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Peter Attia MD164 - Diagnosing, preventing, & treating Alzheimer’s disease, & life lessons from dementia patients
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CHAPTERS
- 0:02 – 4:11
Amanda's Path into Geriatric Psychiatry
Peter Attia introduces Amanda Grant Smith and asks how she came to geriatric psychiatry. She describes growing up around her grandparents' nursing home and a medical-school ER encounter that exposed ageism and fueled her passion for older patients.
- •Her grandparents owned and operated a nursing home, so vibrant aging seemed normal to her
- •In medical school she saw ageism among attending physicians
- •A woman without her dentures was dismissed as incoherent, though she told a clear story
- •She built her electives around geriatrics and found she had patience for dementia and psychotic patients
- 4:11 – 11:17
Behavioral Symptoms and the Patient Experience of Dementia
They discuss how behavioral and psychiatric symptoms fit into dementia care and how it has evolved since 1997. Amanda explains that dementia can present as psychosis and be misdiagnosed, and that patients vary widely in their awareness of their illness.
- •Donepezil was approved the year Amanda graduated, 1997
- •Behavioral problems have always been treatable even when cognition was not
- •Dementia can first present with psychiatric symptoms and be misdiagnosed as schizophrenia or bipolar illness
- •Some patients are blissfully unaware while insightful ones suffer most
- •Lewy body patients may know their hallucinations aren't real
- 11:17 – 21:28
How Dementia Is Defined and Diagnosed Clinically
Amanda defines dementia and explains that diagnosis rests on separate interviews with the patient and an informant, plus cognitive testing, imaging and labs. They cover amyloid PET and CSF, their cost, and the classic pattern of short-term memory loss versus normal forgetfulness.
- •Dementia is an umbrella term for a change in cognition that interferes with daily function
- •Interviewing patient and informant separately is key
- •Frontotemporal dementia often shows language or behavior changes with preserved memory
- •Amyloid PET can cost about $4,000 out of pocket and isn't covered by insurance
- •Frequency and intensity separate normal forgetfulness from concerning memory loss
- 21:28 – 23:59
MRI Findings and What Imaging Can and Can't Tell Us
The conversation turns to MRI findings such as vascular disease and hippocampal shrinkage. Amanda explains that hippocampal volume is an imperfect marker that must be read in clinical context.
- •MRI looks for vascular disease and global and hippocampal shrinkage
- •Small infarcts accumulate with aging and become symptomatic when they coalesce or reach cortical areas
- •Hippocampal atrophy can occur in amyloid-negative people, for example from hippocampal sclerosis
- •Stress hormones and PTSD can also reduce hippocampal size
- •Brain appearance doesn't always match cognitive impairment
- 23:59 – 35:14
Amyloid, Tau, and Redefining Alzheimer's as a Preclinical Disease
Peter and Amanda discuss whether amyloid is necessary for Alzheimer's, how amyloid PET correlates with autopsy, and the coronary-calcification analogy. Amanda explains that amyloid builds up for years while tau tracks symptoms, and that 2011 redefinitions created preclinical, MCI, and dementia stages.
- •Amyloid plaques and tau tangles define Alzheimer's pathologically
- •Florbetapir PET correlated with autopsy about 97%
- •Amyloid builds 10–20 years before symptoms, while tau's spread correlates with symptoms
- •Before 2011 Alzheimer's was defined as dementia, like waiting for a heart attack
- •Peter frames Alzheimer's alongside cancer and atherosclerosis, all resting on metabolic disease
- 35:14 – 44:30
Mixed Pathology, Vascular Disease, Blood Biomarkers, and Tau
They explore how most dementia involves mixed pathology, especially vascular disease, and whether correcting vascular risk would help. Amanda discusses blood-based biomarkers coming, tau without amyloid in other diseases, and the role of glial cells in the damage cascade.
- •Most dementia pathology is mixed, with vascular the most common additional diagnosis
- •Amyloid is part of blood vessel walls, so an interplay with vasculature is plausible
- •Plasma amyloid blood tests show promising progress
- •Tau without amyloid occurs in frontotemporal dementias and CTE
- •Amanda thinks glial cells are more responsible for damage than neurons themselves
- 44:30 – 54:44
ApoE Genotype and Distinguishing Lewy Body Dementia
Amanda explains why ApoE genotyping isn't routine in clinic but is useful in research. They then turn to Lewy body dementia, covering its classic triad, supportive features, course, genetics, and relative frequency in her clinic.
