#138-Lauren Rogen & Richard Isaacson MD: Alzheimer’s disease prevention—patient & doctor perspective

KEYPOINTS

• 01

  Lauren's mother developed symptoms at about 52

  Lauren Miller Rogen's maternal grandfather had Alzheimer's, with symptoms in his late 50s or early 60s. He was in a nursing home for most of her childhood. At Lauren's college graduation, when she was 22 and her mother was 52, her mother repeated the same story several times. Her mother had been a sharp, vibrant first-grade teacher. By Lauren's wedding, when her mother had just turned 60, she couldn't stand with the family at the ceremony. Lauren's father, who was in denial at first, became an exhausted full-time carer.

• 02

  Most Alzheimer's is late-onset, and true genetic early-onset is rare

  Isaacson has seen roughly 1,500–2,000 patients. He says he can count on two hands those with deterministic early-onset mutations, such as amyloid precursor protein mutations, which cause disease in the 40s or 50s. These account for well under 1% of cases. Lauren's family didn't fit that pattern. Theirs was late-onset Alzheimer's that had been pushed earlier.

• 03

  APOE sets a baseline risk, and the genes around it matter too

  E3 is neutral, E2 is protective and E4 raises risk, more so with two copies. Isaacson sees E4 as increasing vascular risk and the build-up of harmful proteins. He says E4 carriers may even have smaller brains at birth. He adds that 'not all APOE4s are created equal': nearby genes such as TOMM40 may change how an E4 behaves. He describes that point as his belief, not a certainty. Every patient in his clinic gets an APOE test.

• 04

  Alzheimer's has three stages, and the first is silent

  Stage one is preclinical: the disease has started in the brain but there are no symptoms. Isaacson cites a figure of about 46 million Americans in this stage while admitting the exact number is uncertain. Stage two is mild cognitive impairment due to Alzheimer's. Stage three is dementia. He says roughly 12–16% of people with MCI progress to dementia each year, depending on the study. He sees the preclinical stage as the most important target for prevention.

• 05

  Women with E4 face a distinct, compounded risk

  Alzheimer's disproportionately affects women, and Attia argues that women's longer lifespan doesn't fully explain the gap. Isaacson credits Maria Shriver with pushing him to study it. Lauren's mother was E4/E4. She also had a hysterectomy with removal of her ovaries at about 46, an abrupt surgical menopause. She didn't exercise, and the household ate dessert most nights. Isaacson calls it 'the perfect storm' of genetics, sex, loss of hormones and lifestyle.

• 06

  Her uncle was also E4/E4 but became ill about 15 years later

  Lauren's uncle, her mother's older brother, also carried two copies of E4. He was a lifelong athlete and an obsessive cyclist, and his symptoms began in his late 60s or early 70s. Because both siblings had the same genotype, Isaacson attributes the gap to sex, the hormone loss and lifestyle, probably in combination.

• 07

  Body fat, especially belly fat, matters more for women

  Isaacson says that as waist size grows, the brain's memory centre gets smaller. He cites a 39% higher risk of dementia in women with enlarged waist circumference. For women he tracks body-fat percentage and where the fat sits, not weight. He also flags widowhood as a major risk factor for cognitive decline.

• 08

  Prevention runs on the ABCs, rechecked every six months

  A is anthropometrics: body composition, fat and muscle. B is blood biomarkers: lipids, inflammation, metabolism, nutrition and genetics. C is cognitive function. Repeating them on a schedule shows whether the plan is working.

• 09

  Hearing loss may be the largest modifiable risk factor

  Isaacson cites the Lancet Commission's 2020 report, which found hearing loss to be the most impactful modifiable risk factor. Attia raises the question of whether it actually causes dementia or simply rises with age alongside it. Isaacson says he doesn't have a perfect answer, but he is considering referring high-risk patients for hearing checks. He blames short 10–15 minute appointments for the lack of screening.