The aim of the study is to evaluate the role of cholesterol in the pathogenesis of neurodegenerative dementias. Hypercholesterolemia is a known risk factor for Alzheimer disease (AD), and oxysterols, the principal cholesterol metabolites, are involved in neuroinflammation, amyloid aggregation, and tau accumulation.

Oxysterols will be measured in different biological samples (post-mortem brain tissue, CSF, and plasma) from patients with different neurodegenerative dementias, including AD, frontotemporal dementia (FTD), and primary tauopathies. This approach will allow determination of whether their modifications correlate primarily with Aß deposition, tauopathy, or neuronal loss, with the goal of identifying correlations with disease severity and progression.

Since preliminary results suggest that the levels of most oxysterols in the brain significantly increase in parallel with the levels of the enzyme PCSK9, the investigators will explore the role of cholesterol metabolism and PCSK9 in AD and other dementias to evaluate whether cholesterol dysregulation represents a common alteration across these neurodegenerative disorders or is specific to AD

The project is a monocentric retrospective and prospective low-intervention clinical study. All samples collected will be sent for analysis to the Laboratory of General Pathology and Pathophysiology, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano (TO), Italy.

1. Selection and characterization of post-mortem brains Twenty brains from patients with AD (ranging from Braak stage II to VI of neurofibrillary pathology severity), ten brains from patients with FTD/tauopathies, and six brains from FTD/TDP43 patients will be included in the study. These samples are already available for the project and have been neuropathologically characterized by Neurology 5 - Neuropathology Unit.

2. Recruitment and follow-up of patients with neurodegenerative dementias

   Retrospective study Samples (CSF and plasma) previously collected from patients at Neurology 5 - Neuropathology Unit over the years will be used. The study will include 40 AD patients, 40 FTD patients, and 20 age-matched non-demented controls. Clinical and MRI data will be retrospectively collected, as well as levels of markers of neurodegeneration (tau, Abeta42, and phospho-tau) in CSF.

   Longitudinal study During the first 18 months of the project, 30 AD patients, 20 FTD patients, and 10 patients with primary tauopathies (PSP/CBD) will be recruited. A group of 20 age-matched healthy subjects will serve as controls. All patients and controls will undergo a comprehensive neurologic assessment, a neuropsychological evaluation, and a brain MRI with a standard protocol at baseline (T0) and after 1 year (T1). CSF collection will be performed at baseline in patients. DNA and plasma will be collected from controls and patients at baseline and follow-up. Measurements of BMI, total cholesterol, LDL and HDL cholesterol, and triglycerides will be performed at baseline and follow-up in all subjects. ApoE genotype will be analyzed for all subjects to determine E2, E3, and E4 polymorphisms. MRI will be performed on a 3T scanner, including volumetric T1, FLAIR, T2, DWI, and DTI sequences at baseline and follow-up.

3. Study of the role of the enzyme PCSK9 in the brain (performed by University of Turin) SK-N-BE cells and mouse-derived primary cortical neurons and astrocytes will be treated with PCSK9 or with an oxysterol mixture obtained from brain dosages.

Inclusion Criteria:

• Age 40-85
• Diagnosis based on the current diagnostic criteria for AD (McKhann et al., 2011), FTD (Gorno-Tempini et al., 2011; Rascovsky et al., 2011), PSP and CBD (Amstrong et al., 2013; Höglinger et al., 2017)
• Mini Mental State Examination MMSE > 10.

Exclusion Criteria:

• Other neurological or psychiatric disorders Severe chronic metabolic diseases

We will use samples (CSF and plasma) already collected from patients from Unit 1 over years. We will include 40 AD, 40 FTD and 20 age-matched non demented controls. Clinical and MRI data will be retrospectively collected as well as the levels of markers of neurodegeneration (tau, Abeta42 and phospho-tau) on CSF.

Longitudinal study We will recruit 30 AD patients, 20 FTD patients and 10 patients with primary tauopathies (PSP/CBD) from out and inpatients of Neurology 5-Neuropathology Unit. A group of 20 age-matched subjects without neurological and/or psychiatric diseases will be enrolled as controls. The duration of enrolment will be 18 months.