The cause of Alzheimer's disease, the most common form of dementia, remains unknown. Neuropathological studies suggest that a small area in the brainstem, the locus coeruleus, might be the site of the onset of the disease. This area is the sole source of noradrenalin to the brain, a neurotransmitter involved in arousal, but also cognitive functions. Animal and pharmacological studies have hinted towards an important role of this area in memory functioning. However, these studies were hampered by the limited spatial resolution, making it hard to clearly localize the locus coeruleus in the brain. New developments in brain imaging allow now to visualize the brain with stunning precision. Furthermore, a non-invasive new stimulation method, transcutaneous vagus nerve stimulation, is believed to excite the locus coeruleus and thereby influencing neuronal networks and memory functioning.

There are three aims in this project:

1. To investigate how the functional interaction between the locus coeruleus and other brain areas, in particular the medial temporal lobe areas, during memory processes (encoding, consolidation and retrieval) change with development of Alzheimer's disease.
2. To investigate associations between noradrenaline, memory performance and brain functioning. The investigators aim to investigate how acute noradrenalin levels change during the different memory processes and whether or not this is beneficial for performance. Furthermore, the investigators will investigate whether this interaction between noradrenalin, memory performance and brain functioning is different healthy older individuals (n =35) or patients with prodromal Alzheimer's disease (n =35).
3. To investigate the underlying neural network changes during transcutaneous vagus nerve stimulation. The investigators will focus on differences in functional connectivity between the locus coeruleus and the medial temporal lobe areas in healthy older individuals and prodromal Alzheimer's disease patients. An experimental condition will be compared with a sham condition in a pseudo-randomized cross-over design.

Inclusion Criteria:

For the patients:

• diagnosis of prodromal Alzheimer's disease based on the latest research criteria (clinical assessment at the memory clinic : presence of at least a memory impairment, memory complaints expressed by the patient or informant, no problems in daily life functioning, no dementia and presence of biomarkers
• Clinical Dementia Rating score of 0.5 (
• Mini-Mental State Examination (MMSE) ≥ 23 and being mentally competent (in general, individuals with a MMSE ≥ 18 are considered mentally competent)
• Age: between 60 and 85 years old
• 50% female
• Right-handedness
• Average level of education
• Informed consent before participation in the study

For the healthy older individuals:

• Average neuropsychological test results, in accordance with normative data, corrected for age, education and gender
• No substantial memory complaints (according to the participant)
• Age: between 60 and 85 years old
• 50% female
• Right-handedness
• Average level of education
• Informed consent before participation in the study

Exclusion Criteria:

• Reduced vision
• Psychoactive medication use
• Abuse of alcohol and drugs
• Cognitive impairment due to alcohol/drug abuse or abuse of other substances
• Past or present psychiatric or neurological disorders (major depression, schizophrenia, bipolar disorder, psychotic disorder (or treatment for it), epilepsy, stroke, Parkinson's disease, multiple sclerosis, brain surgery, brain trauma, electroshock therapy, kidney dialysis, Menière's disease, brain infections)
• Major vascular disorders (e.g. stroke)
• Heart diseases or pacemakers
• Contraindications for scanning (e.g. brain surgery, cardiac pacemaker, metal implants, claustrophobia, body tattoos)

35 healthy older individuals and 35 patients with prodromal Alzheimer's disease