Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline : Decline A Randomized Clinical Trial

IMPORTANCE Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. OBJECTIVE To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. DESIGN, SETTING, AND PARTICIPANTS This 12-month randomized, double-masked, placebocontrolled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. INTERVENTIONS One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (O.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. MAIN OUTCOMES AND MEASURES Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. RESULTS A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage.Peer reviewe

Severity of Subjective Cognitive Complaints and Worries in Older Adults Are Associated With Cerebral Amyloid-β Load

Subjective cognitive decline (SCD) is considered an early risk stage for dementia due to Alzheimer's disease (AD) and the development of pathological brain changes, such as the aggregation of amyloid-beta (amyloid-β) plaques. This study evaluates the association between specific features of SCD and cerebral amyloid-β load measured by positron emission tomography (PET) with 18F-florbetaben in 40 cognitively normal older individuals. Global amyloid-β, as well as regional amyloid-β load for the frontal, temporal, parietal, and cingulate cortex, was quantified. Specific features of SCD, such as subjective cognitive complaints and worry, were assessed using the 39-item Everyday Cognition Scales and the 16-item Penn State Worry Questionnaire. Spearman's rank partial correlation analyses, adjusted for age and apolipoprotein E ε4 status, were conducted to test the associations between specific features of SCD and cerebral amyloid-β load. The severity of subjective cognitive complaints in everyday memory and organization was positively correlated with amyloid-β load in the frontal cortex. In addition, the severity of subjective cognitive complaints in everyday planning was positively correlated with amyloid-β load in the parietal cortex. Higher levels of worry were associated with higher amyloid-β load in the frontal cortex. After correction of the PET data for partial volume effects, these associations were reduced to trend level. In conclusion, the severity of subjective cognitive complaints and the level of trait worry were positively associated with cortical amyloid-β burden, particularly in the frontal and parietal cortex. Further studies are required to elucidate the direction of these associations in order to develop strategies to prevent amyloid deposition and cognitive decline