TABLE 3.

Promising bioenergetic and nutritional biomarkers and their implications for brain functions

Biomarker	Implications for nutritional and metabolic interventions
Fluid biomarkers
Omega-3 index	Lower blood omega-3 index is associated with increased dementia risk.161,261,262 Screen vulnerable populations (with low blood omega-3 index) for LC n-3 PUFA supplementation before the onset of AD dementia.
DHA/AA ratio	A lower plasma or CSF DHA/AA ratio in AD and APOE4127,263 may reflect activation of lipid catabolism pathways and serve as a biomarker for therapies (such as cPLA2 inhibitors).162
Homocysteine	An increase in plasma homocysteine is associated with increased risk of AD.264–266 Reducing homocysteine using vitamin B complexes maybe beneficial to reducing AD risk before the onset of clinical dementia.
25-OH vitamin D	Screen vulnerable populations (with 25-OH-D deficiency [<25 nmol/L]) or insufficiency [25–50 nmol/L]) for vitamin D supplementation.267,268
Acylcarnitines	Lower levels ACC found in AD serum,269 as a biomarker of dysfunctional FAO.
sPDGFRβ	CSF sPDGFRβ levels is a marker of pericyte function, lower in APOE4 and those with lower cognitive function, independently of CSF amyloid beta42.101 Interventions that restore pericyte integrity may improve brain nutrient delivery.
SCFA	SCFA concentrations are lower in CSF of AD participants and are markers of brain energetic failure in AD.149 SCFA levels can guide screening and validation of multitudes of pre- and probiotic co-culture combinations.
Urinary DCA	Biomarker of unsaturated fatty acids oxidative damage.270 Urine DCAs can help select individuals with oxidative damage and guide antioxidant therapeutics.
Imaging biomarkers
DHA PET scans	APOE4 carriers may have a greater vulnerability to omega-3 deficiency before onset of clinical disease.121 DHA PET scan can help identify vulnerable groups and guide supplementation interventions and selection of cognitive outcomes.
Ketone PET scans	Ketone PET guides the uptake of ketones in brain regions directly related to improvements in cognitive outcomes166 including processing speed168 and attention.169 Ketone PET scans can help identify individuals responsive to a ketogenic intervention and selection of cognitive outcomes.
FDG-H215O PET scans	FDG-PET is a presymptomatic marker of brain hypometabolismand AD risk. Dietary behaviors may affect regional cerebral blood flow which maybe used as an efficacy endpoint for appropriate initial trial fine tuning.271
Infra-red spectroscopy	The effects of different interventions (caffeine, wine and tea polyphenols such as resveratrol orepigallocatechin gallate, creatine, DHA-rich fish oil) in infra-red spectroscopy markers may provide surrogate end points in proof-of-concept nutritional trials.272–277
MR proton or phosphorus spectroscopy	The effect of potential interventions with precursors of brain neurotransmitters important for brain metabolism such as choline or citicholine that are derived from diet may be directly measured in the brain using MR spectroscopy approaches.278,279
MRI CBV	Cerebral blood volume has been enhanced in concert with improved cognitive performance in the hippocampal dentate gyrus afteraflavanol intervention. CBV can be used as preliminary efficacy target.280
Structural connectivity MRI DTI	The effect of potential interventions with a variety of nutrients (ω3 and ω6, ω6, vitamin E, different lipids236,281) and dietary patterns such as the MeDi282 may be estimated with structural connectivity measures.
Functional connectivity fMRI	The effects of potential interventions236 including ketones,169 MUFA, SFA, n-3 and n-6 PUFAs,283 B vitamins, vitamin E, carotenoid, carotene and lycopene,283 resveratrol,284,285 cholesterol related lipids,286 beetroot juice287 can be captured with functional connectivity neuroimaging techniques.
MRI DCE	DCE MRI can define BBB integrity and is lower with APOE4 and AD.95 Interventions that restore BBB integrity may improve brain nutrient uptake and metabolism.

Abbreviations: AA, Arachidonic Acid, ACC, Acylcarnitines; DHA, Docosahexaenoic acid; CBV, cerebral blood volume; CSF, cerebrospinal fluid; cPLA2, Calcium-dependent phospholipase A2; DCA, Dicarboxylic Acid; DCE, Dynamic contrast enhancement; DTI, diffusor tensor imaging; FAO, fatty acid oxidations; FDG, Fluorodeoxyglucose; PDGFRβ, soluble platelet-derived growth factor receptor β; SCFA, short chain fatty acids.BBB, blood-brain barrier; MUFA, monounsaturated fatty acids; SFA, saturated fatty acids; PUFAs, polyunsaturated fatty acids; MeDi, mediterranean style diet;