Diagnosing, Preventing, & Treating Alzheimer’s Disease, & Life Lessons from Dementia Patients
Attia delves into Amanda Grant Smith’s insights as a geriatric psychiatrist specializing in dementia and Alzheimer’s disease. They discuss dementia diagnosis, ApoE genotype, various forms of dementia, clinical trials, and a promising amyloid beta monoclonal antibody. They also explore the concept of healthy aging and how understanding dementia can shape one’s perspective on life.
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Full Notes
Amanda’s Background and Interest in Geriatric Psychiatry
- Grew up with active grandparents who owned a nursing home
- Witnessed ageism in medical school and became passionate about geriatric care
- Focused on geriatric psychiatry, working with dementia patients
Alzheimer’s Disease and Behavioral Symptoms
- Behavioral symptoms can occur in dementia patients, such as anxiety, depression, and psychosis
- Some patients present with behavioral symptoms before cognitive decline is apparent
- Early stages of dementia can be unnerving for patients who are aware of their cognitive decline
Diagnosing Dementia and Alzheimer’s Disease
- Dementia: umbrella term for changes in memory and cognition that interfere with daily function
- Alzheimer’s is the most common cause of dementia
- Diagnosis involves a clinical interview with the patient and an observer (separately), cognitive testing, brain imaging, and lab tests to rule out reversible causes of memory loss
- Accurate diagnosis is crucial for proper treatment and management of the disease
Neuropsych Testing and Diagnosing Dementia - Formal neuropsych testing and PET scanning can help diagnose dementia
- Frontotemporal dementia (FTD) often presents with preserved memory but significant changes in language or behavior
- Can be misdiagnosed as bipolar illness due to sudden and profound behavior changes
Clinical Diagnosis in Alzheimer’s Disease
- Unlike cancer, Alzheimer’s diagnosis is not based on imaging or tissue samples
- Cerebrospinal fluid (CSF) sampling can be helpful but not always necessary
- Clinical history is crucial in diagnosing Alzheimer’s and differentiating it from other conditions
Patterns in Alzheimer’s Disease
- Loss of short-term memory is a textbook symptom of Alzheimer’s
- Preservation of long-term memory with difficulty in short-term memory
- Differentiating distraction from the path to dementia
- Frequency and intensity of memory issues can indicate dementia
MRI and Hippocampal Volume
- MRI can help evaluate dementia by:
- Ruling out or quantifying vascular disease
- Assessing shrinking in the hippocampus and other brain areas
- Hippocampal volume can be a biomarker for Alzheimer’s but is not always reliable
- Other factors, such as stress, can affect hippocampal volume
Amyloid and Alzheimer’s Disease
- Amyloid plaques are necessary for Alzheimer’s disease but not for dementia
- Amyloid PET scans can help diagnose Alzheimer’s in living patients with a high correlation to post-mortem findings
- Amyloid imaging has been helpful in making formal diagnoses and designing prevention trials
Alzheimer’s Disease and Amyloid
- Amyloid imaging has been helpful in making formal diagnoses and designing prevention trials
- Suspected diagnosis of Alzheimer’s
- PET scans and brain donations help understand amyloid buildup
- Amyloid buildup starts 10–15 years before cognitive symptoms
- Reaches a critical mass before symptoms appear
- Tau protein spreads in a specific pattern that correlates with symptoms
- Some believe tau stages where things are and whether you’ll be symptomatic or not
- Many people have mixed pathology (Alzheimer’s and other diseases)
- Vascular disease is the most common additional diagnosis
- Amyloid is a component of blood vessel walls
- Relationship between normal amyloid and pathologic amyloid still needs to be elucidated
Blood Biomarkers and Tau
- Blood-based tests for Alzheimer’s are being developed
- Plasma amyloid may be a potential biomarker
- Tau can be present without amyloid in other types of dementia
- Frontotemporal dementia, chronic traumatic encephalopathy (CTE)
- Amyloid Beta and Tau cause damage to neurons
- Exact mechanisms still being studied by neuroscientists
Activation of Glial Cells and Neuronal Damage
- Exact mechanisms still being studied by neuroscientists
- Glial cells protect the brain against intruders
- Can release toxins and cause autophagy (eating up own tissue)
- Damage occurs both inside and outside neurons
- Leads to a cascade that results in cell death
- Glial cells are more responsible for the damage
- Part of the cascade that leads to neuron death
APOE Genotype and Alzheimer’s Risk
- APOE genotyping more important than quantification
- APOE4 genotype carries higher risk for Alzheimer’s and other diseases
- APOE genotype not diagnostic
- Can have APOE4 and not have Alzheimer’s or have APOE2/APOE3 and still have Alzheimer’s
- APOE genotype more useful in research settings
Lewy Body Dementia
- Diagnosis typically made post-mortem
- Classic clinical picture can be compelling enough for accurate diagnosis
- Differentiates from Alzheimer’s with a classic triad of symptoms
- Cognitive impairment that fluctuates
- Parkinsonism component (stiffness, trouble rising from chair, decreased arm swing, etc.)
