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. 2025 Feb;21(2):e14492.
doi: 10.1002/alz.14492. Epub 2025 Jan 27.

A multi-cohort study of longitudinal and cross-sectional Alzheimer's disease biomarkers in cognitively unimpaired older adults

Long Xie  1 , Sandhitsu R Das  2 , Yue Li  2 , Laura E M Wisse  3 , Emily McGrew  2 , Xueying Lyu  2 , Michael DiCalogero  4 , Ujashi Shah  4 , Ademola Ilesanmi  2 , Amanda E Denning  2 , Chris A Brown  4 , Jesse Cohen  2 , Lasya Sreepada  2 , Mengjin Dong  2 , Niyousha Sadeghpour  2 , Pulkit Khandelwal  2 , Ranjit Ittyerah  2 , Sadhana Ravikumar  2 , Shokufeh Sadaghiani  5 , Stanislau Hrybouski  2 , Robin de Flores  6 , Eli Gibson  1 , Paul A Yushkevich  2 , David A Wolk  4 ; Alzheimer's Disease Neuroimaging Initiative
Affiliations

A multi-cohort study of longitudinal and cross-sectional Alzheimer's disease biomarkers in cognitively unimpaired older adults

Long Xie et al. Alzheimers Dement. 2025 Feb.

Abstract

Introduction: The generalizability of neuroimaging and cognitive biomarkers in their sensitivity to detect preclinical Alzheimer's disease (AD) and power to predict progression in large, multisite cohorts remains unclear.

Method: Longitudinal demographics, T1-weighted magnetic resonance imaging (MRI), and cognitive scores of 3036 cognitively unimpaired (CU) older adults (amyloid beta [Aβ]-negative/positive [A-/A+]: 1270/1558) were included. Cross-sectional and longitudinal cognition and medial temporal lobe (MTL) structural measures were extracted. Cross-sectional MTL tau burden (T) was computed from tau positron emission tomography (N = 1095).

Results: We found cross-sectional tau and longitudinal structural biomarkers best separated A+ CU from A- CU. A-T+ CU had significantly faster neurodegeneration rate compared to A-T- CU. MTL tau was significantly correlated with MRI and cognitive biomarkers regardless of Aβ status. MTL tau, MRI, and cognition provided complementary information about disease progression.

Discussion: This large multisite study replicates prior findings in CU older adults, supporting the utility of neuroimaging and cognitive biomarkers in preclinical AD clinical trials and normal aging studies.

Highlights: We investigated neuroimaging and cognitive biomarkers in 3036 cognitively unimpaired (CU) participants. Medial temporal lobe (MTL) tau and longitudinal MTL atrophy best separate amyloid beta positive (A+) CU from amyloid beta negative (A-) CU. A- tau positive (T+) CU had a significantly faster neurodegeneration rate compared to A-T- CU. MTL tau correlated with structural magnetic resonance imaging (MRI) and cognition regardless of amyloid beta status. Combined baseline MTL tau, MRI, and cognition best predict Alzheimer's disease progression.

Keywords: amyloid; biomarkers; disease progression; magnetic resonance imaging; neurodegeneration; normal aging; preclinical Alzheimer's disease; prediction; tau.

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Conflict of interest statement

