Autophagy-Enhancers to Reduce Sleep Disturbances

Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) represent early stages along the continuum of cognitive decline preceding dementia. Individuals with SCD report persistent cognitive complaints despite normal performance on standardized cognitive testing, whereas MCI is characterized by objective cognitive impairment that does not yet interfere substantially with activities of daily living. Both conditions are associated with an elevated risk of progression to Alzheimer's disease and other dementias. Disruption of sleep architecture is increasingly implicated in the pathophysiology of neurodegenerative disorders, and early interventions targeting sleep-related mechanisms could help delay further cognitive decline. This clinical trial evaluates the effects of spermidine supplementation on sleep quality and sleep-dependent memory consolidation in older adults with SCD or MCI.

Following an adaptation night and an initial baseline sleep assessment with overnight electroencephalography (EEG), participants will be randomly assigned to either the spermidine or placebo group. The intervention consists of a daily oral dose of 6 mg spermidine (administered as three 2 mg sachets), continued over a 12-week period. The trial employs a randomized, double-blind, placebo-controlled design. Placebo sachets, identical in appearance and taste, contain only microcrystalline cellulose. After the 12-week supplementation period, participants will return for a second overnight EEG assessment.

A healthy control group (n=38), matched for age and sex, will undergo comparable baseline assessments but will not receive any intervention. These data will provide normative reference values for sleep and cognitive parameters.

The primary objective of the study is to assess the impact of spermidine on sleep architecture, measured via overnight polysomnography, with a specific focus on slow-wave sleep and sleep spindle activity, EEG markers associated with sleep-dependent memory consolidation and known to decline with age and neurodegeneration. Secondary outcomes include changes in memory consolidation (assessed using a battery of cognitive tasks that target declarative, procedural, and visuospatial memory domains), as well as numerical skills (tested via e.g., digit-letter-decision task, Berlin Numeracy Test). Testing occurs before and after each EEG night to evaluate overnight consolidation effects. All participants will wear actigraphs prior to both EEG nights to monitor sleep-wake cycles and physical activity.

Additional biological endpoints will examine changes in circulating neuropeptides, insulin-glucose homeostasis, and autophagy-related biomarkers. Blood samples are collected at each EEG session and two weeks after the start of supplementation. Physiological assessments include measurements of inflammatory markers (e.g., interleukin (IL)-6, tumor necrosis factor (TNF-α), neuroprotective factors (e.g., Neuropeptide Y, eukaryotic translation initiation factor 5A (eIF5A) hypusination), and metabolic indicators (e.g., fasting insulin, glucose, and lipid profiles).

Participants will undergo structural brain imaging using a 3-Tesla MRI scanner to exclude individuals with comorbid neurological conditions (e.g., prior stroke, other neurodegenerative diseases) and to assess brain morphology. Eligibility is determined through standardized pre-screening procedures, including clinical interviews and neuropsychological assessments.

The study includes 76 participants with SCD or MCI, aged 55-70 years, randomly allocated to either the spermidine or placebo group (n=38 per group). The sample size provides adequate statistical power to detect medium-to-large effect sizes, based on previous pilot findings and anticipated attrition rates.

This study aims to investigate the effects of spermidine supplementation on neurophysiological and cognitive outcomes in individuals with early-stage cognitive decline. The results are expected to contribute to the growing body of evidence evaluating spermidine as a safe, nutrition-based strategy for maintaining brain health and cognitive function in the context of aging.

Inclusion criteria

(SCD participants):

• Men and women
• Written consent to participate in the study
• German at native speaker level
• Age between 55 and 70 years
• Subjective Cognitive Decline operationalized as:

• Subjectively reported decline in cognitive function (particularly memory) despite objectively normal cognitive performance (e.g., WMS-LM)
• Preservation of functional independence
• No dementia

Inclusion criteria

(MCI patients):

• Men and women
• Written consent to participate in the study
• German at native speaker level
• Age between 55 and 70 years
• Mild cognitive impairment (MCI) operationalized as:

• A change in cognitive abilities reported by the patient, relatives or clinic staff (i.e. historical or observed evidence of deterioration over time)
• Objective evidence of memory impairment (at least 1.0 Standard Deviation (SD) below the normal range on the Wechsler Logical Memory Scale (WMS-LM)); other cognitive domains may also be affected (i.e. amnestic MCI and amnestic + MCI)
• Preservation of independence of functional abilities
• No dementia

Exclusion criteria

(SCD and MCI participants):

• Patients who are unable to give informed consent
• Polyamine intake via dietary supplements and/or participation in corresponding intervention studies
• Dementia according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)
• Any condition that impairs clinical or neuropsychological examination procedures
• Diabetes mellitus
• Polycystic ovary syndrome
• Signs of epilepsy, focal brain lesion or head injury with loss of consciousness or immediate post-injury confusion
• Previous stroke
• Severe untreated medical problems or unstable medical condition
• Current major depressive episode
• Psychotic disorder
• Bipolar disorder
• Current or previous substance abuse
• Other neurodegenerative disease, e.g. Parkinson's disease
• Vascular dementia
• Alcohol abuse
• Participation in an interventional study in the last 3 months and during the entire study period
• Sleep disorders
• Taking medication that primarily affects the central nervous system (e.g. antipsychotics, antidepressants, benzodiazepines or any type of over-the-counter sleep-inducing medication such as valerian; anti-dementia medication)
• Known intolerances or allergies to wheat germ, gluten or histamine

Inclusion criteria

(healthy controls):

• Men and women
• Written consent to participate in the study
• German at native speaker level
• Age between 55 and 70 years
• Subjective cognitive disorders are denied

Exclusion criteria

(healthy controls):

• Subjects who are not able to give informed consent
• Polyamine intake via dietary supplements and/or participation in corresponding intervention studies
• Dementia according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)
• Mild cognitive impairment (MCI), defined as described above in the patient inclusion criteria
• Any condition that interferes with clinical or neuropsychological examination procedures
• Diabetes mellitus
• Polycystic ovary syndrome
• Signs of epilepsy, focal brain lesion or head injury with loss of consciousness or immediate post-injury confusion
• Previous stroke
• Severe untreated medical problems or unstable medical condition
• Current major depressive episode
• Psychotic disorder
• Bipolar disorder
• Current or past substance abuse
• Other neurodegenerative disease, e.g. Parkinson's disease
• Vascular dementia
• Alcohol abuse
• Participation in an interventional study in the last 3 months and during the entire study period
• Sleep disorders
• Taking medication that primarily affects the central nervous system (e.g. antipsychotics, antidepressants, benzodiazepines or any type of over-the-counter sleep-inducing medication such as valerian; anti-dementia medication)