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Background and purpose CLOCK and PER2 genes have been implicated in sleep-wake cycle alterations and neurodegenerative diseases. Our aim was to evaluate the effect of CLOCK T3111C and PER2 C111G on cognitive functioning in subjective cognitive decline (SCD) patients and mild cognitive impairment (MCI) patients at the baseline of a longitudinal study, and the effect of these two polymorphisms on the progression to Alzheimer's disease (AD) of the two groups. Methods Sixty-eight 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 were included. Subjects who developed AD (SCD-c and MCI-c) and non-converters (SCD-nc, MCI-nc) were considered. Results CLOCK T3111C was detected in 47% of cases (21 SCD, 11 MCI) and PER2 C111G in 19% of cases (eight SCD and five MCI). PER2 G carriers presented lower premorbid intelligence score (P = 0.049), fewer years of education (P = 0.007) and a 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 visuospatial abilities at baseline. During follow-up, two 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.

BACKGROUND AND PURPOSE Subjective cognitive decline (SCD) is a self-experienced decline in cognitive capacity with normal performance on standardized cognitive tests and has been shown to increase the risk of Alzheimer's disease (AD). SCD could also be related to other conditions such as normal aging, psychiatric, neurological or medical disorders. The SCD Initiative proposed a set of features (SCD-plus) that increase the likelihood of preclinical AD in individuals with SCD. Our aim was to assess the effect of these features on the risk of conversion from SCD to AD. METHODS In total 150 SCD subjects who underwent extensive neuropsychological investigation, assessment of cognitive complaints and apolipoprotein E (ApoE) genotyping at baseline and clinical-neuropsychological follow-up for a mean time of 11 years were included. RESULTS During the follow-up, 20 subjects developed AD. Considering SCD-plus features, age at onset ≥60 years and ApoE e4 significantly increased the risk of conversion from SCD to AD. When our sample was stratified into three groups (no risk factor, one risk factor, two risk factors), the proportion of conversion was statistically significantly different between the three groups. CONCLUSIONS Our model allows the risk of AD to be stratified in patients experiencing SCD according to age at onset and ApoE genotype.