Table 5 Proposed classification of the biomarkers here reviewed that proved diagnostic or prognostic significance according to level of evidence, clinical utility and reproducibility

	Type of biomarker	Level of evidence¹	Clinical utility²				Reproducibility³
	Type of biomarker	Level of evidence¹	Clinical/research application	Diagnostic/prognostic yield	Non-invasiveness	Accessibility	Reproducibility³
Diagnosis	*Neuroimaging*
	Atrophy of the insula, and frontal and temporal lobes	B2	C	+	+	-	+
	Altered DMN activity	B2	R	-	+	-	-
	Higher PET tau-binding in the entorhinal region	B2	C	+	+	-	-
	*Neurophysiology*
	EEG/MEG cortical rhythm slowing	B2	C	+	+	+	+
	Abnormal connectivity measures	B2	R	-	+	-	-
	Reduced SAI	B2	C	+	+	-	+
	Increased SICI, reduced ICF	B2	C	+	+	-	+
	Delayed P300 latency	B2	R	-	+	-	+
	*Biofluids – CSF*
	Increased albumin quotient	B2	C	-	-	-	+
	Anormal amyloid and tau biomarkers	B2	C	+	-	-	+
	*Biofluids – plasma/serum*
	Increased albumin quotient	B2	C	-	+	+	+
	Increased homocysteine, cystatin C	B2	C	-	+	+	+
	Decreased vitamin B12 and folate	B2	C	-	+	+	+
	Increased NfL	B2	C	+	+	-	-
Prognosis	*Neuroimaging*
	Atrophy of the hippocampus, fronto-temporal lobes, caudate, thalamus, NAcc, WM	B2	C	+	+	-	+
	*Neurophysiology*
	EEG/MEG cortical rhythm slowing	B2	C	+	+	+	+
	*Biofluids - CSF*
	Abnormal amyloid biomarkers	B2	C	+	-	-	+
	Genetics
	BDNF Val66Met polymorphism	B2	R	+	+	-	+
	APOE ε2/ε4 alleles	B2	C	+	+	-	+

APOE apolipoprotein E gene, BDNF brain-derived neurotrophic factor, C clinical, CSF cerebrospinal fluid, DMN default mode network, EEG electroencephalography, ICF intracortical facilitation, MEG magnetoencephalography, NAcc nucleus accumbens, NfL neurofilament light chain, PET positron emission tomography, R research, SAI short afferent inhibition, SICI short-interval intracortical inhibition, WM white matter.
¹Level of evidence defined according to the following classification ¹⁰⁶: A = proven/consensus association in human medicine; B1 = prospective, randomized clinical trial; B2 = cross-sectional and longitudinal cohort biomarker studies; B3 = retrospective biomarker studies; C = individual case reports from clinical journals; D = in vivo or in vitro models support associations; E = indirect evidence.
²Clinical utility, i.e., the actual usefulness/added value of the biomarker in clinical routine considering the defined context of use (i.e., clinical, research), diagnostic/prognostic yield (i.e., + = definite, - = uncertain), non-invasiveness (i.e., + = non-invasive, - = invasive) and accessibility (i.e., + = available in both primary and specialized care centers; - = access limited to some primary and specialized care centers or available only in specialized care centers).
³Reproducibility has been defined according to standardization and interoperability (i.e., + = established, - = unclear or not defined).

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