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Linking higher amyloid beta 1-38 (Aβ(1-38)) levels to reduced Alzheimer's disease progression risk.

Alzheimer's & dementia : the journal of the Alzheimer's Association

Authors: Luisa Sophie Schneider, Silka Dawn Freiesleben, Gerard van Breukelen, Xiao Wang, Frederic Brosseron, Michael T Heneka, Stefan Teipel, Luca Kleineidam, Melina Stark, Nina Roy-Kluth, Michael Wagner, Annika Spottke, Matthias Schmid, Sandra Roeske, Christoph Laske, Matthias H Munk, Robert Perneczky, Boris-Stephan Rauchmann, Katharina Buerger, Daniel Janowitz, Emrah Düzel, Wenzel Glanz, Frank Jessen, Ayda Rostamzadeh, Jens Wiltfang, Claudia Bartels, Ingo Kilimann, Anja Schneider, Klaus Fliessbach, Josef Priller, Eike Jakob Spruth, Julian Hellmann-Regen, Oliver Peters

INTRODUCTION: The beneficial effects of amyloid beta 1-38, or Aβ(1-38), on Alzheimer's disease (AD) progression in humans in vivo remain controversial. We investigated AD patients' cerebrospinal fluid (CSF) Aβ(1-38) and AD progression.

METHODS: Cognitive function and diagnostic change were assessed annually for 3 years in 177 Aβ-positive participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia from the German Center for Neurodegenerative Diseases (DZNE) longitudinal cognitive impairment and dementia study (DELCODE) cohort using the Mini-Mental State Examination (MMSE), Preclinical Alzheimer's Cognitive Composite (PACC), Clinical Dementia Rating (CDR), and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Mixed linear and Cox regression analyses were conducted. CSF was collected at baseline.

RESULTS: Higher Aβ(1-38) levels were associated with slower PACC (p = 0.001) and slower CDR Sum of Boxes (CDR-SB) (p = 0.002) but not MMSE decline. Including Aβ(1-40) beyond Aβ(1-38) in the model confirmed an association of Aβ(1-38) with slower PACC decline (p = 0.005), but not with CDR-SB or MMSE decline. In addition, higher Aβ(1-38) baseline levels were associated with a reduced dementia conversion risk.

DISCUSSION: Further research is needed to understand the role of Aβ(1-38) in AD and its potential for future therapeutic strategies.

HIGHLIGHTS: This study not only replicates but also extends the existing findings on the role of Aβ(1-38) (amyloid beta 1-38) in Alzheimer's disease (AD) in humans in vivo. Higher baseline Aβ(1-38) levels were associated with a decreased risk of conversion to AD dementia in subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Different linear-mixed regression models suggest an association between higher Aβ(1-38) baseline levels and slower Preclinical Alzheimer's Cognitive Composite (PACC) and Clinical Dementia Rating Sum of Boxes (CDR-SB) decline. Including Aβ(1-40) beyond Aβ(1-38) in the model confirmed a link between Aβ(1-38) and PACC decline, but showed no association of Aβ(1-38) on CDR-SB and Mini-Mental State Examination (MMSE) decline. The impact of short Aβ isoforms in AD progression might have been under-investigated These findings underscore the urgent need for additional research on the role of these shorter Aβ peptides in AD, as they may hold key insights for future therapeutic strategies.

© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

PMID: 39868793

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