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. 2025 Mar;21(3):e70075.
doi: 10.1002/alz.70075.

Amyloid PET predicts longitudinal functional and cognitive trajectories in a heterogeneous cohort

Kyan Younes  1 , Emily Johns  1 , Christina B Young  1 , Gabriel Kennedy  1 , Shubhabrata Mukherjee  2 , Hillary A Vossler  1 , Joseph Winer  1 , Karly Cody  1 , Victor W Henderson  1   3 , Kathleen L Poston  1 , Tobey J Betthauser  4 , Bill Bevis  4 , William M Brooks  5 , Jeffrey M Burns  5 , Stephen A Coombes  6 , Charles DeCarli  7 , Frank P DiFilippo  8 , Ranjan Duara  6 , Audrey P Fan  7 , Laura E Gibbons  2 , Todd Golde  6 , Sterling C Johnson  4 , Rebecca J Lepping  5 , James Leverenz  8 , Sean McDougall  7 , Emily Rogalski  9 , Elizabeth Sanders  2 , Joshua Pasaye  10 , Jaiashre Sridhar  10 , Andrew J Saykin  11 , Anjali Sridharan  4 , Russell Swerdlow  5 , Emily H Trittschuh  12   13 , David Vaillancourt  6 , Eric Vidoni  5 , Wei-En Wang  5 , Jesse Mez  14 , Timothy J Hohman  15 , Duygu Tosun  16 , Sarah Biber  17 , Walter A Kukull  17 , Paul K Crane  2 , Elizabeth C Mormino  1   18
Affiliations

Amyloid PET predicts longitudinal functional and cognitive trajectories in a heterogeneous cohort

Kyan Younes et al. Alzheimers Dement. 2025 Mar.

Abstract

Introduction: Amyloid positron emission tomography (PET) is increasingly available for diagnosis of Alzheimer`s disease (AD); however, its practical implications in heterogenous cohorts are debated.

Methods: Amyloid PET from 890 National Alzheimer`s Coordinating Center participants with up to 10 years post-PET follow up was analyzed. Cox proportional hazards and linear mixed models were used to investigate amyloid burden prediction of etiology and prospective functional status and cognitive decline.

Results: Amyloid positivity was associated with progression from unimpaired to mild cognitive impairment and dementia. Amyloid burden in the unimpaired group was associated with lower initial memory levels and faster decline in memory, language, and global cognition. In the Impaired group, amyloid was associated with lower initial levels and faster decline for memory, language, executive function, and global cognition.

Discussion: Amyloid burden is an important prognostic marker in a clinically heterogeneous cohort. Future work is needed to establish the proportion of decline driven by AD versus non-AD processes in the context of mixed pathology.

Highlights: Our findings highlight the importance of amyloid positron emission tomography (PET) in heterogenous cohorts, including diverse demographics, clinical syndromes, and underlying etiologies. The results also provide evidence that higher amyloid levels were linked to functional progression from unimpaired cognition to mild cognitive impairment (MCI) and from MCI to dementia. In cognitively unimpaired individuals, higher amyloid burden was associated with poorer memory at baseline and subsequent declines in memory, language, and global cognition. Among individuals with cognitive impairment, amyloid burden was associated with worse initial memory, language, executive function, and global cognition, and faster declines over time.

Keywords: Alzheimer's disease; amyloid PET; neurodegenerative disease heterogeneity.

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Conflict of interest statement

