252 ‒ Latest insights on Alzheimer’s disease, cancer, exercise, nutrition, and fasting

KEYPOINTS

• 01

  Patrick increasingly sees blood-brain barrier breakdown as an early driver of dementia, ahead of amyloid.

  Patrick, who carries one APOE4 allele and has Alzheimer's and Parkinson's in her family, cites work by Berislav Zlokovic (USC) and Axel Montagne (Edinburgh). Their research found markers of barrier leakage decades before cognitive decline, in more than half of dementias, independent of amyloid and tau. A leaky barrier lets substances like fibrinogen into the brain, where it damages myelin-making cells, and impairs the glymphatic clearance of debris during sleep. It also disrupts GLUT1 transporters, which carry glucose into the brain without needing insulin. That may explain the brain's reduced glucose use better than 'brain insulin resistance' does.

• 02

  Type 2 diabetes and APOE4 both damage the barrier, and diabetes is preventable.

  Patrick says 50–80% of people with Alzheimer's also have type 2 diabetes. Attia estimates diabetes roughly doubles risk, about the same as carrying one APOE4 copy (two copies raise risk up to about tenfold). High glucose produces advanced glycation end products that damage tiny blood vessels, as in the eyes and kidneys. Attia sees atherosclerosis and cancer as eventually inevitable for humans, but not type 2 diabetes, which he calls 'gasoline on the fire of aging.'

• 03

  The omega-3 DHA transporter may be key to barrier health.

  In animals, disrupting the DHA transporter MFSD2A causes about 50% barrier breakdown and more than 50% loss of brain omega-3. In humans it declines with age, faster in Alzheimer's and with APOE4, and genetic defects cause small heads and cognitive impairment. Patrick has joined Bill Harris's Fatty Acid Research Institute to study omega-3 and barrier integrity. She calls trials giving 500 mg–2 g to people who already have Alzheimer's far too little, too late. EPA may help through inflammation; small trials suggest EPA helps depression.

• 04

  Blood pressure damage builds up over a lifetime.

  About half of US adults and about 20% of 18–39-year-olds have hypertension. Patrick says high blood pressure in midlife, before about 50, is linked to dementia, while starting at 70–80 is much less so. She aims for systolic below 130; Attia cites SPRINT's 120. Exercise and sauna both lower blood pressure, and some people are genetically salt-sensitive.

• 05

  Patrick trains hard specifically to raise lactate for her brain.

  Lactate, once seen as waste, is used by the brain as fuel and as a signal. George Brooks's 'lactate shuttle' work shows it raises VEGF, which repairs and grows vessels at the barrier, and BDNF, which supports neuroplasticity. Patrick does Tabata-style intervals (16 rounds of 20 seconds on, 10 off) on a Peloton five days a week, reaching about 7–8 mmol. Attia combines zone 2 rides at about 1.9 mmol with 4-minute all-out VO2 max intervals reaching 15–16 mmol, describing fitness as a pyramid needing a wide base and a high peak. He suggests she rest completely in the 10-second off periods to push the 'on' periods harder, and that blood flow restriction training can also spike lactate.

• 06

  Exercise and cancer: real but more modest, with stronger effects after diagnosis.

  Studies of Olympians found they lived about 5–6 years longer than the general population, about two of those years from fewer cancer deaths. In observational data, aerobic exercise is linked to roughly 10–20% lower risk of breast and colorectal cancer. After diagnosis, active patients had about 50% lower mortality and recurrence. Patrick thinks preventing cancer may require more exercise, toward the upper end of the guidelines (300 minutes a week of moderate exercise), than heart benefits do. One proposed mechanism: shear stress from fast blood flow kills circulating tumour cells. Trials show exercise reduces them.

• 07

  Both changed their minds on protein: muscle matters more than results in lab mice.

  Low-protein longevity results come from mice in sterile labs that die of lymphomas, not from infections, falls or bed rest. Worm daf-2 mutants live longer only by entering a dormant state humans don't have. Stuart Phillips's newer tracer studies suggest a minimum of about 1.2 g/kg, not 0.8, and more for older or active people because of anabolic resistance. Attia targets about 1 g per pound (2.2 g/kg), spread over four meals and snacks of about 40–50 g each. He notes that in Levine's study, protein intake wasn't linked to IGF-1 in people over 65. Attia cites a 70% lower dementia risk with strong versus weak grip.

• 08

  Exercise 'forgives a lot of sins.'

  Patrick's continuous glucose monitor as a new mother showed broken sleep pushing her glucose into the prediabetic range. Exercise largely blunted this for about 48 hours. She also cites data where poor sleep raised mortality only in inactive people. Because of her APOE4, she drinks rarely. Attia argues no amount of alcohol is healthy and the J-curve is due to confounding, though harm at a few drinks a week is probably too small to measure. He says APOE4 carriers are more vulnerable, partly through poorer sleep.