2025 Hyper Recent •CC0 1.0 Universal

This work is dedicated to the public domain. No rights reserved.

Access Preprint From Server
June 30th, 2025
Version: 2
Yale University
neuroscience
biorxiv

Basal forebrain volume is associated with cortical amyloid burden in cognitively unimpaired older adults at varying genetic risk for Alzheimers disease

Cho, G.Open in Google Scholar•Kelly, K.Open in Google Scholar•Toyonaga, T.Open in Google Scholar•Carson, R. E.Open in Google Scholar•Miner, B.Open in Google Scholar•Gelernter, J.Open in Google Scholar•Varma, P.Open in Google Scholar•Van Dyck, C.Open in Google Scholar•Mecca, A. P.Open in Google Scholar•O'Dell, R.Open in Google Scholar

Background: In mild cognitive impairment and dementia due to Alzheimers disease (AD), postmortem and in vivo neuroimaging studies have demonstrated significant neuronal loss in the basal forebrain cholinergic system (BFCS), which provides the primary cholinergic input to the cerebral cortex. Within this region, atrophy is most prominent in the nucleus basalis of Meynert (nbM), a group of posteriorly clustered magnocellular neurons in the BFCS. However, less is known surrounding the relationship between amyloid deposition, BFCS atrophy, and medial temporal lobe (MTL) volume loss in the preclinical stages of AD. The current study investigates the relationship between sub-structural BFCS volume and cortical amyloid-beta burden in cognitively unimpaired middle-aged individuals at varying genetic risk for AD. Methods: Cognitively unimpaired participants aged 50-65 with a first-degree family history for AD were genetically screened to select three groups: APOE genotype e3e3 (n=15), e3e4 (n=15), and e4e4 (n=15), matched for age and sex. Participants underwent imaging with [11C]PiB PET and structural 3T MRI. Distribution volumes ratios (DVR) with a whole cerebellum reference region were calculated for [11C]PiB PET analyses. BFCS sub-structural volumes were obtained from the SPM8 Anatomy Toolbox (Cholinergic nuclei [Ch] 1-3, Ch4). MTL subregional volumes (entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus) were extracted using Freesurfer. Results: BFCS amyloid burden was highest among APOE e4 homozygotes (Ch1-3, F(2, 42)=3.26, P=0.048; Ch4, F(2, 42)=3.82, P= 0.03). Ch4 (nbM), but not Ch1-3 volume, was found to be inversely associated with global amyloid-beta burden (Pearson r=-0.40, P=0.007). MTL subregional volumes were not associated with global amyloid-beta burden in the pooled sample. Exploratory analyses in groups stratified by amyloid positivity demonstrated reduced Ch4 volume (P=0.032) and significant inverse associations between Ch4 volume and amyloid burden (Pearson r = -0.70, P=0.02) in amyloid+ participants. Conclusions: We observed nbM (Ch4), but not MTL volume, to be significantly inversely associated with cortical amyloid burden in cognitively unimpaired, amyloid+, middle-aged adults at varying genetic risk for AD. These findings provide further in vivo evidence suggesting that nbM atrophy is an early structural correlate of AD pathogenesis, potentially preceding MTL atrophy.

