Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer’s disease
Authors: Mengel David , Soter Ester , Ott Julia Maren , Wacker Madeleine , Leyva Alejandra , Peters Oliver , Hellmann-Regen Julian , Schneider Luisa-Sophie , Wang Xiao , Priller Josef , Spruth Eike , Altenstein Slawek , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Hansen Niels , Rostamzadeh Ayda , Düzel Emra , Glanz Wenzel , Incesoy Enise I. , Buerger Katharina , Janowitz Daniel , Ewers Michael , Perneczky Robert , Rauchmann Boris , Teipel Stefan , Kilimann Ingo , Laske Christoph , Sodenkamp Sebastian , Spottke Annika , Brustkern Johanna , Brosseron Frederic , Wagner Michael , Stark Melina , Kleineidam Luca , Shao Kai , Lüsebrink Falk , Yakupov Renat , Schmid Matthias , Hetzer Stefan , Dechent Peter , Scheffler Klaus , Berron David , Jessen Frank , Synofzik Matthis ,   the DELCODE study group
Published: July 2024

Introduction

Subjective cognitive decline (SCD) is proposed to indicate transitional stage-2 in the AD continuum, yet longitudinal fluid biomarker data for this stage is scarce. We investigated if blood-based biomarkers in amyloid-positive individuals with SCD (A+SCD) support stage-2 as distinct from AD stages-1 and -3 and identify those at high risk for progression.

Methods

We analyzed plasma phospho-tau-181 (p181) and neurofilament-light-chain (NfL) in a prospective multicenter study of 460 participants across the AD continuum, assessing their association with cognition, hippocampal atrophy, and clinical progression.

Results

Baseline plasma p181 was elevated and increased faster in A+SCD compared to amyloid-positive cognitively unimpaired (A+CU) individuals (stage-1). NfL rose across A+CU, A+SCD, and A+MCI (stage-3). In A+SCD, higher p181 predicted cognitive decline and transition to MCI.

Discussion

Plasma p181 provides biomarker evidence for A+SCD as a distinct pre-dementia AD stage and helps identify individuals at risk for cognitive decline early in the AD continuum.

Research in Context

Systematic Review

Research on subjective cognitive decline (SCD) and its association with Alzheimer’s disease (AD), as well as investigations into stage-2 of the AD continuum, is quickly expanding, but fluid biomarker evidence is scarce. We conducted a comprehensive review across PubMed, recent meeting abstracts, and oral presentations, focusing on cross-sectional and longitudinal case-control studies, cohort studies, and meta-analyses.

Interpretation

Our plasma phospho-181 tau (p181) findings provide molecular fluid biomarker evidence for A+SCD as a pre-dementia AD stage (stage-2) distinct from A+CU (stage-1). Plasma p181 assessment aids in identifying individuals at risk of future disease progression early in the AD continuum.

Future directions

The here proposed concept of SCD as an indicator of stage 2 of the Alzheimer’s disease continuum - supported and stratified by easily accessible blood-based biomarkers - warrants further validation in memory clinics. It could facilitate earlier- and thus even higher-effect - treatments in the pre-dementia stages of AD.

Highlights

A+SCD exhibits a distinct trajectory of plasma p181 compared to A+CU

Higher plasma p181 levels in A+SCD predict PACC5 decline and transition to MCI

Plasma p181 serves as a biomarker that delineates the A+SCD stage from A+CU

Plasma p181 levels stratify SCD patients, facilitating early interventions