Brain and Lifestyle: exercise, sugar, genetics
Brain. Three major levers directly influence the risk of cognitive decline.
- PHYSICAL EXERCISE : 150 min/week of moderate aerobic activity reduces dementia risk by 28%.
The main mediator is BDNF (brain-derived neurotrophic factor) which stimulates hippocampal neurogenesis, synaptic plasticity and neuronal survival via TrkB → PI3K/Akt and MAPK/ERK.
Exercise raises BDNF via irisin (myokine released by muscles, crosses the BBB, activates FNDC5 → CREB → BDNF, PMID 38002258), osteocalcin and lactate.
BDNF also stimulates α-secretase, directing APP toward the non-amyloidogenic pathway (less Aβ produced). Science 2018 (PMID 30190379) : restoring adult hippocampal neurogenesis (AHN) requires both exercise AND elevated BDNF.
- SUGAR : chronic hyperglycaemia generates AGEs (advanced glycation end products). AGE + RAGE receptor → oxidative stress, TLR4 activated, IL-1β and TNF-α → neuroinflammation.
AGEs glycosylate Tau (reinforces PHF formation, independently of phosphorylation, PMID 38947632) and Aβ (worsens aggregation).
Alzheimer's is called 'type 3 diabetes' : ApoE e4 carriers show cerebral insulin resistance on PET scan from age 40-50.
- GENETICS : ApoE e4 multiplies risk by 3-4 (heterozygous) to 8-12 (homozygous), present in 20% of the population. But these carriers also benefit the most from exercise (45% reduction).
Homozygous MTHFR C677T reduces enzyme activity by 70% → elevated homocysteine → brain atrophy; correctable by methylfolate + B12 + B6.
COMT Val158Met modulates dopamine degradation (Val/Val = reduced working memory, increased pain sensitivity).
DIO2 variant reduces cerebral T4→T3 conversion, impacting neuronal energy.
Mutated FADS1/FADS2 reduces ALA→DHA conversion → direct EPA/DHA supplementation (fish, algae) essential.
Multimodal approach for ApoE e4 : Mediterranean diet + exercise 150 min/week + normalised homocysteine + optimised vitamin D + quality sleep.
References : PMID 30190379, 38002258, 38947632.