Per2 C111G polymorphism influences cognition in Subjective Cognitive Decline and Mild Cognitive Impairment. A 10-year follow-up study

Background: CLOCK and PER2 genes have been implicated in sleep-wake cycle alterations and neurodegenerative diseases. We aimed to evaluate the effect of CLOCK T3111C and PER2 C111G on cognitive functioning in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) patients at the baseline of a longitudinal study, and the effect of these two polymorphisms on the progression to AD of the two groups. Methods: We included 68 subjects (41 SCD and 27 MCI), who underwent clinical evaluation, neuropsychological assessment, CLOCK and PER2 genotyping at baseline and neuropsychological follow-up every 2 years for a mean time of 10 years. We considered subjects who developed AD (SCD-c and MCI-c) and non-converters (SCD-nc, MCI-nc). Results: CLOCK T3111C was detected in 47% of cases (21 SCD, 11 MCI), PER2 C111G in 19% of cases (8 SCD and 5 MCI). PER2 G carriers presented lower premorbid intelligence score (p=0.049), fewer years of education (p=0.007), and lower frequency of family history of AD (p=0.04) than G non-carriers. MCI PER2 G carriers had worse performance in tests assessing memory, executive function, language and visuo-spatial abilities at baseline. During follow-up, 2 SCD and 15 MCI subjects progressed to AD: both of the SCD-c subjects presented the PER2 G allele, while none of the SCD PER2 G non-carriers converted to AD (p=0.003). Conclusion: PER2 seems to have a role in cognitive reserve and cognition in SCD and MCI patients. Nevertheless, further studies are needed to assess the role of PER2 C111G on the risk of progression to AD.