With disease-modifying therapies emerging for dementia and related conditions, identifying cognitive decline as early as possible is increasingly important. This prospective, single-center, repeated-measures study evaluates whether VR-based eye-tracking pupillometry can provide a practical, non-invasive biomarker of cognitive impairment and its progression over time. Pupil responses are linked to brain arousal systems relevant to cognitive dysfunction, including the locus coeruleus, which is affected early in Alzheimer's disease. Adults aged 18-80 years will be assigned to one of four cohorts (n=35 per cohort): i) Alzheimer's disease (supported by CSF biomarkers), ii) mild cognitive impairment (MCI) without Alzheimer's Disease, iii) depressive disorder with cognitive impairment, iv) healthy controls. Participants will undergo initial assessments at baseline and follow-up visits after 3 and 6 months. At each visit, pupil responses and behavioral metrics are recorded during a pupillary light reflex paradigm, a resting-state fixation block, a working-memory task (N-back), and a reward task. Pupillometric and behavioral metrics will be compared across cohorts and related to routine neuropsychological measures (MoCA, CERAD) and available clinical biomarkers (CSF markers; blood biomarkers). The primary objective is to determine whether task-evoked pupil response profiles sensitively quantify cognitive impairment, differ between cohorts, and track change over time. The long-term goal is to validate an easy-to-use, outpatient-compatible assessment to support objective characterization and monitoring of cognitive disorders.

Cognitive performance typically declines with age and is usually accompanied by attention and memory deficits. While such changes can be consistent with normal ageing, they may also reflect affective disorders or early stages of neurodegenerative diseases (e.g. Alzheimer's Disease; AD). In clinical practice, neurocognitive tests are commonly used to distinguish age-appropriate change from pathological decline. As these tests quantify behavioral performance, they are better at detecting cognitive decline, once measurable deficits are manifested. However, they have limited sensitivity to subtle changes that can precede overt clinical symptoms by several years. This study evaluates a diagnostic approach based on pupil dilation measurements that may support earlier detection and longitudinal monitoring, potentially enabling earlier interventions.

Pupillometry provides a noninvasive index of pupil dynamics linked to arousal systems relevant to cognition, including the locus coeruleus-noradrenergic (LC-NA) system. LC-NA activity is coupled to pupil dilation via autonomic pathways, and this coupling has been demonstrated across animal and human studies. Given its widespread projections, the LC-NA system is implicated in psychiatric and neurological conditions through roles in arousal regulation, stress responsivity, attention, and memory. Pupillometry in Alzheimer's disease has often been examined using pupillary light reflex paradigms. However, simple light-flash measures may be less informative in early-stage impairment because pupil responses vary with cognitive state and task demands and do not provide a uniform, task-independent readout of LC-linked function. Accordingly, analyzing pupil responses during and immediately following cognitive tasks may be better suited to capturing subtle dysfunction relevant to prodromal processes, with light-reflex alterations potentially becoming more apparent once impairment is established. In prior work, the investigators observed pupil diameter increased with working-memory load during an N-back task. Most participants showed the expected increase in pupil dilation with task difficulty, whereas a subset exhibited pronounced atypical pupil responses despite only slight differences on standard neurocognitive measures. Building on these principles, this study uses a VR-based assessment to examine adults presenting with early, non-specific cognitive complaints. By systematically recording pupil dynamics during and following cognitive paradigms, the investigators aim to obtain readouts of LC-NA system function that may support differential diagnosis among conditions with overlapping clinical presentations (e.g. depression-related cognitive impairment vs. early dementia).

At each visit, participants are fitted with a VR headset by trained study personnel and complete VR-based assessments with concurrent eye tracking and behavioral performance recording. Assessments are conducted at baseline (T0) and repeated after 3 months (T1) and 6 months (T2). At each visit, pupil responses and task performance are recorded during a pupillary light reflex paradigm, a resting-state fixation block, a working-memory task (N-back), and a reward task. Participants also complete routine neuropsychological testing, including the Montreal Cognitive Assessment (MoCA) and the CERAD battery comprising semantic fluency, Boston Naming Test, Mini-Mental State Examination (MMSE), word list learning, word list delayed recall, word list recognition, figure copying, figure delayed recall, phonemic fluency, and Trail Making Test. Additional assessments include the Bayer Activities of Daily Living scale (Bayer-ADL) and the Geriatric Depression Scale (GDS), as well as questionnaires assessing subjective cognitive impairment (FLei) and childhood adversity (CTQ). Sociodemographic data are recorded, including age, sex, education (years of schooling), and occupation. Blood is collected for routine laboratory measures and blood-based biomarker analyses (including phosphorylated tau 217), and clinical data from routine care are linked where available. In some cases, cerebrospinal fluid biomarkers from routine clinical evaluation are available and linked, including AD pathology markers (amyloid-β and tau measures).

Pupillometric and behavioral measures will be compared across cohorts and evaluated longitudinally across follow-up visits. Measures will also be related to routine neuropsychological assessment, as well as available clinical biomarkers (CSF amyloid-β and tau measures blood-based biomarkers and anatomical neuroimaging sequences). Prior observations suggest that pupil dilation scales with cognitive load and that task-evoked pupil responses can differ, even when standard neurocognitive measures show only subtle differences. The investigators hypothesize that task-evoked pupil response patterns will differ between cohorts and may be sensitive to change over time.

Inclusion Criteria:

1. Written informed consent.
2. Age 18-80 years.
3. Ability to read and understand German.
4. For patient cohorts: suspected or confirmed diagnosis of AD/MCI/depressive disorder with cognitive impairment according to clinical assessment and routine documentation.

Exclusion Criteria:

1. Acute suicidality (e.g. BDI suicidality item > 1).
2. Change of psychotropic medication within the last 4 weeks.
3. Lifetime psychotic disorder (ICD-10 F20-29).
4. Lack of capacity to consent.
5. Lifetime bipolar disorder (ICD-10 F31).
6. Acute substance abuse or harmful use of alcohol or other psychoactive substances.
7. Parkinson's syndrome (ICD-10 G20).
8. Multiple sclerosis (ICD-10 G35).
9. Stroke within the last 12 months.

Adults aged 18-80 years will be recruited at the Max Planck Institute of Psychiatry (Munich, Germany) from inpatient wards and outpatient clinics. Patients have a suspected or confirmed clinical diagnosis of Alzheimer's disease, mild cognitive impairment, or depressive disorder with cognitive impairment. Routine clinical measures (neuropsychological testing and, CSF biomarkers, blood biomarkers, imaging) will be linked to study pupillometry outcomes.