Subjective cognitive decline (SCD) is receiving increasing attention as a risk factor for incident dementia due to AD. SCD manifests prior to the onset of clinical impairment, and as such could serve as a potential target population for early intervention trials. The pathogenesis of AD is complex and involves a dysregulation of the neuroendocrine immune (NEI) system, a network of signaling molecules, such as neurotransmitters, hormones and cytokines. As a result, it may be unlikely that cognitive decline may be mitigated by drugs acting on a single specific target. Plant extracts acting at different levels of the NEI regulation could represent appealing therapeutic strategies for cognitive decline. Citrus-derived phytochemicals, like auraptene and naringenin, showed antioxidant, anti-inflammatory, and neuroprotective effects in preclinical studies of AD mouse models and preservation of cognition in elderly without cognitive impairment. This is a pilot randomized controlled trial to determine clinical and biological effects of Citrus-phytochemicals in individuals with SCD. Participants will be randomized to receive Citrus-phytochemicals standardized in auraptene and naringenin or placebo for 9 months. Cognitive tests and blood-based biological markers will be done at baseline and at the end of treatment as outcome measures.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder which represents a major health issue and financial burden for health care systems around the world. The impact will further increase over the next decades due to increasing life expectancies. AD leads to progressive and irreversible disturbances of cognition and functional abilities. AD is the fifth-leading cause of death among those age 65 and older and is also a leading cause of disability and poor health. Due to the absence of a cure against AD, the public health priority has focused more recently on improvement of cognitive performance in older age and, possibly, prevention of cognitive decline. Subjective cognitive decline (SCD) in older adults is increasingly recognized as a potential indicator of non-normative cognitive decline and eventual progression to dementia. Longitudinal studies in SCD showed an up to 4.5-fold increased risk for progression to mild cognitive impairment. SCD has also been characterized by pathological changes of the brain associated with AD. These findings suggest that SCD may be an early clinical marker for AD, making an ideal target to test preventive interventions. Several nutraceuticals have displayed over the years the ability or potential to improve cognitive impairment. Among these, auraptene (AUR) and naringenin (NAR) are natural bioactive compounds derived from peels of Citrus fruits, with a strong preclinical rationale for cognitive enhancement. In fact, preclinical studies showed that they have anti-inflammatory, antioxidant, and neuroprotective effects in mouse brain and, specifically, in AD mouse models. These effects are mediated by a number of neuropeptides, growth factors, hormones, and cytokines, which are components of the neuroendocrine and immune (NEI) system, a complex network of communication, which showed altered functioning in ageing and neurodegenerative diseases.

The capacity of some nutraceutical in restoring and remodelling the NEI response at both neuroendocrine and immune level, could represent a new strategy in order to reach healthy ageing and prevent cognitive decline in the elderly. This perspective is supported by the results of a randomized, placebo-controlled, double blind study of 84 older adults, in which administration of AUR for 24 weeks showed significantly higher percentage of improvement in the immediate memory in the AUR group compared to the placebo.

Specific aims: This is a pilot randomized controlled trial to determine the cognitive and biological effects of Citrus peels extracts standardized in auraptene and naringenin, in individuals with SCD.

Specific aim 1. The investigators will enrol 80 individuals with SCD randomized into two groups of treatments, i.e. control and Citrus peels extracts. Cognitive assessment will be carried out at baseline and after 9 months of treatment, in order to evaluate the effect on cognition.

The investigators hypothesize that treatment group has an improvement in cognition compared to placebo group.

Specific aim 2. To evaluate the biological effects of the Citrus peels extracts treatment on the NEI system, through blood samples taken at baseline, and after 9 months of treatment.

The investigators hypothesize that treatment group has an improvement in the NEI functions as indicated by biological markers (increase of the growth factors, reduction of stress hormones levels, reduction of inflammation) compared to placebo group.

Inclusion Criteria:

• subjective cognitive decline,
• lack of objective cognitive impairment.

Exclusion Criteria:

• clinically significant depression and anxiety,
• psychiatric disorders,
• unstable medical conditions.

The data collected in this study will not be publicly available but will be provided to any qualified researcher interested in the topic of this project, upon presentation of a research study and approval of the local Ethics Committee.

Local Ethics Committee approval.