#18 – Richard Isaacson, M.D.: Alzheimer’s prevention

KEYPOINTS

• 01

  A clinical diagnosis of Alzheimer's is often wrong

  Isaacson, who directs the Alzheimer's Prevention Clinic at Weill Cornell, explains that Alzheimer's has traditionally been diagnosed clinically: progressive short-term memory loss plus other changes that impair daily activities. It accounts for about 60–70% of dementia. Ordinary cognitive aging, such as misplacing keys or a word on the tip of the tongue, doesn't disrupt independent living. He cites a study in which 40% of patients clinically diagnosed with Alzheimer's, and receiving anti-amyloid drugs, had no amyloid in the brain.

• 02

  'A-G-E': age, genetics, environment

  Isaacson's mnemonic captures the constant tug of war between genes and environment. Age is the top risk factor. Genes such as APOE4, along with others, can make the disease unavoidable for some people despite doing everything right. For others, changing their environment changes how their genes play out.

• 03

  About one in three cases may be preventable, and delay matters too

  Based on conservative population risk models, Isaacson says one in three Alzheimer's cases may be preventable. For the rest, the goal is delay of two, five, seven or 10 years, long enough that many people die of something else first. Attia frames it as optionality: getting the disease at 78 instead of 69 buys nine years in which much can change.

• 04

  APOE4 risk estimates have been revised down

  Everyone inherits two APOE copies, making six combinations. About 55–60% of people are 3/3, the neutral baseline. Isaacson has seen only one or two 2/2 patients, a genotype carrying about 20% lower risk. 3/4 covers about 20–25% of the population, with risk once quoted as three to four times higher, now perhaps two. For 4/4, early-2010s literature said about 25-fold. Recent papers say eight to 10-fold, which Isaacson believes overestimates the risk, and Attia unofficially guesses four to six times. Two copies don't guarantee the disease.

• 05

  Women may be in the 'express lane' because of menopause

  Attia doubts that women's higher risk is explained only by living longer. Isaacson believes Alzheimer's is fundamentally mitochondrial, with amyloid as the garbage that accumulates. He thinks the bioenergetic shifts of the perimenopause transition 'fast-forward' women toward the disease. His group studies women around menopause and, with a small grant, men aged 40–65 (15 a year for four years).

• 06

  Many roads lead to Alzheimer's

  Isaacson describes several routes into the disease. Diabetes 'will put you in the fast lane', and hormonal change and mitochondrial dysfunction are others. MTHFR, a gene in folate metabolism, is another road. He says it matters mainly for people with high homocysteine.

• 07

  The 'ABCs' of prevention

  In his precision-medicine programme, patients are stratified by APOE and MTHFR genes, then by A: anthropometrics such as body fat, lean mass and visceral fat (not BMI), B: blood biomarkers and C: cognitive testing. Attia praises Isaacson for running deeper lipid panels, including apoB, LDL particle number and particle subtypes, than most cardiologists.

• 08

  Pro-statin, but not one-size-fits-all

  Isaacson thinks different statins work differently in different people, that there is a sex difference, and that low dose is better when in doubt. He cites atorvastatin slowing hippocampal shrinkage in men. He urges real caution in APOE4 carriers, especially 4/4, and has seen men switched to a high-potency statin whose cholesterol numbers looked great but whose memory got worse.

• 09

  Exercise has the strongest evidence for risk reduction

  When Attia's team checked about 200 references in a review by Dale Bredesen, they couldn't verify about a third. One resveratrol citation had nothing to do with Alzheimer's. Starting again from first principles, the only intervention with top-level evidence was exercise. Isaacson adds it is the only thing shown to reduce or slow amyloid build-up in people who already have it.