Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: evidence across two independent cohorts

Raffaele Cacciaglia; Carles Falcón; Gonzalo Sánchez Benavides; Anna Brugulat-Serrat; Marta Milà Alomà; Marc Suárez Calvet; José Luis Molinuevo; Karine Fauria; Carolina Minguillón; Gwendlyn Kollmorgen; Clara Quijano-Rubio; Kaj Blennow; Henrik Zetterberg; Luigi Lorenzini; Alle Meije Wink; Silvia Ingala; Frederik Barkhof; Craig W Ritchie; Juan Domingo Gispert; ALFA study

doi:10.1002/alz.14415

Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: evidence across two independent cohorts

Raffaele Cacciaglia^*
, Carles Falcón
, Gonzalo Sánchez Benavides
, Anna Brugulat-Serrat
, Marta Milà Alomà
, Marc Suárez Calvet
, José Luis Molinuevo
, Karine Fauria
, Carolina Minguillón
, Gwendlyn Kollmorgen
, Clara Quijano-Rubio
, Kaj Blennow
, Henrik Zetterberg
, Luigi Lorenzini
, Alle Meije Wink
, Silvia Ingala
, Frederik Barkhof
, Craig W Ritchie
, Juan Domingo Gispert
, ALFA study

^*Corresponding author for this work

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

Abstract

INTRODUCTION: Identifying the link between early Alzheimer's disease (AD) pathological changes and neurodegeneration in asymptomatic individuals may lead to the discovery of preventive strategies. We assessed longitudinal brain atrophy and cognitive decline as a function of cerebrospinal fluid (CSF) AD biomarkers in two independent cohorts of cognitively unimpaired (CU) individuals.

METHODS: We used longitudinal voxel-based morphometry (VBM) in combination with hippocampal subfield segmentation. Changes in neuroimaging and cognitive variables were inspected using general linear models (GLMs) adjusting by age, sex, apolipoprotein E (APOE) status, follow-up time, and years of education.

RESULTS: In both cohorts, baseline CSF amyloid beta (Aβ) biomarkers significantly predicted medial temporal lobe (MTL) atrophy rates and episodic memory (EM) decline independently of CSF phosphorylated tau (p-tau).

DISCUSSION: Our data suggest that soluble Aβ dyshomeostasis triggers MTL longitudinal atrophy and EM decline independently of CSF p-tau. Our data underscore the need for secondary preventive strategies at the earliest stages of the AD pathological cascade.

Original language	English
Article number	e14415
Pages (from-to)	1-13
Number of pages	13
Journal	Alzheimer's and Dementia
Volume	21
Issue number	2
Early online date	3 Feb 2025
DOIs	https://doi.org/10.1002/alz.14415
Publication status	Published - 24 Feb 2025

Keywords

Humans
tau Proteins/cerebrospinal fluid
Male
Female
Alzheimer disease/pathology
Amyloid beta-Peptides/cerebrospinal fluid
Aged
Atrophy/pathology
Cognitive dysfunction/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Cohort studies
Longitudinal studies
magnetic resonance imaging
Brain/pathology
Middle aged
Aged, 80 and over
Phosphorylation
Neuropsychological tests
Memory, Episodic

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Cacciaglia-et-al-2025-Soluble-A-beta-pathology-predicts-Alzheimers&Dementia-21-e14415-CCBY
Copyright © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Cacciaglia, R., Falcón, C., Benavides, G. S., Brugulat-Serrat, A., Alomà, M. M., Calvet, M. S., Molinuevo, J. L., Fauria, K., Minguillón, C., Kollmorgen, G., Quijano-Rubio, C., Blennow, K., Zetterberg, H., Lorenzini, L., Wink, A. M., Ingala, S., Barkhof, F., Ritchie, C. W., Gispert, J. D., & ALFA study (2025). Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: evidence across two independent cohorts. Alzheimer's and Dementia, 21(2), 1-13. Article e14415. https://doi.org/10.1002/alz.14415

@article{b77dc27f75324369bc47cb63c51b0181,

title = "Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: evidence across two independent cohorts",

abstract = "INTRODUCTION: Identifying the link between early Alzheimer's disease (AD) pathological changes and neurodegeneration in asymptomatic individuals may lead to the discovery of preventive strategies. We assessed longitudinal brain atrophy and cognitive decline as a function of cerebrospinal fluid (CSF) AD biomarkers in two independent cohorts of cognitively unimpaired (CU) individuals.METHODS: We used longitudinal voxel-based morphometry (VBM) in combination with hippocampal subfield segmentation. Changes in neuroimaging and cognitive variables were inspected using general linear models (GLMs) adjusting by age, sex, apolipoprotein E (APOE) status, follow-up time, and years of education.RESULTS: In both cohorts, baseline CSF amyloid beta (Aβ) biomarkers significantly predicted medial temporal lobe (MTL) atrophy rates and episodic memory (EM) decline independently of CSF phosphorylated tau (p-tau).DISCUSSION: Our data suggest that soluble Aβ dyshomeostasis triggers MTL longitudinal atrophy and EM decline independently of CSF p-tau. Our data underscore the need for secondary preventive strategies at the earliest stages of the AD pathological cascade.",

keywords = "Humans, tau Proteins/cerebrospinal fluid, Male, Female, Alzheimer disease/pathology, Amyloid beta-Peptides/cerebrospinal fluid, Aged, Atrophy/pathology, Cognitive dysfunction/cerebrospinal fluid, Biomarkers/cerebrospinal fluid, Cohort studies, Longitudinal studies, magnetic resonance imaging, Brain/pathology, Middle aged, Aged, 80 and over, Phosphorylation, Neuropsychological tests, Memory, Episodic",

