Journal of Aging Research circadian CLOCK gene expression in the murine CNS [17]. Further, medication with typical neuroleptic haloperidol has been found to alter the rhythmicity of rest-activity cycle and to deteriorate the cognitive state in early-onset Alzheimer patients [39]. 4. The Dilemma of How and When to Monitor the CLOCK Genes There are signiﬁcant diﬃculties in monitoring CLOCK genes, either when one monitors the genes themselves or their RNA or protein products. Starting at the gene level, it is important to know exactly when the material was collected during the day from patients with AD. Since the genes are inﬂuenced by circadian rhythms, a sample collected during the night will be diﬀerent from ones collected during the day (or even morning/evening). Finding a matched control may also be diﬃcult. Background substraction and data manip- ulation to eliminate false positive or false negative results is also important and diﬃcult to address. It is also important to know what is inﬂuenced by circadian rhythms: the gene, the RNA, the protein, protein posttranslational modiﬁcations, protein-protein interactions, or a combination of more than one? Also, if only CLOCK proteins are responsible for the circadian phase, what phenomenon aﬀects the level of the proteins per se? Is it the increase in RNA translation (and increased gene transcription) leading to increased protein expression or is it just prevention of protein degradation? Is it reduced rate of phosphorylation or increased rate of dephosphorylation? Trying to answer these and other questions as well as ﬁnding the right way to investigate these genes and their transcriptional and translational products, as well as posttranslational modiﬁcations and protein-protein interactions is challenging and time consuming. 5. Discussion During recent years, better understanding of the molecular and cellular basis of the clinically frequently observed sleep disturbances and disrupted diurnal and nocturnal rhythms of Alzheimer patients is slowly evolving. CLOCK genes are crucially involved in the maintenance of such rhythmicity, and studies linking this molecule family to brain and body processes in Alzheimer patients can further elucidate the etiopathogenesis of this most frequent dementia. However, to date, the number of such studies is limited and there are only very few reliable and reproducible data available. Further research is urgently needed, especially regarding the exact role CLOCK genes play within the AD pathological cascade and regarding the exact interaction with other pathogenic factors such as amyloid, neuroﬁbrillary tangles, oxidative stress, advanced glycation end products, lipidomic alterations, altered immune modulation, excitotoxicity, and so forth. Another important feature of CLOCK genes is their close interrelation with external, that is, environmental factors; thus, very few other gene families exhibit such strong gene- environment interaction and interdependency. Therefore, 3 they might be crucial in the integration of exogenous factors and noxae (such as stress) and endogenous vulnerability fac- tors (such as inherited genetic variants), ultimately leading to the clinical phenomenology of AD. Finally, using and applying this knowledge for the development of improved treatment strategies with better eﬃcacy and tolerability will be an important challenge which, if faced, might lead to signiﬁcant contributions to the improvement of the quality of life of millions of people suﬀering from AD. Acknowledgments J. Thome has received ﬁnancial support from pharmaceutical companies (Astra Zeneca, Bristol-Myers Squibb, Janssen- Cilag, Lilly, Lundbeck, MEDICE, Merz, Novartis, Pﬁzer, Servier, and Shire) some of which manufacture medication used in the treatment of Alzheimer patients. C. C. Darie has received ﬁnancial support from the U.S. Army research oﬃce through the Defense University Research Instrumentation Program (DURIP Grant no. W911NF-11-1-0304). References [1] D. E. Barnes and K. Yaﬀe, “The projected eﬀect of risk factor reduction on Alzheimer’s disease prevalence,” The Lancet Neurology, vol. 10, no. 9, pp. 819–828, 2011. [2] A. Alzheimer, “U¨ ber eine eigenartige Erkrankung der Hirn- rinde,” Allgemeine Zeitschrift fu¨r Psychiatrie und psychisch- gerichtliche Medizin, vol. 64, pp. 146–148, 1907. [3] K. Bettens, K. 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