

AU - Hernandez, Hernan

AU - Cruzat, Josephine

AU - Baez, Sandra

AU - Medel, Vicente

AU - Cuadros, Jhosmary

AU - Santamaria-Garcia, Hernando

AU - Valdes-Sosa, Pedro A.

AU - Lopera, Francisco

AU - Ochoa-Gómez, John Fredy

AU - González-Hernández, Alfredis

AU - Bonilla-Santos, Jasmin

AU - Gonzalez-Montealegre, Rodrigo A.

AU - Aktürk, Tuba

AU - Yıldırım, Ebru

AU - Anghinah, Renato

AU - Legaz, Agustina

AU - Fittipaldi, Sol

AU - Yener, Görsev G.

AU - Escudero, Javier

AU - Babiloni, Claudio

AU - Lopez, Susanna

AU - Whelan, Robert

AU - Fernández, Alberto

AU - Huepe, David

AU - Caterina, Gaetano Di

AU - Soto-Añari, Marcio

AU - Gonzalez-Gomez, Raul

AU - Herrera, Eduar

AU - Abasolo, Daniel

AU - Kilborn, Kerry

AU - Rubido, Nicolás

AU - Clark, Ruaridh

AU - Herzog, Rubén

AU - Yerlikaya, Deniz

AU - Güntekin, Bahar

AU - Deco, Gustavo

AU - Prado, Pavel

AU - Parra, Mario A.

AU - Orio, Patricio

AU - Tagliazucchi, Enzo

AU - Lawlor, Brian

AU - Ibanez, Agustin

N1 - Conceptualization was provided by A.I. and C.C.-O. Supervision was provided by A.I. Methodology and analyses were performed by C.C.-O., H.H. and J. Cruzat. Data were collated by R.G.-G., J. Cruzat and P.P. The original draft was written by C.C.-O. and A.I. Review and editing of the paper were carried out by C.C.-O., S.M., H.H., J. Cruzat, S.B., V.M., J. Cuadros, H.S.-G., P.A.V.-S., F.L., J.F.O.-G., A.G.-H., J.B.-S., R.A.G.-M., T.A., E.Y., R.A., A.L., S.F., G.G.Y., J.E., C.B., S.L., R.W., A.F., D.H., G.D.C., M.S.-A., R.G.-G., E.H., D.A., K.K., N.R., R.C., R.H., D.Y., B.G., G.D., P.P., M.A.P., P.O., E.T., B.L. and A.I.

PY - 2025/10

Y1 - 2025/10

N2 - Brain clocks track the deviations between predicted brain age and chronological age (brain age gaps, BAGs). These BAGs can be used to measure accelerated aging, monitoring deviations from the healthy brain trajectories associated with brain diseases and different cumulative burdens. However, the underlying biophysical mechanisms associated with BAGs in aging and dementia remain unclear. Here we combine source space connectivity (via electroencephalography) with generative brain modeling in healthy controls from the global south and north, alongside patients with Alzheimer’s disease and behavioral variant frontotemporal dementia (bvFTD) (N = 1,399). BAGs in aging were influenced by geography (south > north), income (low > high), sex (female > male) and education (low > high), with larger BAGs in patients, especially females, with Alzheimer’s disease. Biophysical modeling revealed BAGs related to hyperexcitability and structural disintegration in aging, while hypoexcitability and severe disintegration were linked to dementia. Our work sheds light on the biophysical mechanisms of accelerated aging and dementia in diverse populations.

AB - Brain clocks track the deviations between predicted brain age and chronological age (brain age gaps, BAGs). These BAGs can be used to measure accelerated aging, monitoring deviations from the healthy brain trajectories associated with brain diseases and different cumulative burdens. However, the underlying biophysical mechanisms associated with BAGs in aging and dementia remain unclear. Here we combine source space connectivity (via electroencephalography) with generative brain modeling in healthy controls from the global south and north, alongside patients with Alzheimer’s disease and behavioral variant frontotemporal dementia (bvFTD) (N = 1,399). BAGs in aging were influenced by geography (south > north), income (low > high), sex (female > male) and education (low > high), with larger BAGs in patients, especially females, with Alzheimer’s disease. Biophysical modeling revealed BAGs related to hyperexcitability and structural disintegration in aging, while hypoexcitability and severe disintegration were linked to dementia. Our work sheds light on the biophysical mechanisms of accelerated aging and dementia in diverse populations.

KW - brain clocks

KW - biophysical modeling

KW - E/I balance

KW - structural disintegration

KW - Global south

KW - Dementia

KW - Electroencephalography

U2 - 10.1038/s44220-025-00502-7

DO - 10.1038/s44220-025-00502-7

M3 - Article

SN - 2731-6076

VL - 3

SP - 1214

EP - 1229

JO - Nature Mental Health

JF - Nature Mental Health

IS - 10

ER -

Diversity-sensitive brain clocks linked to biophysical mechanisms in aging and dementia

Abstract

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