Alzheimer's disease (AD) is the leading cause of dementia in humans, currently affecting almost one million people in France. It results from an irreversible degeneration of neurons responsible for a progressive decline in the main cognitive and memory functions due to a cerebral accumulation of plaques containing fibrillary amyloid peptide (Aβ) and neurofibrillary tangles composed of truncated, hyperphosphorylated tau protein (pTau).

There is currently no curative treatment for this disease in France. However, two treatments aimed at reducing beta-amyloid plaques in the brain have been approved by the U.S. Food and Drug Administration. The failure of the latest therapeutic strategies is largely due to the fact that the disease is diagnosed too late, starting with a long asymptomatic phase, which is the one that needs to be targeted in order to prevent irreversible neurodegenerative mechanisms.

The development of diagnostic tools is gradually making it possible to detect such a sequence, but this has its drawbacks (radioactive load, invasive procedure, cumbersome set-up).

Over the last ten years, research has focused on the development of plasma or salivary markers. Although encouraging, these studies show either a lack of sensitivity or reproducibility, or a lack of specificity or precocity.

The expression of Aβ and Tau proteins has recently been demonstrated in the enteric nervous system and enterocytes. Intestinal Aβ is involved in various gut functions and regulation.

What recent work by investigators demonstrates is the essential and hitherto unrecognized role of the gut-brain axis in maintaining brain homeostasis. In a mouse model of AD, the investigators have demonstrated a mechanism for intestinal elimination (clearance) of toxic brain forms of Tau and Aβ proteins, via the lymphatic network.

The clearance of cerebral Tau and Aβ proteins in the stool may constitute a reliable and powerful diagnostic signature of AD. Its study would represent a new, non-invasive and easily accessible technique for the early diagnosis of AD in humans.

Inclusion Criteria:

For subjects with Alzheimer's disease MA TCM (A+ T+):

• Subjects diagnosed with AD according to IWG 2021 criteria
• Subject at the stage of major cognitive impairment
• At least 40 years of age
• Presence of a caregiver or support person
• No informed opposition

For subjects with AD TCm (A+ T+):

• Subject diagnosed with AD according to IWG 2021 criteria
• Subject at the stage of minor cognitive impairment
• Minimum age 40
• No informed opposition For subjects with minor or major cognitive impairment who do not have AD TC Non-AD LCR negative (A- T-)
• Subject at stage of minor or major cognitive impairment
• CSF negative (A-T-) for Alzheimer's disease biomarkers: A-T- according to ATN classification
• Minimum age 40
• No informed objection and TCm CSFdiscordant (A+ T-) or (A- T+):
• Subject at stage of minor cognitive impairment
• CSF discordant (A-T+ or A+T-) with Alzheimer's disease biomarkers
• Minimum age 40
• No informed opposition

For healthy volunteers (VS) :

• No cognitive complaints
• MMSE ≥ 26
• CDR 0
• Minimum age 40
• No informed opposition

Exclusion Criteria:

For MA TCM (A+ T+), MA TCm (A+T+) and TC Non MA LCR negatif (A-T-) and TCm LCRdiscordant (A+ T-) or (A- T+):

• Inability to understand search instructions or to give informed non-opposition
• Absence of social security affiliation or plan
• Persons covered by articles L1121-5 to L1121-8 of the CSP (legally protected adult, subject under administrative or judicial supervision)

For healthy volunteers:

• Incapacity to understand research instructions or to give informed non-opposition
• Persons covered by articles L1121-5 to L1121-8 of the CSP (legally protected adult, subject under administrative or judicial supervision)
• Absence of social security affiliation or of such a scheme

Single-center study, recruitment among patients consulting the CMRR of the Alpine arc