Kyan Younes received research support from the National Instituite of Health (NIH), Alzheimer's Association, and to conduct clinical trials (paid to institution) from Stanford Knight Initiative for Brain Resilience, consulted for GLG, and has served as a sub‐I on clinical trials funded by Janssen, Ari Bio, Eli Lilly and Company, Biogen, Cognition Therapeutics, and EIP Pharma. Christina B. Young has received research support from the NIH, Alzheimer's Association, and New Vision Research. Victor W. Henderson has received funding from the NIH and Good Planet Foundation. Joseph Winer has received funding from Simons Foundation. Timothy J. Hohman is on the Scientific Advisory Board for Vivid Genomics and serves as Deputy Editor for Alzheimer's & Dementia: Translational Research and Clinical Intervention, and Senior Associate Editor for Alzheimer's & Dementia. Kathleen L. Poston is a consultant for Curasen, Novartis, Biohaven and Neuron23, and on the Scientific Advisory Board for Amprion and Curasen. Jeffrey M Burns has received research support from the NIH, research support to conduct clinical trials (paid to institution) from Eli Lilly, Amylyx, Biogen, Eisai, AbbVie, Astra‐Zeneca, and Roche, has served as a consultant for Renew Research, Eisai, Eli Lilly, Labcorp, Roche, and Renew Biotechnologies, and serves on a Data Monitoring Committee for Intra‐Cellular Therapies, Inc. Elizabeth C. Mormino is a consultant to Eli Lilly, Roche, and Neurotrack. Andrew J. Saykin receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, and U19 AG074879). He has also received in‐kind support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (PET tracer precursor) and Gates Ventures, LLC (SomaScan 7K proteomics panel assays on IADRC participants as part of the Global Neurodegeneration Proteomics Consortium), and has participated in Scientific Advisory Boards (Bayer Oncology, Eisai, Novo Nordisk, and Siemens Medical Solutions USA, Inc) and an Observational Study Monitoring Board (MESA, NIH NHLBI), as well as External Advisory Committees for multiple National Instituite on Aging (NIA) grants. He also serves as Editor‐in‐Chief of Brain Imaging and Behavior, a Springer‐Nature Journal. Karly Cody, Tobey J. Betthauser, Shubhabrata Mukherjee, Stephen A. Coombes, Sterling C. Johnson, Rebecca J. Lepping, James Leverenz, William M. Brooks, Russell Swerdlow, Emily Rogalski, Emily H. Trittschuh, Wei‐en Wang, David Vaillancourt, Eric Vidoni, Sarah Biber, Walter A. Kukull, and Paul K. Crane have received funding from the NIH. Emily Johns, Gabriel Kennedy, Hillary A. Vossler, Bill Bevis, Charles DeCarli, Frank P. DiFilippo, Ranjan Duara, Audrey P. Fan, Laura E. Gibbons, Todd Golde, Sean McDougall, Elizabeth Sanders, Joshua Pasaye, Jaiashre Sridhar, Anjali Sridharan, Jesse Mez, and Duygu Tosun have nothing to disclose. Author disclosures are available in the Supporting Information

Figures

FIGURE 1
FIGURE 1
Clinical heterogeneity and amyloid burden. (A) Flowchart depicting three diagnostic levels include (functional status, clinical syndrome, and suspected etiology). All the variables are extracted from the NACC Unified Dataset (UDS) D1 form. Dashed boxes indicate the name of the specific NACC variable used. The number of participants and percent of amyloid positivity is included for each variable (the shaded portion of the box reflects the percent of amyloid positivity). In the suspected etiology boxes, numbers indicate the number of participants with a certain etiology. (B) Amyloid burden is quantified with Gaussian Mixture Model (GMM) probablities and plotted against clinical groups. Abu, Drug abuse; AD, Alzheimer's disease; Alc, Alcohol abuse; Anx, anxiety; APP, amyloid precursor protein genetic mutation; BiP, bipolar disorder; CVD, cerebrovascular disease; Deprs, depression; ET, essential tremor; FTD, frontotemporal dementia; LBD, Lewy body dementia; MCI, mild cognitive impairment; Meds, medication side effects; PARK, Parkinson's disease; PSP, progressive supranuclear palsy; PTSD, posttraumatic stress disorder; Schz, schizophrenia; Slp ds, sleep‐related disease; Sys, systemic disorder; TBI, traumatic brain injury; VBI, vascular brain injury; Othr A‐G are detailed in eMethods 1.
FIGURE 2
FIGURE 2
Amyloid PET association with prospective functional and cognitive measures. (A) Survival plots and (B) longitudinal cognitive decline by dichotomous GMM status (50% cutoff, dichotomous amyloid status is used for visualization purposes only). A–, amyloid negative; A+, amyloid positive; CDR: Clinical Dementia Rating; d, day; MCI, Mild Cognitive Impairment; Neg, negative; pos, positive; y, year.
See this image and copyright information in PMC

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