Biology subjects

Breitner, J. C.

Publications and source records attributed to Breitner, J. C..

3 recordsLinked to original sources

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

Joint signatures of morphological and microstructural inter-individual variation in the Alzheimer's spectrum

Alzheimers disease (AD) is primarily characterized by the accumulation of amyloid and tau pathologies. However, alterations in the detailed organization and composition of neural tissue also contribute to the diseases early stages. Here, we sought to explore whether hippocampal and cortical microstructural changes, such as myelin alterations and inflammation-mediated increases in iron, could serve as indices of AD-related pathophysiology. In this study, we included 158 participants across the AD spectrum: from individuals without cognitive impairment, at high risk for AD, in the prodromal phase with mild cognitive impairment, and suffering from clinical dementia. We measured atrophy using structural magnetic resonance imaging (MRI) and estimated myelin and iron content using quantitative MRI (qMRI) metrics derived from T1 and T2* relaxation, times respectively. We integrated these contrasts to estimate a joint multivariate signature of tissue alterations across the cortex and hippocampus using non-negative matrix factorization. The relevance of these signatures to AD-spectrum measures of medical history, lifestyle, and cognition were further explored using partial least squares correlation. Our results reveal lower disease-related cortical thickness over large areas of the cortex while T2* provided specific variation across the brain (lower in dorsomedial and superior temporal areas, superior frontal cortex, and premotor cortex, and higher in the occipital lobe). Additionally, we observed longer T1 and T2* times in the hippocampus associated with specific lifestyle risk factors like past smoking, high blood pressure, high cholesterol levels, and higher anxiety. These patterns were significantly related to older age, associated with AD progression, being female, and being an APOE-{square}4 carrier. Taken together, our results suggest that qMRI metrics could serve as a valuable non-invasive tool for exploring the role of myelin and inflammation in AD-related pathophysiology and could be sensitive to modifiable risk factors related to lifestyle and medical history. Future studies may use these signatures to investigate their relationship in investigations related to lifestyle interventions or novel therapeutics.

neuroscience↗

bioRxiv2020

Vascular burden is associated with a decline in default-mode and global resting-state functional connectivity in individuals at risk for Alzheimer's disease

IntroductionCross-sectional studies suggest that cardiovascular risk factors and Alzheimers disease (AD) biomarkers are associated with abnormal brain resting-state functional connectivity in aging and AD; however, evidence is missing regarding longitudinal changes in functional connectivity. In this study, we investigate whether cholesterol levels and blood pressure are associated with changes in functional connectivity over time in asymptomatic individuals at risk for AD. The analyses were repeated with cerebral {beta}-amyloid (A{beta}) and tau deposition in a subset of the participants. MethodsThe study sample included 247 cognitively unimpaired individuals (185 women/ 62 men; mean [SD] age of 63 [5.3] years) of the PREVENT-AD cohort with a parental or multiple-sibling history of sporadic AD. Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global brain functional connectivity, and connectivity from canonical functional networks, were computed from resting-state functional MRI obtained at baseline and up to four years of annual follow-ups, using a predefined functional parcellation. A subset of participants underwent tau-PET ([18F]Flortaucipir) and A{beta}-PET ([18F]NAV4694). Vascular and AD measures were examined as predictors of brain functional connectivity changes in linear mixed-effects models. ResultsHigher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, while overall whole-brain functional connectivity showed an increase over time across the entire sample higher diastolic blood pressure was associated with reduction in whole-brain functional connectivity. The associations were similar when the analyses were repeated using two other functional brain parcellations. The findings with total-cholesterol and diastolic blood pressure were also similar but attenuated when performed in a subsample of participants with PET (n=91), whereas AD biomarkers were not associated with changes in functional connectivity over time in this subsample. ConclusionThese findings provide evidence that vascular burden is associated with a decrease in brain functional connectivity over time in older adults with elevated risk for AD. The impact of vascular risk factors on functional brain changes might precede AD pathology-related changes.

neuroscience↗