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Peter Attia MD#138-Lauren Rogen & Richard Isaacson MD: Alzheimer’s disease prevention—patient & doctor perspective
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CHAPTERS
- 0:11 – 13:52
Lauren's Family History: Watching Alzheimer's Take Her Grandparents and Mother
Peter Attia introduces his guests, then asks Lauren when she first became aware of Alzheimer's in her family. Lauren describes her grandfather and grandmother, and how her mother began showing symptoms at 52, along with the denial, fear and depression that followed.
- •Lauren's grandfather and grandmother both had Alzheimer's, and as a child she did not grasp the seriousness
- •Her mother, a first-grade teacher, repeated stories at Lauren's college graduation at age 52
- •Her mother would not let the family discuss it, and Lauren kept her fear to herself for a long time
- •In a car conversation, her mother said she was scared not for herself but for her children and husband
- •Lauren searched online for a cure and found nothing, feeling helpless
- 13:52 – 25:26
Early-Onset Alzheimer's, Epigenetics, and the Role of ApoE
Peter asks Richard how he thinks about such an early, familial case. Richard explains that Alzheimer's starts in the brain decades before symptoms and describes the rare early-onset genes, polygenic risk and epigenetics. He also explains ApoE alleles and why E4 raises risk.
- •Only three genes (presenilin 1, presenilin 2, APP) guarantee early-onset disease, and they are very rare
- •Most early cases involve polygenic risk and epigenetics, meaning genes plus environment and lifestyle
- •ApoE 2 is protective, 3 is neutral, and 4 increases risk, with two copies raising it more
- •ApoE4 acts through a cholesterol-like, vascular pathway that accelerates amyloid buildup
- •Richard says genes are not destiny and individuals can win the tug-of-war
- 25:26 – 29:57
Lauren's Mother at Her Wedding and the Toll on Family Caregivers
Peter asks about the course of Lauren's mother's disease up to Lauren's wedding. Lauren recounts how her mother was disoriented, how the wedding was changed to accommodate her, the one day she seemed present, and the hard flight home that led Lauren's parents to move to Los Angeles. Peter then notes why Hilarity for Charity focuses on families.
- •At the wedding her mother had just turned 60 and was being fully cared for by Lauren's father
- •Her mother wanted to go home at the rehearsal dinner but on the wedding day knew Lauren was the bride and felt proud
- •People often ask whether a patient has good days, but Lauren says lost abilities are gone
- •Her father's stress was so great that the family moved her parents to Los Angeles
- •Peter says caring for families matters while research is still underway
- 29:57 – 39:16
Why Alzheimer's Is Heterogeneous and Its Three Stages
Peter asks why Alzheimer's produces such varied symptoms, and Richard explains that symptoms depend on where pathology spreads, giving examples such as dysexecutive syndrome and PART. Peter compares this to cancer being many diseases. Richard then lays out the three stages: preclinical, mild cognitive impairment, and dementia.
- •Symptoms manifest wherever the pathology goes, such as executive function, memory or visual perception
- •Peter compares Alzheimer's to cancer as an umbrella term for many related diseases
- •Stage one is preclinical, with Alzheimer's in the brain but no symptoms; Richard cites 46 million Americans in this state
- •Stage two is mild cognitive impairment, where the person can still care for themselves
- •Richard says Lauren's mother's course sounded like Alzheimer's starting at the preclinical-to-MCI border
- 39:16 – 46:54
How Lauren Met Richard Through HFC and Her Uncle's Illness
Peter asks how Lauren and Richard met. Lauren describes starting Hilarity for Charity, her uncle's emerging symptoms, finding Richard's email, discovering a shared high school, and asking to become a patient herself.
- •The first Hilarity for Charity event in 2012 drew young people who felt seen for the first time
- •Lauren's uncle, her mother's older brother, began showing symptoms and the family asked her for help
- •She emailed Richard directly and found he had attended the same high school as her mother and uncle
- •She asked to become a patient on her first visit to the clinic
- •By then her mother was bedridden while her uncle was around the MCI stage
- 46:54 – 1:01:10
Richard's Detective Work on the Family: Genotype, Phenotype and Hormones
Richard describes piecing together the family history from videos, yearbook handwriting, clinical history and genetic testing. He explains why he suspected both Lauren's mother and uncle were ApoE 4/4, then discusses her mother's early hysterectomy and its possible role.