author = "Raffaele Cacciaglia and Carles Falc{\'o}n and Benavides, \{Gonzalo S{\'a}nchez\} and Anna Brugulat-Serrat and Alom{\`a}, \{Marta Mil{\`a}\} and Calvet, \{Marc Su{\'a}rez\} and Molinuevo, \{Jos{\'e} Luis\} and Karine Fauria and Carolina Minguill{\'o}n and Gwendlyn Kollmorgen and Clara Quijano-Rubio and Kaj Blennow and Henrik Zetterberg and Luigi Lorenzini and Wink, \{Alle Meije\} and Silvia Ingala and Frederik Barkhof and Ritchie, \{Craig W\} and Gispert, \{Juan Domingo\} and \{ALFA study\}",

year = "2025",

month = feb,

day = "24",

doi = "10.1002/alz.14415",

language = "English",

volume = "21",

pages = "1--13",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley \& Sons, Ltd",

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Cacciaglia, R, Falcón, C, Benavides, GS, Brugulat-Serrat, A, Alomà, MM, Calvet, MS, Molinuevo, JL, Fauria, K, Minguillón, C, Kollmorgen, G, Quijano-Rubio, C, Blennow, K, Zetterberg, H, Lorenzini, L, Wink, AM, Ingala, S, Barkhof, F, Ritchie, CW, Gispert, JD & ALFA study 2025, 'Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: evidence across two independent cohorts', Alzheimer's and Dementia, vol. 21, no. 2, e14415, pp. 1-13. https://doi.org/10.1002/alz.14415

Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: evidence across two independent cohorts. / Cacciaglia, Raffaele; Falcón, Carles; Benavides, Gonzalo Sánchez et al.
In: Alzheimer's and Dementia, Vol. 21, No. 2, e14415, 24.02.2025, p. 1-13.

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

TY - JOUR

T1 - Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum

T2 - evidence across two independent cohorts

AU - Cacciaglia, Raffaele

AU - Falcón, Carles

AU - Benavides, Gonzalo Sánchez

AU - Brugulat-Serrat, Anna

AU - Alomà, Marta Milà

AU - Calvet, Marc Suárez

AU - Molinuevo, José Luis

AU - Fauria, Karine

AU - Minguillón, Carolina

AU - Kollmorgen, Gwendlyn

AU - Quijano-Rubio, Clara

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Lorenzini, Luigi

AU - Wink, Alle Meije

AU - Ingala, Silvia

AU - Barkhof, Frederik

AU - Ritchie, Craig W

AU - Gispert, Juan Domingo

AU - ALFA study

PY - 2025/2/24

Y1 - 2025/2/24

N2 - INTRODUCTION: Identifying the link between early Alzheimer's disease (AD) pathological changes and neurodegeneration in asymptomatic individuals may lead to the discovery of preventive strategies. We assessed longitudinal brain atrophy and cognitive decline as a function of cerebrospinal fluid (CSF) AD biomarkers in two independent cohorts of cognitively unimpaired (CU) individuals.METHODS: We used longitudinal voxel-based morphometry (VBM) in combination with hippocampal subfield segmentation. Changes in neuroimaging and cognitive variables were inspected using general linear models (GLMs) adjusting by age, sex, apolipoprotein E (APOE) status, follow-up time, and years of education.RESULTS: In both cohorts, baseline CSF amyloid beta (Aβ) biomarkers significantly predicted medial temporal lobe (MTL) atrophy rates and episodic memory (EM) decline independently of CSF phosphorylated tau (p-tau).DISCUSSION: Our data suggest that soluble Aβ dyshomeostasis triggers MTL longitudinal atrophy and EM decline independently of CSF p-tau. Our data underscore the need for secondary preventive strategies at the earliest stages of the AD pathological cascade.

AB - INTRODUCTION: Identifying the link between early Alzheimer's disease (AD) pathological changes and neurodegeneration in asymptomatic individuals may lead to the discovery of preventive strategies. We assessed longitudinal brain atrophy and cognitive decline as a function of cerebrospinal fluid (CSF) AD biomarkers in two independent cohorts of cognitively unimpaired (CU) individuals.METHODS: We used longitudinal voxel-based morphometry (VBM) in combination with hippocampal subfield segmentation. Changes in neuroimaging and cognitive variables were inspected using general linear models (GLMs) adjusting by age, sex, apolipoprotein E (APOE) status, follow-up time, and years of education.RESULTS: In both cohorts, baseline CSF amyloid beta (Aβ) biomarkers significantly predicted medial temporal lobe (MTL) atrophy rates and episodic memory (EM) decline independently of CSF phosphorylated tau (p-tau).DISCUSSION: Our data suggest that soluble Aβ dyshomeostasis triggers MTL longitudinal atrophy and EM decline independently of CSF p-tau. Our data underscore the need for secondary preventive strategies at the earliest stages of the AD pathological cascade.

KW - Humans

KW - tau Proteins/cerebrospinal fluid

KW - Male

KW - Female

KW - Alzheimer disease/pathology

KW - Amyloid beta-Peptides/cerebrospinal fluid

KW - Aged

KW - Atrophy/pathology

KW - Cognitive dysfunction/cerebrospinal fluid

KW - Biomarkers/cerebrospinal fluid

KW - Cohort studies

KW - Longitudinal studies

KW - magnetic resonance imaging

KW - Brain/pathology

KW - Middle aged

KW - Aged, 80 and over

KW - Phosphorylation

KW - Neuropsychological tests

KW - Memory, Episodic

U2 - 10.1002/alz.14415

DO - 10.1002/alz.14415

M3 - Article

C2 - 39898436

SN - 1552-5260

VL - 21

SP - 1

EP - 13

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 2

M1 - e14415

ER -

Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: evidence across two independent cohorts

Abstract

Keywords

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