Dementia caused by neurodegenerative diseases affects over 50 million people worldwide, Alzheimer's disease (AD) being the most common cause. As life expectancy increases, the prevalence of these diseases is expected to grow in coming decades, placing a significant social and economic burden on National Health Systems. AD is pathologically defined by two major hallmarks: amyloid-ß (Aß) accumulation in extracellular plaques, and hyperphosphorylated tau (p-tau) accumulation in intracellular neurofibrillary tangles. In recent decades, increased understanding of AD pathophysiology and technological advancements have allowed the development of new techniques providing an objective measure of AD pathological processes in vivo. Established biomarkers such as those obtained by cerebrospinal fluid (CSF) examination and positron emission tomography (PET) measures have been progressively introduced into clinical practice, consistently with the most recent NIA-AA diagnostic criteria. However, the widespread use of these methods remains limited due to their low availability, perceived invasiveness, high costs, and contraindications. Accordingly, there is a pressing need for costeffective biomarkers that can be less invasively obtained. Therefore, recent promising results in the development of ultrasensitive detection methods for blood biomarkers could facilitate a breakthrough in the field, simplifying and accelerating the diagnostic process of subjects with cognitive decline.

The main hypothesis of this study is that new plasma biomarkers of amyloidopathy, tauopathy, neurodegeneration, measured through a novel CLEIA methodology, may have the potential to change the diagnostic process of neurodegenerative diseases by reducing the need for unnecessary exams thus providing valuable information from a clinical and public health perspective. The larger availability and easier procedures for obtaining AD biomarkers from plasma, as compared to CSF, may also help to reduce territorial and economic disparities in reaching AD diagnosis. In addition, investigating biomarkers of neuroinflammation may provide new insights about the complex relations between AD pathogenetic processes, disease severity, and its prognosis.

This study aims to validate the reliability of biomarkers for AD and major neurodegenerative diseases, obtained from plasma instead of CSF. The findings will facilitate a paradigm shift in clinical practice toward the implementation of reliable and costeffective diagnostic tools that can be used not only for research purposes but also in clinical practice. This will also create new opportunities for population-based interventions, as well as future screening campaigns in primary care, reducing expenditures unnecessary investigations in individuals at low risk for dementia and delays in access to diagnosis and interventions that will slow cognitive decline in subjects at high risk for dementia. Thus, the validation of these novel biomarkers could have relevant positive economic and social implications for National Health Systems as well as for those personally affected by a neurodegenerative disease or their caregivers.

Inclusion Criteria:

• consecutive subjects with a clinical indication to undergo lumbar puncture for the determination of cerebrospinal fluid biomarkers of amyloidosis, tauopathy, and neurodegeneration during diagnostic assessments for cognitive impairment (as per clinical practice)
• informed consent form signed by patient or caregiver

Exclusion Criteria:

• Age under 50 or over 80 years
• Non-native Italian speakers
• History of previous or concurrent neurological diseases that could impact cognition (e.g., severe cerebrovascular accidents, brain tumors, traumatic injuries, etc.)
• History of major psychiatric disorders that could affect cognitive abilities
• History of alcohol use disorder
• Medical conditions that may interfere with cognitive functions (e.g., renal or hepatic failure, respiratory diseases, hypothyroidism, vitamin B12 deficiency, etc.)
• Uncompensated systemic disease with instability and significant organ failure
• Contraindications to lumbar puncture (e.g., presence of spinal malformations or current use of anticoagulant therapy)
• Previous or current participation in experimental studies involving amyloid-targeting agents

The population will include subjects referred to the for an initial evaluation of cognitive disorders.