2 2. Sleep and Circadian Rhythmicity in Alzheimer Patients Nocturnal sleep disturbance is often reported by caregivers of Alzheimer patients and seems to be associated with disease severity [19]. Additionally, sleep quality is often very poor [20] and AD patients suﬀering from apathy seem to exhibit less consolidated nocturnal sleep [21]. Furthermore, disturbed sleep patterns in patients can have adverse consequences for the health of caregivers [22]. Interestingly, a delayed endogenous circadian phase of core body temperature was found in patients with probable AD by Harper and coworkers [13]. The same group also described that the deviation from normal circadian rhyth- micity increases with the severity of Alzheimer pathology [23] and that there might be distinct diﬀerences in the pattern of desynchronisation depending on the type of neurodegeneration [12]. These ﬁndings can be interpreted as support for the hypothesis that disturbed circadian rhythmicity in patients with AD is mediated by pathological CNS (central nervous system) changes. Hatﬁeld et al. [23] monitored rhythmicity via actigra- phy and cortisol determination in a group of mildly and moderately demented Alzheimer patients over the course of a year and report that as disease progresses, so does the activity rhythm, but the cortisol rhythm is relatively spared. These ﬁndings suggest that in the earlier stages of the disease process, circadian deterioration may not be a global phenomenon, but may aﬀect speciﬁc domains. A recent study by Hu et al. [24] shows that AD attenuates the scale invariance of the motor rhythm, perhaps reﬂect- ing pathological alterations in the SCN (suprachiasmatic nucleus). Such pathological changes in the SCN have been noted in postmortem analysis of the brains from severely demented patients, with neuronal loss and tangles noted, but rarely plaques in the SCN [25]. There are also decreases in speciﬁc neurochemical phenotypes in the SCN that are lost [25, 26], with such neurochemicals (VIP (vasoactive intestinal peptide), AVP (arginine-vasopressin)) being cru- cially implicated in SCN function. Such disturbances in SCN function and the resultant circadian abnormalities are postulated to in part underpin “sundowning” in Alzheimer patients, in which behavioural agitation arises in the late afternoon/evening [27]. In this context, the results of an animal model experiment are interesting: the study involved the implantation of genetically modiﬁed, beta/A4-expressing cells into the SCN of adult rats. It was possible to demon- strate that such overexpression of beta/A4 amyloid led to signiﬁcant alterations in the activity pattern of the animals and disruption of circadian rhythmicity [28]. The 3xTg (triple transgenic) mouse models of AD, which exhibits both Abeta and tau neuropathology, show deteriorated circadian organisation of locomotor behaviour, although there was no weakening of the ability of the system to respond appropriately to light stimulus, whilst the SCN of these animals also showed a decrease of VIP and AVP cells [29]. Bero et al. [30] demonstrated, again in a murine model, that the concentration of interstitial-ﬂuid Abeta and, thus, the Abeta aggregation depend on endogenous neuronal activity, Journal of Aging Research implying that disturbed sleep could contribute to amyloid deposition. Craig et al. [31] suggested that the common and distressing sleep disruption in Alzheimer patients is associated with genetic factors, speciﬁcally with a variation of the MAO-A (monoamine oxidase A) gene. Other obvious candidate genes are CLOCK genes. While this gene family has been implicated in other neuropsychiatric disorders [32], a recent study failed to reveal possible associations between CLOCK gene single-nucleotide polymorphisms (SNPs) and sleep-wake disturbance in AD [14]. Nevertheless, even if CLOCK gene variants have not yet been identiﬁed as possible risk factors, it is possible that the expression of these genes is altered in Alzheimer patients and that a changed expression pattern of these genes contributes to disturbed circadian rhythms [33]. 3. The Role of CLOCK Genes in AD It has been shown that age, the most important risk factor for AD, inﬂuences the expression of molecules involved in immunity as well as in cell signaling and transcription factor regulation, such as transforming growth factor-beta and phosphorylated SMAD3 (Mothers against decapenta- plegic homolog 3), in the mouse suprachiasmatic (SCN) and paraventricular nuclei, that is, the neuroanatomical areas crucially involved in the maintenance of circadian rhythmicity [34]. In a recent postmortem study, Cermakian and coworkers found signiﬁcant diﬀerences in the expression pattern of CLOCK genes between Alzheimer patients and controls. The RNA (ribonucleic acid) expression level of the CLOCK gene PER1 (period circadian protein homolog 1), PER2 (period circadian protein homolog 2), and BMAL1 (brain and muscle aryl-hydrocarbon-receptor-nuclear translocator- (ARNT-) like) were quantiﬁed via RT-PCR (reverse tran- scription polymerase chain reaction) for the following brain areas: bed nucleus of the stria terminalis, cingulate cortex, and the pineal gland [33]. A previous study had already shown that in the brain of Alzheimer patients vasopressin gene expression is altered in the SCN [35]. Additionally, a possible noncircadian role of CLOCK genes in psychiatric disorders has been discussed, mainly aﬀecting behavioural phenomena; however, this could also be an epiphenomenon of underlying rhythmicity at the cellular and systemic level [36]. A further important point is also the possibility of using a “resetting” of the internal clock in the treatment of AD. For example, there is evidence that the use of light therapy may delay cognitive decline in AD as well as noncognitive symptoms such as depression [37, 38]. In this context, the possible impact of AD medication on CLOCK gene expression and, thus, indirectly on circadian rhythmicity must also be discussed. To our knowledge, there are no studies published which address this issue speciﬁcally for medication used in Alzheimer treatment. However, there is considerable evidence that neuropsychiatric medication can signiﬁcantly alter the expression of CLOCK genes in various brain areas. In animal models, haloperidol alters the