Peter Attia MDOptimizing brain health: Alzheimer's risk factors, APOE, & prevention strategies [AMA 46 sneak peek]
CHAPTERS
- 0:02 – 2:33
Setting the Stage for a Brain Health AMA
The hosts chat about Austin's ice storm, then explain that this AMA collects audience questions on Alzheimer's, dementia and neurodegeneration, a topic not yet covered in an AMA. They note the point attributed to Richard Isaacson that anyone with a brain is at risk.
- •Austin ice storm and kids home from school
- •AMA built from organized audience questions on the brain
- •Earlier podcasts on the topic featured several guests
- •Richard Isaacson's point that anyone with a brain is at risk
- 2:33 – 5:36
How Alzheimer's Disease Is Diagnosed
Peter Attia explains that Alzheimer's is the most common neurodegenerative disease and cause of dementia, but other dementias exist. Diagnosis is clinical, based on symptoms, cognitive testing and ruling out other causes, and is only definitive at autopsy, though blood biomarkers and amyloid PET are improving certainty.
- •Other dementias include vascular and Lewy body, plus Parkinson's disease
- •Neurologists assess memory, planning, orientation and language problems
- •Lab tests rule out mimics such as hypothyroidism or B12 and B6 deficiency
- •Definitive diagnosis comes only at autopsy
- •Serum amyloid and tau plus amyloid PET raise diagnostic confidence
- 5:36 – 11:32
Biomarkers and the C2N Test
Asked whether there is an Alzheimer's equivalent to APOB, Attia says there is nothing as neat. He describes the C2N amyloid score, which combines APOE status, plasma AB 42/40 ratio and age, and explains why his practice uses it only in a few high-risk patients given pretest probability and predictive value.
- •No simple equivalent to APOB for Alzheimer's
- •CSF amyloid and tau via lumbar puncture is impractical
- •C2N uses APOE genotype, AB 42/40 ratio and age
- •Practice uses it in only six or seven patients and amyloid PET rarely
- •Applying the test to everyone would lower positive and negative predictive value
- 11:32 – 16:39
Genes That Confer Alzheimer's Risk
Attia covers the near-deterministic genes PSEN1, PSEN2 and APP, which account for about 1% of cases, then focuses on APOE4, carried by about 25% of people but by two-thirds of the remaining cases. He discusses modifiers such as Klotho KLVS, mitochondrial haplotype, TGF beta and TOMM40, and the testing options for them.
- •PSEN1, PSEN2 and APP cause early-onset disease in about 1% of cases
- •APOE4 is not deterministic; some centenarians carry it
- •Klotho KLVS variant attenuates E4 risk
- •Other genes can amplify risk
- •Practice uses whole genome sequencing rather than 23andMe-style tests
- 16:39 – 21:21
APOE Alleles, Genotypes and Why Test
Attia explains the three APOE alleles (E2, E3, E4), the six genotype combinations and their approximate prevalence. He notes there is no turnkey test for the full set of Alzheimer's genes and defends testing APOE, arguing knowledge allows planning and that risk can be reduced.
- •E2, E3 and E4 are wild-type alleles, not mutations
- •About 50-55% are 3/3 and about 25% are 3/4
- •No turnkey test for the full suite of relevant genes
- •Attia calls the backlash over APOE testing in the Limitless series baseless
- •He believes onset can be delayed and risk reduced
- 21:21 – 25:09
Prevalence, Sex Differences and Genotype Risk Figure
Attia says women are twice as likely as men to get Alzheimer's and walks through a figure of ten-year risk by decade, outcome and genotype. It shows 4/4 carries markedly higher risk, 3/3 is the baseline, and women have about 20% higher risk per decade, which together with longer lifespan may explain the two-to-one gap.
- •Prevalence is two to one in women versus men, reversed in Parkinson's
- •Figure shows ten-year risk for Alzheimer's, vascular and all dementia
- •4/4 has significantly higher risk, with 3/4 and 4/2 next
- •Women have about 20% higher risk per decade
- •Longer female lifespan likely contributes to the gap
- 25:09 – 29:55
Can Prevention Work? Evidence from the Chicago Health and Aging Project
Asked how robust the case for prevention is, Attia says controlled trials are hard given the time course, so much data is epidemiologic. He describes the Chicago Health and Aging Project, which followed nearly 4,000 older adults and compared those with few versus many healthy lifestyle factors, split by E4 status.
- •Trials of prevention are difficult because of long time courses
- •Chicago study followed nearly 4,000 people aged 65+ from the early 1990s to about 2012
- •Participants were grouped as zero to one versus four to five healthy lifestyle factors
- •Analysis is observational with confounders such as education and socioeconomic status
- 29:55 – 31:28
Healthy Behaviors Offset E4 Risk
Attia interprets the graph: all groups started with similar cognition, E4 carriers still declined faster than non-carriers with healthy habits, but E4 carriers with healthy behaviors resembled non-E4s without them. He concludes risk is malleable and that healthy behaviors seem to help E4 carriers even more.
- •All four groups began with similar cognitive scores
- •E4 carriers decline faster even with healthy behaviors
- •E4s with healthy behaviors look like non-E4s without them
- •The gap between lifestyle groups is larger in E4 carriers
- 31:28 – 34:59
Moving On to Prevention Factors and Sneak Peek Wrap-Up
The host says the rest of the AMA focuses on what can be done to prevent Alzheimer's and asks Attia for a quick list of factors. The sneak peek then ends with a membership message.
- •Rest of the AMA focuses on prevention strategies
- •Host asks for a quick list of factors before detailed discussion
- •Full AMA is available to members
