By Michael T. Lin, MD, PhD
Synopsis: In a retrospective review of patients followed in the Wisconsin Alzheimer Disease Research Center, the time course of early deposition of amyloid-β correlated with regional atrophy in temporoparietal regions of interest independent of tau positivity.
Source: Stephenson HG, Langhough R, Jonaitis E, et al. Abnormal amyloid-β, tau, and neurodegeneration in cranial images. JAMA Netw Open. 2025;8(9):e2531093.
The long preclinical course of Alzheimer’s disease (AD), in which amyloid plaques may be present decades before symptoms develop, raises questions about the relative contribution of amyloid-β (Aβ) to the neurodegenerative process. The current orthodoxy is that neurodegeneration is more strongly associated with the later accumulation of tau/neurofibrillary tangles than with Aβ.1 However, in their recent article, Stephenson and colleagues showed that in predominantly cognitively unimpaired subjects, the presence and possibly the duration of Aβ-positivity (Aβ+) was associated with more rapid volume loss in several medial temporal lobe and neocortical regions, even controlling for tau-positivity.
Subjects were drawn from the Wisconsin Registry of Alzheimer’s Prevention (WRAP) and from the Wisconsin Alzheimer Disease Research Center Clinical Core Study. A replication study was conducted using the Open Access Series of Imaging Studies 3 (OASIS-3) dataset. Inclusion criteria were at least two T1-weighted volumetric magnetic resonance images (MRIs), one Pittsburgh B compound (PiB) positron emission tomography (PET) assessment of Aβ, one MK-6240 PET assessment of tau, cognitive status or diagnosis within two years of baseline MRI, and apolipoprotein E (apoE) genotype.
On the longitudinal volumetric MRIs, atrophy was assessed in 16 temporoparietal regions of interest (ROI). Duration of Aβ positivity from a single PiB PET was estimated using a statistical model previously trained on a longitudinal PET dataset. Tau positivity was assessed in the anterior parahippocampal gyri. Cognitive status or diagnosis was determined by multidisciplinary consensus review.
The Wisconsin dataset contained 95 Aβ+ subjects (11 cognitively impaired, 49 tau+) and 275 Aβ- subjects (10 cognitively impaired, 22 tau+). The median follow-up was 8.8 (interquartile range [IQR], 5.9 to 10.6) years. The OASIS-3 replication dataset contained 32 Aβ+ subjects (five cognitively impaired, 16 tau+) and 159 Aβ- subjects (four cognitively impaired, 15 tau+). The median (IQR) follow-up was 6.1 (3.5 to 9.0) years.
In the Wisconsin dataset, the presence of Aβ was associated with accelerated atrophy in 10 of 16 ROIs, particularly the amygdala, precuneus, temporooccipital inferior temporal gyrus, and hippocampus. Cognitive impairment was associated with significantly faster atrophy in nine of 16 ROIs relative to cognitively unimpaired individuals, but association of Aβ with accelerated atrophy was robust to exclusion of cognitively impaired subjects, as well as controlling for tau positivity. In the OASIS-3 replication dataset, presence of Aβ was associated with accelerated atrophy in 14 of 16 ROIs, controlling for tau positivity.
In the Wisconsin dataset, the median (IQR) duration of Aβ positivity was 3.6 (1.2 to 7.5) years. Despite the short duration, duration of Aβ positivity was associated with accelerated atrophy in 14 of 16 ROIs, although effect sizes generally were small. The association was robust to exclusion of cognitively impaired subjects, as well as controlling for tau positivity. However, in the OASIS-3 replication dataset, duration of Aβ positivity was associated with accelerated decline in only six of 16 ROIs, controlling for tau-positivity.
Commentary
These results show that Aβ itself is associated with more rapid volume loss in AD-relevant regions, even after controlling for tau-positivity, and this occurs even with a relatively short duration of Aβ (median 3.6 years). There also was an association of increasing duration of Aβ positivity with accelerated volume loss, even after controlling for tau. These results suggest that Aβ does contribute to critical degenerative processes even very early in the presymptomatic period, and they highlight the importance of current trials of anti-amyloid monoclonals in cognitively unimpaired subjects with positive Aβ biomarkers.
Michael T. Lin, MD, PhD, is Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College.
Reference
1. Gordon BA, McCullogh A, Mishra S, et al. Cross-sectional and longitudinal atrophy is preferentially associated with tau rather than amyloid β positron emission tomography pathology. Alzheimers Dement (Amst). 2018;10:245-252.
