Amyloid β accelerates white matter changes leading to Alzheimer’s
Amyloid-β (Aβ) deposits appear to promote Alzheimer’s disease (AD)-related changes in white matter microstructure even in cognitively healthy elderly adults, a new Singapore study has found.
“[K]ey AD-related fibres, such as the [right uncinate fasciculus (RUNC)] and [right inferior longitudinal fasciculus (RILF)], showed Aβ- and age-associated baseline [free-water (FW)] increases and Aβ-associated longitudinal FW increases, respectively,” said researchers.
In 21 Aβ-positive and 51 Aβ-negative brains of cognitively normal elderly adults, researchers found a significant Aβ × age × time interaction in RILF FW (p=0.0061; false discovery rate (FDR)-corrected p<0.05). That is, Aβ-positive participants who were older at baseline showed a steeper increase in FW over time relative to their Aβ-negative counterparts. [Hum Brain Mapp 2019;doi:10.1002/hbm.24507]
Researchers also found a cross-sectional interaction between Aβ and RUNC FW (p=0.0092; FDR-corrected p<0.10). This finding suggests that RUNC FW was greater in Aβ-positive vs -negative participants at baseline.
The fractional anisotropy measure of RUNC showed a significant longitudinal Aβ × time effect (p=0.0038; FDR-corrected p<0.05), indicating that the reduction over time was greater in those who were Aβ-positive. A cross-sectional association between age and Aβ was also reported (p=0.0022; FDR-corrected p<0.05).
As both the ILF and UNC fibres pass through the hippocampus, researchers also evaluated the cross-sectional and longitudinal effects of Aβ burden of hippocampal volume. They found Aβ-related reductions in right hippocampal volumes at baseline (p=0.012) and over time (p=0.0056). No such effect was reported for the left hippocampus.
Similar significant cross-sectional (p=0.045) and longitudinal (p=0.0071) effects were observed between Aβ burden and total hippocampal volume.
In terms of functional outcomes, researchers observed a significant cross-sectional association between age at baseline and memory (p=0.0000073), executive function (p=0.00265) and scores in the Alzheimer’s Disease Assessment Scale (ADAS; p=0.000616). No significant time effect was detected.
Notably, while researchers found no baseline or longitudinal effect of Aβ burden on measures of cognition, linear regression revealed a significant association between higher ADAS scores and greater baseline RUNC FW at baseline (p=0.005). Moreover, the rate of change in RILF FW showed a significant and age-dependent correlation with the change in memory score (p=0.0306).
“Our results highlighted the Aβ-associated effect on white matter microstructure in RUNC and RILF fibres, known to play important roles in AD development,” said researchers.
“[A] possible temporal sequence of biomarker trajectory in the asymptomatic elderly at risk of AD could involve early Aβ deposition which then drives early microstructural changes in the UNC and other related fibres like the ILF, closely followed by grey matter atrophy and subsequent cognitive decline as disease sets in,” they explained. [Neuroimage 2015;123:42-50; Curr Opin Psychiatry 2013;26:244-251]
Clinically, the present findings may eventually lead to the use of changes in brain microstructure as biomarkers for the early assessment of AD risk, researchers pointed out. These may also help to more clearly elucidate the underlying pathophysiology of AD, contributing to basic research.
“Collectively, our study underlines the importance of longitudinally examining asymptomatic elderly individuals to help decipher changes in the brain that could contribute to early disease detection such that corrective measures can be taken before irreversible damage occurs,” they said.