| Tier |
Rank |
Node / Lever |
What it Supports (Bioenergetic Role) |
Key Enzymes / Targets |
AD-Relevant Mechanism |
TSF |
Evidence |
Common Constraints / Gotchas |
| 1 | 1 |
Thiamine (B1) / TPP |
Glucose → acetyl-CoA entry + TCA throughput + NADPH support |
PDH, α-KGDH, Transketolase (PPP) |
Addresses cerebral glucose hypometabolism; improves mitochondrial flux; PPP→NADPH supports redox |
R, G |
Mechanistic + small clinical |
Benefit strongest if low status; standard thiamine vs lipophilic derivatives differ |
| 1 | 2 |
Benfotiamine |
Higher-bioavailability B1 strategy |
Transketolase ↑; glycation axis ↓ |
AGE/RAGE burden reduction + metabolic support (model/trial dependent) |
G |
Small clinical + mechanistic |
Not a “rapid” effect; mostly longer-term metabolic/toxicity load reduction |
| 1 | 3 |
Riboflavin (B2) / FAD, FMN |
ETC redox enzymes + mitochondrial dehydrogenases |
Complex I/II flavoproteins; many oxidoreductases |
Supports electron handling; can be limiting in mitochondrial enzyme insufficiency |
R, G |
Mechanistic |
Direct AD cognitive trial support limited; “helps” mostly when deficient or enzyme-limited |
| 1 | 4 |
Niacin forms (B3) → NAD pool |
NAD+/NADH redox + signaling + repair |
NAD salvage; sirtuins; PARP substrate |
NAD decline is an aging/inflammation theme; supports mitochondrial redox capacity |
R, G |
Emerging human + mechanistic |
Different forms behave differently; NAD raising ≠ guaranteed clinical cognition benefit |
| 1 | 5 |
Pantothenic acid (B5) → CoA |
Acetyl-CoA formation; lipid metabolism; TCA entry |
CoA biosynthesis; acetylation capacity |
Foundational for fuel oxidation and acetylation balance |
G |
Mechanistic |
Often overlooked; deficiency uncommon but suboptimal intake can matter in frailty |
| 1 | 6 |
Magnesium |
ATP handling (Mg-ATP) + enzyme kinetics |
ATP-dependent enzymes; synaptic function |
Supports neuronal energy usage + plasticity; deficiency can worsen excitotoxic vulnerability |
R, G |
Supportive human + mechanistic |
Form/absorption variability; renal constraints for supplementation in some patients |
| 2 | 1 |
NAD+ precursors (NR/NMN/NA/NAM) |
Restores NAD+ availability for redox + signaling |
NAMPT salvage; sirtuins; PARPs; CD38 |
Supports mitochondrial function; may improve resilience under oxidative/repair load |
R, G |
Animal > human (emerging) |
NAD “sinks” (CD38/PARP) can dominate; response varies by inflammation/age |
| 2 | 2 |
Alpha-lipoic acid (ALA) |
Mitochondrial redox cofactor + antioxidant recycling |
PDH/α-KGDH cofactor; GSH recycling support |
Improves redox tone and mitochondrial efficiency (signals strongest in metabolic/oxidative phenotypes) |
R, G |
Small AD trials + mechanistic |
“Antioxidant” framing can be misleading—main value is mitochondrial/redox coupling support |
| 2 | 3 |
Glutathione system support |
Detox + peroxide handling |
GSH, GPx, GR, NADPH supply (PPP) |
Reduces oxidative damage load that impairs mitochondria/synapses |
R, G |
Mechanistic |
GSH depends on substrates + NADPH; pushing one component may not fix system |
| 2 | 4 |
Selenium (GPx capacity) |
Peroxide detox via selenoenzymes |
Glutathione peroxidases |
Supports antioxidant enzyme capacity (context-dependent) |
G |
Mixed human |
Narrower safety margin; avoid “more is better” mindset |
| 3 | 1 |
CoQ10 (ubiquinone) |
ETC electron carrier (I/II→III) + membrane redox |
Complex I/II→III transfer |
Supports OXPHOS efficiency; may reduce electron leak under some conditions |
R, G |
Limited AD-specific |
Bioavailability/formulation matters; AD cognition data not robust |
| 3 | 2 |