- •Richard says he suspected ApoE4/4 from a video of Lauren's mother, and testing showed both she and her uncle were 4/4
- •Richard views Alzheimer's as a life-course disease, citing the nun study and smaller brains at birth in E4 carriers
- •Women with E4 carry higher risk, and Lauren's mother had a hysterectomy around 46 that removed her ovaries
- •Even with 4/4, female sex and surgical menopause, Richard thought something else had to be involved
- •Lauren's mother got little cardio, ate a lot of sugar and slept poorly, while her uncle was an athlete
- 1:01:10 – 1:08:46
Why Alzheimer's Affects Women More: Perimenopause and Body Fat
Peter asks about the gender gap in Alzheimer's. Richard argues that the perimenopause transition is a major under-recognized factor and describes other female-specific risks such as widowhood and visceral fat, contrasting them with muscle mass in men.
- •Richard says bioenergetic shifts in the brain during perimenopause create a window of opportunity for intervention
- •He calls perimenopause a brain condition, not just a set of symptoms
- •Age remains the number one risk factor, and widowhood is an important risk factor for cognitive decline
- •In women, a larger waist circumference is tied to a 39% higher dementia risk, and visceral fat matters more than thigh fat
- •Richard thinks muscle mass may matter more in men, but says this still needs to be teased out
- 1:08:46 – 1:15:54
Lauren's Diagnosis, ApoE Testing, and Head Trauma Questions
Lauren shares learning she is ApoE 3/4 and her motivation to act. Peter recounts a couple whose PCP objected to ApoE testing, and Richard discusses early omega-3 use, head trauma and findings from the REVEAL study on learning one's status.
- •Lauren is a 3/4, which she says felt like information she could act on rather than a death sentence
- •She did not want to live in the dark and not use the tools science offers
- •Peter says he would test children of E4 carriers and would reconsider football for boys with an E4
- •Richard says head trauma plus E4 may increase risk, though his opinion has shifted
- •Richard cites the REVEAL study showing no lasting negative psychological outcomes from learning ApoE4 status
- 1:15:54 – 1:22:42
Other Risk Genes: TOMM40, TNF-alpha and Polygenic Risk
Peter asks about other genes beyond ApoE, and Richard describes about 30 known risk genes, the role of TOMM40, and a TNF-alpha-related gene found in Lauren's mother and Lauren but not her uncle. Peter draws an analogy to Lp(a) in cardiology.
- •Richard says around 30 Alzheimer's risk genes have been found, and not all ApoE4s are created equal
- •TOMM40, next to ApoE, may influence how an E4 behaves
- •A TNF-alpha-related gene interacting with E4 was found in Lauren, and her uncle lacked it
- •Richard says his mother-in-law-type single explanations don't work, and polygenic risk is the likely answer
- •Peter compares E4 variability to Lp(a), where some families show premature heart disease and others don't
- 1:22:42 – 1:25:30
Lauren's Motivation and the ABCs of Prevention
Peter asks why Lauren embraced risk reduction so fully, and she cites what she saw over fifteen years. Richard then describes the clinical trial, the average of 21 interventions, and the ABCs framework of anthropometrics, blood biomarkers and cognition tracked every six months.
- •Lauren says that having seen the last fifteen years, she wants to do everything she can to avoid that for herself and her family
- •Seth supports her and has changed his eating and exercise habits
- •Richard's clinical trial, published in Alzheimer's & Dementia, found people received an average of 21 interventions
- •The ABCs are anthropometrics, blood-based biomarkers and cognitive function, rechecked every six months
- •Lauren's plan emphasizes exercise including high-intensity interval training
- 1:25:30 – 1:36:30
Lauren's Supplement and Nutrition Protocol
Richard and Peter walk through the specifics of Lauren's protocol: omega-3 dosing, cocoa flavanols, curcumin and theracurcumin, B vitamins for homocysteine, vitamin D, and magnesium L-threonate. They discuss dosing targets and the evidence behind each.
