Biology subjects

Wearn, A.

Publications and source records attributed to Wearn, A..

4 recordsLinked to original sources

bioRxiv2026

Longitudinal changes in control energy of brain networks in older adults at familial risk for Alzheimers disease

The ability of structural brain networks to control neural dynamics is affected by healthy and pathological aging, including Alzheimers disease (AD). According to network control theory, transitions between functional brain states incur energetic costs. How these costs change longitudinally with aging remains unknown. Here, in 279 older adults at familial risk for AD, control energy increased longitudinally for state maintenance and transitions between sensorimotor and attentional networks, while decreasing for another sensorimotor--attentional transition. Changes in transition costs between higher-order networks were associated with cognitive performance: greater DorsAttn--Executive cost was associated with poorer immediate memory, while lower Executive--Def+Lim cost was associated with poorer attention. Higher plasma p-tau181 was associated with lower DorsAttn--Def+Lim transition cost. These findings reveal transition-specific alterations in the energetic landscape of aging and distinct relationships with cognition and AD pathology. Together, they highlight energetic constraints on brain network reconfiguration as a complementary perspective on neurocognitive aging.

neuroscience↗

bioRxiv2025

Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease

INTRODUCTIONThe locus coeruleus (LC) is among the first sites of tau pathology in Alzheimers disease (AD) and may seed neocortical tau. METHODSWe used longitudinal neuromelanin-sensitive MRI to assess LC integrity in vivo in a cohort of cognitively unimpaired older adults with familial risk of AD in relation to tau and amyloid PET and long-term cognitive trajectories. RESULTSWe showed that both LC integrity at baseline and its rate of degeneration over time independently predicted a neocortical pattern of tau deposition. In keeping with the known function of the LC, neuropsychological tests showed that LC integrity at baseline predicted changes in attention. Finally, we found that longitudinal LC degeneration correlated with memory decline in people with elevated neocortical amyloid burden. DISCUSSIONOur findings underscore the importance of LC in AD pathogenesis. Longitudinal measurement of LC degeneration may help distinguish trajectories of age-related cognitive decline and early AD.

neuroscience↗

bioRxiv2025

Cholinergic synaptic plasticity shapes resilience and vulnerability to tau

Synaptic dysfunction is a hallmark of Alzheimers disease (AD). Yet due to their plasticity, synapses may also adapt to early AD pathology. Here, we demonstrate that cholinergic neurons mount a presynaptic response to tau pathology in the living human brain. Using multi-tracer positron emission tomography in cognitively normal older adults at risk for AD, we observe that cholinergic neurons increase presynaptic vesicular acetylcholine transporter (VAChT) protein levels when colocalized to tau, but not amyloid. Notably, stronger VAChT responses were associated with cognitive resilience over a decade. Whole-brain single-nucleus RNA sequencing in human and mouse tissue reveal that cholinergic neurons are enriched for a plasticity gene-network anchored to the microtubule-associated protein tau (MAPT) gene. In mice, forebrain-specific deletion of VAChT impairs cortical plasticity and hippocampal structural integrity. Overall, our findings identify cholinergic synaptic plasticity, and its failure, as a fundamental mechanism of resilience and vulnerability to tau in presymptomatic AD.

neuroscience↗

bioRxiv2024

Sex and APOE4-specific links between cardiometabolic risk factors and white matter alterations in individuals with a family history of Alzheimer's disease

INTRODUCTIONWhite matter (WM) alterations are among the earliest changes in Alzheimers disease (AD), yet limited work has comprehensively characterized the effects of AD risk factors on WM. METHODSIn older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and risk factors. Multiple MRI-derived metrics were integrated using a multivariate approach based on the Mahalanobis distance (D2). The links between WM D2 and cognition were also explored. RESULTSWM D2 in several regions was associated with high systolic blood pressure, BMI, and glycated hemoglobin, and low cholesterol, in both males and females. APOE4+ displayed a distinct risk pattern, with LDL-cholesterol having a detrimental effect only in carriers, and this pattern was linked to immediate memory performance. Myelination was the main mechanism underlying WM alterations. DISCUSSIONOur findings reveal that combined exposure to multiple cardiometabolic risk factors negatively impacts microstructural health, which may subsequently affect cognition. Notably, APOE4 carriers exhibited a different risk pattern, especially in the role of LDL, suggesting distinct underlying mechanisms in this group.

neuroscience↗