- •ApoE is not diagnostic and mainly makes people worry in routine care
- •Peter tells patients with 2/3 they are not off the hook
- •Lewy body features fluctuating cognition, parkinsonism, and visual hallucinations
- •REM sleep behavior disturbance and restless leg are supportive features
- •Her clinic is about 50–60% Alzheimer's, 20% vascular, 20% Lewy body
- 54:44 – 1:02:32
Amanda's Practice and How Dementia Care Has Changed
Peter asks how patients reach Amanda and about her career at USF and the Suncoast Gerontology Center. She describes how awareness, prevention interest, and early treatment have changed in two decades while the fear stays the same.
- •Patients come from primary doctors, neurologists, or self-referral
- •She trained at USF and took over Eric Pfeiffer's role directing the center in 2008
- •People fear losing their minds, as always
- •Public awareness that dementia is a disease, not normal aging, has grown
- •An old study showed donepezil delayed nursing home placement by about 24 months
- 1:02:32 – 1:14:28
Treating Depression and Anxiety and Supporting Caregivers
Amanda describes treating the behavioral symptoms common in dementia, favoring SSRIs and avoiding benzodiazepines. She also describes the support she gives caregivers, practical tips, and the grief stages families go through.
- •About 90% of people have some behavioral issue during illness, and these are highly treatable
- •SSRIs are common; benzodiazepines are avoided due to confusion and hip fractures
- •She advises minimizing medications and deprescribing
- •Caregivers get education, a place to vent, and practical tips like a Cheetos reward for showering
- •Behaviors are not intentional, and the stages of grief apply to patients and families
- 1:14:28 – 1:19:04
Facing the End of Life and Focusing on the Present
Peter asks how Amanda handles the specific fears about how Alzheimer's ends. She explains she answers honestly, but steers people toward living in the present and notes that hospice support exists.
- •Peter compares this to oncology patients worrying about mechanism of death
- •Amanda describes difficulty swallowing, aspiration pneumonia, and loss of mobility when asked
- •Many people die of something else before reaching terminal dementia
- •She focuses families on making each day better since patients have only today
- 1:19:04 – 1:35:40
The Alzheimer's Drug Pipeline and Why Trials Have Failed
Peter lays out about 120 drugs in the pipeline by phase and category, and Amanda explains symptomatic, behavioral, and disease-modifying treatments. They discuss amyloid biology, side effects of enzyme-targeting drugs, why early trials in moderate disease failed, and drug-development costs.
- •About 80% of the pipeline is disease-modifying, while all approved drugs are symptomatic
- •Approved drugs are cholinesterase inhibitors and memantine
- •Gamma secretase and BACE inhibitors cause unwanted side effects
- •Early trials tested anti-amyloid drugs in mild-to-moderate disease for about 18 months and were negative
- •A drug costs roughly a billion dollars and 10–15 years to approval
- 1:35:40 – 1:47:27
Patient Selection, Prevention Trials, and Outcome Measures
Peter contrasts cardiovascular trial design with Alzheimer's endpoints and asks who the right patients to study are. Amanda argues prevention trials hold the most promise, notes that anti-amyloid drugs clear amyloid on PET but clinical outcomes matter, and mentions donanemab data.
- •Peter describes the FOURIER and ODYSSEY trials as models of hard outcomes
- •Alzheimer's cognitive endpoints seem soft to Peter
- •Anti-amyloid drugs reliably clear amyloid on PET
- •Amanda says MCI remains open but prevention is likely the best route
- •Donanemab reportedly met almost all primary and secondary endpoints
- 1:47:27 – 1:56:12
Aducanumab, the FDA Decision, and the Problem of Subjective Endpoints
Peter and Amanda review Biogen's aducanumab EMERGE and ENGAGE trials, the futility analysis reversal, dosing and ARIA risk in ApoE4 carriers, and the pending FDA decision. They discuss the subjectivity of the CDR and the need for better cognitive and biomarker outcome measures.
- •The trials initially missed endpoints but high-dose participants appeared to meet them
- •ARIA edema and microhemorrhage risk was higher in E4 carriers, explaining lower early dosing
- •The FDA decision was expected June 7th, with advisory panels split
- •Families are pushing for approval while strict-science voices urge caution
- •The CDR is subjective and can be skewed by depressed caregivers
- 1:56:12 – 2:11:30
Healthy Aging, Relationships, and Not Waiting to Live
Peter asks what Amanda has learned about healthy aging. She emphasizes attitude, focusing on what remains, and avoiding regret, and Peter offers a framework of physical, cognitive, and emotional health, with identity rooted in relationships. The episode closes with Amanda's note on exercise's benefit even in dementia.
- •Patients who focus on what they can still do age more successfully than those who compare themselves to their former selves
- •Peter proposes shifting identity toward emotional health rooted in relationships
- •Social isolation harms quality of life
- •Amanda learned from patients not to wait, buying her beach condo
- •Amanda cites data that aerobic exercise can improve cognitive scores even with dementia