- •Lauren takes high-dose omega-3s because Richard says E4 carriers need more than fish alone, targeting a red blood cell index of at least 12 to 14
- •B vitamins are used only in people with high homocysteine, with sufficient omega-3 levels
- •Lauren's vitamin D was 17 to 19; Richard says 30 is normal but he'd aim for about 50, taken with fat
- •Theracurcumin is favored for high-risk patients because of a UCLA study showing less amyloid accumulation
- •Richard rates magnesium L-threonate as evidence-based and safe but not at the top of his list
- 1:36:30 – 1:41:56
E4-Specific Strategies and the CBD/THC Question
Peter asks what changes for E4 carriers. Richard summarizes a paper on ApoE-based precision medicine covering exercise, smoking, alcohol, diet and saturated fat. Peter then asks about THC, and Richard says he is neither for nor against it and calls it a precision medicine answer.
- •Exercise is likely preferentially effective in E4 carriers, and a sedentary lifestyle is worse for them
- •Richard says tobacco is worse in E4s and abstaining from or cutting alcohol may help carriers more
- •E4 carriers should be more cautious with high saturated fat, and MCTs should be personalized
- •Richard says CBD and THC studies point in both directions, so he is in the middle
- •He suggests an N-of-one approach with objective tracking of sleep and cognition
- 1:41:56 – 1:49:24
Cognitive Testing and Lauren's Improved Results
Peter asks Lauren about the cognitive tests. She recalls a bad day and Richard's concern that pushed her back on track. Richard describes the battery, practice effects in E4s, and Lauren's improvement from slightly below average to well above.
- •Lauren has done the battery about six or seven times and feels nervous before each
- •Richard says processing speed and attention suffer with poor sleep, whereas early Alzheimer's shows in memory and naming tasks
- •A bad result at a stressful time prompted Richard's concern and a renewed push, which led to involving Peter
- •Richard says her memory moved from .87 standard deviations below the mean to a standard deviation above
- •Richard says E4s are more resistant to practice effects
- 1:49:24 – 1:57:55
Smell and Hearing as Early Indicators
Peter asks about odor identification testing, and Richard explains its link to neurodegeneration, with Lauren noting her mother's poor smell. After a COVID tangent, they discuss hearing loss as a potentially modifiable risk factor and whether to screen high-risk patients.
- •Odor identification is a more objective test, and loss of smell can precede Parkinson's and Alzheimer's
- •Lauren's mother had a poor sense of smell
- •Richard notes that COVID could complicate using smell testing for Alzheimer's
- •The 2020 Lancet Commission report found hearing loss to be the most impactful modifiable risk factor, though why is unclear
- •Peter sees no downside to protecting hearing and considers sending high-risk patients to audiologists
- 1:57:55 – 2:00:31
Emotional Benefits of Taking Control
Richard asks Lauren whether she feels different cognitively, and she says she feels physically better and sees her labs improve. Peter and Lauren reflect that the greatest benefit may be reduced fear, because she now has control.
- •Lauren says she feels physically better with more energy but is not sure she feels greatly better cognitively
- •She wonders whether her own hormonal journey affects how she feels
- •Peter says he and Richard see no reason to believe she will get Alzheimer's if she stays the course
- •Lauren says much of her fear has dissipated as she watches blood work go from red to green
- 2:00:31 – 2:11:50
Hilarity for Charity: Mission, Care and Closing Thoughts
Lauren explains HFC's mission of supporting people today and teaching brain health for tomorrow, through support groups, respite care, caregiver training and research, and how people can get involved. The episode closes with Richard noting that four out of ten cases may be preventable.
- •HFC offers personalized support groups and provides caregivers to give family members respite
- •It focuses on activating young people and teaching that it is never too early to care for the brain
- •People can donate, share stories, run their own fundraisers, and a partnership with the Rosalynn Carter Institute trains caregivers
- •HFC uses comedy to draw people in, then shares facts and hope
- •Richard says the latest data suggest four out of ten Alzheimer's cases may be preventable
