The ALFA study is a long term, prospective, observational study of AD patients' adult children aimed at studying and characterizing key physio-pathological features of the preclinical phase of AD.

The natural history of AD includes an asymptomatic or preclinical phase characterized by pathological cerebral alterations without any evident symptoms of the disease. The beginning of the preclinical phase can be detected using a series of biological and neuroimaging markers that indicate the presence of Aβ deposition in the brain. A variety of factors such as inflammation, genetic load (e.g., APOE4), diet, cardiovascular risk, sleep disorders and cognitive reserve, produced by endogenous or exogenous factors, vary among individuals and may determine the beginning and evolution of the preclinical phase of the disease. It is possible to identify subclinical, biological, cognitive and neuroimaging changes, in the AD preclinical phase. The longitudinal study of intra-individual changes will be more sensitive than cross-sectional inter-individual studies to detect the cognitive evolution during the AD preclinical phase. Similarly, it would be possible to identify factors in subjects at the preclinical phase that will influence their evolution to the clinical stage of the disease.

The study will start with a screening of 3.000 recruited volunteers (NCT01835717) complying as much as possible with study selection criteria and perfectly aware of the study needs.

The selected 400 participants fulfilling the inclusion criteria will undergo detailed phenotyping consisting in: clinical history, AD family history, full cognitive evaluation, cognitive reserve determination, CSF sample collection, blood and urine sample collection, neuroimaging (MRI), quality of life and habits of life questionnaires (physical activity, diet, sleeping habits, social activity, toxics habits, pollution exposure).

The longitudinal study will consist in a every 3-year follow-up visit in which the participant will undergo a review of the clinical history data, a full cognitive evaluation, neuroimaging (MRI), samples collection (blood, urine, CSF) and update of the life habits changes.

Inclusion Criteria:

• Adult children of AD patient: First-degree descendant of an AD patient (following diagnosis as define in protocol).
• Age: 45 to 64 years old.
• Long-term commitment to the study: baseline and follow-up visits. Potential participants have to agree to undergo to all the procedures described in the protocol.

Exclusion Criteria:

• Cognitive impairment: to be included the participant must show no signs of objective cognitive impairment.
• Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol.
• Illiteracy or functional illiteracy.
• Any contraindication to any test or procedure at the time of study inclusion.
• Family history of monogenic AD.
• Not willing to undergo one or more of the tests and procedures described in the protocol at baseline.

Offsprings of subjects diagnosed of probable AD before reaching 75 years of age, according to McKhann et al. [McKhann et al., 1984] criteria, will be selected from spontaneous volunteers and Alzheimer's patients associations members.