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Preprint WatchModerateSeptember 2nd, 2026

The circadian system is affected by Alzheimers disease independently from amyloid beta deposits

Calligaro, H.; Khov, B.; Noel, K.; Glina, A.; van Rosmalen, L.; Ramasamy, R.; Li, Y.; Lam, M. T. Y.; Le, H.; Kim, K.-Y.; Ju, W.-K.; Ellisman, M.; Panda, S.

Circadian and sleep disruption in the APP/PS1 model arises from suprachiasmatic nucleus connectomic degeneration and retinal ganglion cell dysfunction, and tracks independently of amyloid beta deposition.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that circadian disruption in the APP/PS1 mouse model develops independently of amyloid beta deposits, locating the deficit in suprachiasmatic nucleus connectomics and melanopsin retinal ganglion cell activity rather than in plaque burden. The Claidex record for APP contains one documented failure, valiltramiprosate-alz801-app-apoe4-alzheimers-phase3-efficacy-failure, a Phase 3 efficacy failure in APOE4 homozygotes with early Alzheimer's disease. The two sit on the same fault line. If a measurable domain of Alzheimer's pathophysiology dissociates from amyloid in a model built to accumulate amyloid, then trials that select on amyloid biology and read out on global cognition carry an unmeasured mismatch between the mechanism modified and the endpoint scored. This preprint does not test any therapeutic, and it is a mouse study, so it constrains interpretation rather than settling it. It flags an amyloid-independent axis that an APP-directed program would need to account for in endpoint selection.

Abstract excerpt

Circadian disruption, notably sleep disturbances, serves as an early indicator of Alzheimers disease (AD), preceding cognitive symptoms like memory loss. The suprachiasmatic nucleus (SCN) governs biological rhythms and receives direct retinal input via melanopsin-expressing retinal ganglion cells (mRGCs) to synchronize with environmental light cycles. The anatomical and functional basis for circadian disruption in AD remains unclear. Here, we explored the multi-level relationships between gene expression, the SCN connectome, and regulations of sleep and circadian rhythms in the APP/PS1 mouse model. The sleep architecture of APP/PS1 mice displayed significantly reduced rapid eye movement sleep (REM), associated with a reduced daily core body temperature amplitude and locomotor hyperactivity. Lastly, APP/PS1 mice showed an impaired response to acute light pulse stimulation and present hyperactivity of mRGCs at a young age and hypoactivity of these cells at older ages. These physiological functions are known to be, at least in part, regulated by the SCN, the main target of mRGCs. We noted several modifications in SCN connectomics using serial blockface electron microscopy (SBEM), including a reduction of the dendro-dendritic chemical synapse (DDCS) network that receives a large part of the retinal input and is thought to be crucial for synchronicity between SCN neurons. In addition, we observed multiple signs of dystrophy, including modifications of the shape of dendrites and cell soma, accumulation of aggregated lysosomes, and swelling of axons. At the same time, we investigated the changes in gene expression using spatial transcriptomics. The SCN presents changes in the expression of genes associated with synapse formation, cell adhesion, and neurite growth. These results suggest that, despite the absence of amyloid plaques in the ventral hypothalamus, the SCN of APP/PS1 mice still undergo profound gene expression changes, impacting connectomics and physiological functions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/744599v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@ceedb0org.highwire.dtl.DTLVardef@156cfaaorg.highwire.dtl.DTLVardef@5bc262org.highwire.dtl.DTLVardef@36df4d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.