Cardiolipin / mitochondrial membranes (support axis) |
ETC supercomplex stability; cristae integrity |
Inner mitochondrial membrane architecture |
Membrane integrity affects ETC efficiency and ROS leak |
G |
Mechanistic |
Hard to “target” nutritionally in a clean way; effects indirect |
| 3 | 3 |
Iron / copper homeostasis (burden control) |
Prevents metal-catalyzed oxidative damage |
Fenton chemistry burden; metal transport/storage |
Metal dyshomeostasis can amplify ROS and mitochondrial injury |
R, G |
Mechanistic + mixed human |
“Chelation” is not casually safe; needs careful framing and evidence |
| 4 | 1 |
Ketone utilization (BHB/acetoacetate axis) |
Alternative brain fuel bypassing glucose bottlenecks |
MCT1/2 transport; ketolysis enzymes |
Addresses brain glucose hypometabolism by providing alternate substrate |
R, G |
Moderate (human MCI/AD signals exist) |
GI tolerance and adherence; response varies by genotype/metabolic status |
| 4 | 2 |
Creatine / phosphocreatine shuttle |
ATP buffering and rapid energy stabilization |
Creatine kinase system |
May stabilize energy during stress; supports muscle/functional reserve that impacts cognition indirectly |
G |
Limited AD |
CNS benefit uncertain; stronger for muscle/functional outcomes |
| 4 | 3 |
Acetyl-L-carnitine (ALCAR) |
Fatty acid oxidation support + acetyl group handling |
Carnitine shuttle; acetyl-CoA support |
May support mitochondrial energy and neuronal function (mixed clinical results) |
R, G |
Mixed human |
Benefits heterogeneous; not a universal cognitive improver |
| 4 | 4 |
Medium-chain triglycerides (MCT oil → ketones) |
Rapid ketone support strategy |
Hepatic ketogenesis; brain ketone uptake |
Practical ketone-raising approach for some phenotypes |
R, G |
Moderate human |
GI effects; calorie load; titration matters |
| 5 | 1 |
AMPK → PGC-1α biogenesis axis |
Mitochondrial number/quality regulation |
AMPK, PGC-1α, SIRT1 |
Supports long-term mitochondrial capacity and stress resistance |
G |
Mechanistic |
Most effects are slow; many “activators” are indirect and context-dependent |
| 5 | 2 |
Mitophagy / autophagy quality control |
Removes damaged mitochondria |
PINK1/Parkin axis; autophagy machinery |
Damaged mitochondria drive ROS and energy failure; quality control is protective in theory |
G |
Mechanistic |
Autophagy modulation is double-edged; oversimplified “more autophagy = good” is risky |
| 5 | 3 |
Exercise signaling (the “master cofactor”) |
Improves vascular + mitochondrial + neurotrophic tone |
BDNF; insulin sensitivity; AMPK/PGC-1α |
Most evidence-backed multi-pathway energy intervention for aging brain |
R, G |
Strong (human) |
Adherence/ability constraints; must be individualized |
| 6 | 1 |
Cerebral perfusion / vascular health |
Fuel + oxygen delivery and waste clearance support |
Neurovascular unit; endothelial function |
Vascular dysfunction worsens hypometabolism and inflammation |
R, G |
Strong (human) |
Often upstream of “supplement” efficacy; if delivery is poor, cofactors underperform |
| 6 | 2 |
Sleep / glymphatic clearance |
Waste clearance & metabolic recovery |
Glymphatic system; circadian regulation |
Supports clearance of metabolic byproducts; indirectly supports energy balance |
G |
Strong (human) |
Often neglected; impacts cognition and inflammation strongly |
| 6 | 3 |
Oxygen utilization context (respiratory capacity) |
Oxidative metabolism support |
OXPHOS dependence |
If oxygen delivery/usage is limited, pushing mitochondrial cofactors won’t fully translate |
R, G |
Supportive |
More about system constraints than a “node to supplement” |