FASEB journal : official publication of the Federation of American Societies for Experimental BiologyJul 5, 2006

Disturbed daily rhythm of the pineal gland in Alzheimer's disease linked to loss of connection with the brain's main clock

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

Rhythmic expression of clock genes in the pineal gland was lost in Alzheimer's disease patients.

The suprachiasmatic nucleus (SCN) regulates peripheral clocks, including the pineal gland's melatonin production.
In healthy controls, clock genes hBmal1, hCry1, and hPer1 exhibited rhythmic expression in the pineal gland.
In Alzheimer's disease patients, both preclinical and clinical, this rhythmic expression of clock genes was disrupted.
A positive correlation between hPer1 and hbeta1-adrenergic receptor mRNA was observed in controls but lost in Alzheimer's disease.
In clinical Alzheimer's disease, hCry1 mRNA levels were increased despite the loss of rhythmic clock gene expression.
Functional disruption of the SCN may begin in the early stages of Alzheimer's disease, indicated by decreased vasopressin mRNA.

Simplified

The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer's disease (AD). Here we show that the clock genes hBmal1, hCry1, and hPer1 were rhythmically expressed in the pineal of controls (Braak 0). Moreover, hPer1 and hbeta1-adrenergic receptor (hbeta1-ADR) mRNA were positively correlated and showed a similar daily pattern. In contrast, in both preclinical (Braak I-II) and clinical AD patients (Braak V-VI), the rhythmic expression of clock genes was lost as well as the correlation between hPer1 and hbeta1-ADR mRNA. Intriguingly, hCry1 mRNA was increased in clinical AD. These changes are probably due to a disruption of the SCN control, as they were mirrored in the rat pineal deprived of SCN control. Indeed, a functional disruption of the SCN was observed from the earliest AD stages onward, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. Thus, a functional disconnection between the SCN and the pineal from the earliest AD stage onward could account for the pineal clock gene changes and underlie the circadian rhythm disturbances in AD.

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Disturbed daily rhythm of the pineal gland in Alzheimer's disease linked to loss of connection with the brain's main clock

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