D. A. W. has served as a paid consultant to Eli Lilly, GE Healthcare, and Qynapse. He serves on DSMB for Functional Neuromodulation and GSK. He is a site investigator for a clinical trial sponsored by Biogen. S. R. D. received consultation fees from Rancho Biosciences and Nia Therapeutics. L. X. received personal consulting fees from Galileo CDS, Inc. L. X. has become an employee of Siemens Healthineers since May 2022 but the current study was conducted during his employment at the University of Pennsylvania. E. G. is a paid employee of Siemens Healthineers. The other authors have nothing to disclose. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Schematic figure with the list of cross‐sectional and longitudinal neuroimaging and cognitive/global functional biomarkers used in this study (top) and the analyses performed (bottom). Longitudinal tau biomarkers were not analyzed due to limited longitudinal tau PET data. Structural MRI, cognition, and tau PET measures were color‐coded in green, red, and purple, respectively, for easier interpretation of the results in the other tables and figures. See section 2.5 for the details of statistical analyses performed. AH, anterior hippocampus; BA35/36, Brodmann area 35/36; ERC, entorhinal cortex; MRI, magnetic resonance imaging; PET, positron emission tomography; PH, posterior hippocampus; PHC, parahippocampal cortex
FIGURE 2
FIGURE 2
Two views of the statistical maps comparing cross‐sectional thickness (A) and longitudinal atrophy rate (B) between Aβ and tau subgroups of CU older adults specified above respective maps. Analyses of subgroups defined by Aβ alone are shown to the left of the white dashed line. Analyses of subgroups defined by both Aβ and tau are shown to the right of the white dashed line. Each statistical map plots the t statistics associated with the null hypothesis that structural measurement (either cross‐sectional thickness or longitudinal atrophy rate) at a given location in the MTL is equal between the two groups. Red colored t scores represent stronger disease effect (thinner thickness in cross‐sectional analyses and faster atrophy rate in longitudinal analyses), while blue colored t scores represent less disease effect. Clusters highlighted by black contours are statistically significant at p < 0.05 after correcting for multiple comparisons using cluster‐level FWER permutation test approach with 1000 permutations and cluster threshold is uncorrected p < 0.05 for thickness and p < 0.01 for longitudinal atrophy rate. A+/A–, amyloid beta positive/negative; Aβ, amyloid beta; AH, anterior hippocampus; BA35/36, Brodmann area 35/36; CU, cognitively unimpaired; ERC, entorhinal cortex; FWER, family‐wise error rate; MTL, medial temporal lobe; PH, posterior hippocampus; PHC, parahippocampal cortex; T+/T–, tau positive/negative
FIGURE 3
FIGURE 3
Two views of the statistical maps of association between tau tracer uptake in ERC and BA35 and cross‐sectional thickness (A) or longitudinal atrophy rate (B) structural measures. Analyses were done separately in Aβ positive/negative (A+/A–) CU subgroups. Each statistical map plots the t statistics associated with the null hypothesis that there is no correlation between structural measurement (either cross‐sectional thickness or longitudinal atrophy rate) and MTL tau tracer uptake. Clusters highlighted by black contours are statistically significant at p < 0.05 after correction for multiple comparisons using cluster‐level FWER permutation test approach with 1000 permutations and cluster threshold uncorrected p < 0.05. A+/A–, amyloid beta positive/negative; Aβ, amyloid beta; AH, anterior hippocampus; BA35/36, Brodmann area 35/36; CU, cognitively unimpaired; ERC, entorhinal cortex; FWER, family‐wise error rate; MTL, medial temporal lobe; PH, posterior hippocampus; PHC, parahippocampal cortex; T+/T–, tau positive/negative
FIGURE 4
FIGURE 4
ROC analyses for discriminating fast versus slow progressors. Curves include models using none (yellow, null model with age, sex, education, APOE ɛ4 status, and follow‐up time), only tau‐based (purple), only MRI‐based (green), only cognition‐based (red), or all the (light blue) selected baseline cross‐sectional biomarkers in Table 4. Analyses were done in A– (first row) and A+ (second row) CU separately. Tau PET and cognitive biomarkers provided complementary information in the predictions. A+/A–, CU. See Figure 1 for biomarker abbreviations. Structural MRI, cognition and tau PET measures were color‐coded in green, red and purple respectively for easier interpretation in all tables and figures. A+/A–, amyloid beta positive/negative; APOE, apolipoprotein E; CU, cognitively unimpaired; PET, positron emission tomography; ROC, receiver operating characteristic
See this image and copyright information in PMC

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