Similar Papers

biorxiv
Mon Jun 30 2025
Progressive overfilling of readily releasable pool underlies short-term facilitation at recurrent excitatory synapses in layer 2/3 of the rat prefrontal cortex
Short-term facilitation of recurrent excitatory synapses within the cortical network has been proposed to support persistent activity during working memory tasks, yet the underlying mechanisms remain poorly understood. We characterized short-term plasticity at the local excitatory synapses in layer 2/3 of the rat medial prefrontal cortex and studied its presynaptic mechanisms. Low-frequency stimul...
Shin, J.
•
Lee, S. Y.
•
Kim, Y.
•
Lee, S.-H.
biorxiv
Mon Jun 30 2025
Maintenance of neuronal TDP-43 expression requires axonal lysosome transport
TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate TDP-43 in neurons are not well understood. We generated a Halo-TDP-43 knock-in iPSC line and performed a genome-wide CRISPR interference FACS-based screen to identify modifiers of TDP-43 levels in neurons. A meta-analysis of our screen and publicly available screens identified b...
Ryan, V. H.
•
Lawton, S.
•
Reyes, J. F.
•
Hawrot, J.
...•
Ward, M.
biorxiv
Mon Jun 30 2025
Whisker stimulation reinforces a resting-state network in the barrel cortex: nested oscillations and avalanches
The cerebral cortex operates in a state of restless activity, even in the absence of external stimuli. Collective neuronal activities, such as neural avalanches and synchronized oscillations, are also found under rest conditions, and these features have been suggested to support sensory processing, brain readiness for rapid responses, and computational efficiency. The rat barrel cortex and thalamu...
Mariani, B.
•
Guevara, R.
•
Tambaro, M.
•
Maschietto, M.
...•
Suweis, S.
biorxiv
Mon Jun 30 2025
How spatial attention alters visual cortical representation during target anticipation
Attention enables us to efficiently and flexibly interact with the environment by prioritizing specific image locations and features in preparation for responding to stimuli. Using a concurrent psychophysics-fMRI experiment, we investigated how covert spatial attention modulates responses in human visual cortex before target onset and how it affects subsequent behavioral performance. Performance i...
Tüncok, E.
•
Carrasco, M.
•
Winawer, J.
biorxiv
Mon Jun 30 2025
Disrupted resting-state fMRI coherence at vasomotor frequency links carotid artery stenosis to functional connectivity loss
Vasomotor dynamics at the infra-slow frequencies (~0.1 Hz), driven by synchronized oscillation of smooth muscle cells in vessel walls, play an important role in regulating cerebral perfusion and constitute a physiological basis for resting-state functional connectivity (FC). Invasive animal studies have demonstrated that vasomotor activity contributes to coherent blood oxygenation-dependent level ...
Choi, S.
•
Hoffmann, G.
•
Schneider, S.
•
Kaczmarz, S.
...•
Preibisch, C.
biorxiv
Mon Jun 30 2025
Endophilin A1 facilitates organization of the GABAergic postsynaptic machinery to maintain excitation-inhibition balance
The assembly and operation of neural circuits in the brain rely on the coordination and balance of excitatory and inhibitory activities. Inhibitory synapses are key regulators of the functional balance of neural circuits. However, due to the diversity of inhibitory presynaptic neurons, the complex composition of postsynaptic receptor subunits and the lack of typical postsynaptic dense structure, t...
Chen, X.
•
Pan, D.
•
Liu, J.-J.
•
Yang, Y.
biorxiv
Mon Jun 30 2025
WITHDRAWN: Humans can walk economically on uneven terrain without deliberative optimization with a Simple Feedback Control Policy
The author Osman Darici has withdrawn this manuscript because, after further reflection and ongoing work, the author has determined that the analyses presented in the current version of the preprint are incomplete and require substantial revision and further development. As such, the author believes the manuscript does not yet reflect the standards that he aims to uphold in his scientific contribu...
Darici, O.
•
Kuo, A.
biorxiv
Mon Jun 30 2025
F2,6BP restores mitochondrial genome integrity in Huntingtons Disease
Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntingtons disease (HD). Mitochondrial genome damage, particularly DNA strand breaks, is a potential cause for its compromised functionality. Here we show that the activity of polynucleotide kinase 3-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly decrea...
Chakraborty, A.
•
Mandal, S. M.
•
Mankevich, M.
•
Mani, R. S.
...•
Hazra, T.
biorxiv
Mon Jun 30 2025
Disturbed engram network caused by NPTXs downregulation underlies aging-related memory deficits
Engram cells storing specific memories are allocated to separate neuronal ensembles, which preferentially recruit either excitatory or inhibitory inputs to drive precise memory expression. However, how these formed neuronal ensembles maintain their stability, and whether the disturbed stability contributes to aging-related memory deficits remain elusive. Here, we show that neuronal pentraxin1 (NPT...
Jin, T.
•
Yang, Y.
•
Guo, Y.
•
Zhang, Y.
...•
Wang, F.