- Prominent visual hallucinations and delusions
- Additional supportive features include restless leg syndrome and REM sleep behavior disturbances
- Typically an 8–10 year process from diagnosis
Hereditary Factors in Lewy Body Dementia
- Not well-established genetic factors for Lewy Body dementia
- Alzheimer’s has known risk factors (diabetes, microvascular disease, dyslipidemia) that Lewy Body dementia does not
Incidence of Alzheimer’s vs. Lewy Body Dementia
- Lewy Body dementia diagnosed less but found more on autopsy
- In Dr. Amanda Smith’s practice:
- 50–60% Alzheimer’s
- 20% vascular dementia
- 20% Lewy Body dementia
- Remaining cases are frontotemporal dementia (FTD) and other less common conditions
Referral Paths to Dr. Amanda Smith’s Practice
- Patients referred by primary doctors, self-referred, or referred by neurologists
- Some patients may not differentiate between psychiatry and neurology
- Referrals may be for diagnosis or management of behavioral aspects of dementia
Dr. Amanda Smith’s Experience in Geriatric Psychiatry - Dr. Smith joined USF in 1997 for her residency in psychiatry and fellowship in geriatric psychiatry
- Worked with Suncoast Gerontology Center under Eric Pfeiffer, a leader in geriatric psychiatry and Alzheimer’s disease
- Took over as principal investigator for clinical trials after Pfeiffer’s retirement in 2008
Changes in Dementia Patients Over Time
- Fear of losing memory and mind remains a constant motivator for seeking help
- Increased awareness of Alzheimer’s as a disease and that it’s not a normal consequence of aging
- Shift towards seeking baseline evaluations, prevention, and early intervention
- Better understanding of available treatments and their benefits
Treating Mood and Behavioral Issues in Dementia Patients
- Majority of patients have mood or behavioral issues that require treatment
- Depression and anxiety in dementia patients are treatable
- SSRIs commonly prescribed for depression and anxiety, while benzodiazepines are generally avoided
- Treatment should be targeted, with the safest and lowest dose for the shortest period necessary
Support for Caregivers
- Dr. Smith provides support and education for caregivers, sometimes even prescribing medication for their own mental health
- Offers advice and tools for handling difficult behaviors in dementia patients
- Helps caregivers understand that their loved one’s behaviors are not intentional, but a result of the disease
Stages of Grief in Alzheimer’s Disease - Similar to Kubler Ross’s five stages of grief in cancer patients
- Grieving for someone while they’re still alive
- Applies to both patients and caregivers
- Focus on the present, not the end
Concerns about Suffering and End of Life
- In oncology patients, concern about the mechanism of death and preventing discomfort
- In Alzheimer’s patients, focus on making each day better
- Honest about potential outcomes, but emphasize support through hospice and other resources
Clinical Trials in Alzheimer’s Disease
- Alzheimer’s disease has a poor track record for drug development
- About 120 drugs in the pipeline
- 27 in Phase 1 (evaluating safety)
- 65 in Phase 2 (evaluating efficacy)
- 29 in Phase 3 (larger trials for FDA approval)
- Categories of drugs:
- 12 for cognitive enhancement
- 12 for neuropsychiatric and behavioral improvement
- 97 for disease modification
Types of Alzheimer’s Drugs
- Symptomatic treatments (e.g., colonesterase inhibitors, NMDA receptor antagonists)
- Help slow cognitive decline or improve memory and thinking
- Do not target underlying disease process
- Behavioral drugs
- Target specific behavior problems (e.g., apathy, agitation, psychosis, sleep issues, appetite)
- Disease-modifying treatments
- Target underlying pathology (e.g., monoclonal antibodies against amyloid and Tau)
Amyloid Beta Production
- Amyloid precursor protein on chromosome 21
- Down syndrome patients have higher risk of Alzheimer’s due to extra chromosome 21
- Abnormal cleavage of amyloid at lengths of 40 or 42 amino acids
- Pathologic amyloid folds and forms plaques
- Targeting enzymes that abnormally cleave amyloid is one area of study
Gamma Secretase Inhibitors and Alzheimer’s Disease - Gamma secretase inhibitors studied as potential Alzheimer’s treatment
- Responsible for cleaving amyloid precursor protein
- Side effects and downstream effects have been problematic
- Liver toxicity, cardiac arrhythmias, etc.
Alzheimer’s Drug Development and Clinical Trials
- 80% of drugs in development pipeline are disease-modifying
- 20% are symptomatic
- 6 approved drugs for Alzheimer’s, all symptomatic
- High cost of drug development
- 10–15 years and $1–1.4 billion for one drug to get FDA approval
- For every successful drug, 4000 fail
Challenges in Alzheimer’s Clinical Trials
- Patient selection and study design crucial
- Struggle to understand and measure endpoints
- Cognitive improvement difficult to quantify
- Ideal patient selection still uncertain
- Mild cognitive impairment and mild dementia may still benefit from disease-modifying therapies
- Prevention trials may be most effective for a “cure”
Anti-Amyloid Drugs and PET Scans
- Anti-amyloid drugs successfully reduce amyloid levels
- Patients can go from positive to negative amyloid PET scans
- Demonstrated in multiple trials with different compounds
Clinical Outcomes and Alzheimer’s Drug Trials
- Alzheimer’s drug trials focus on clinical outcomes and symptoms
- Removing amyloid may not improve patients’ conditions if they already have significant neurodegeneration
- Mild Cognitive Impairment (MCI) group may benefit from these drugs
- Prevention is the ideal approach for disease modification
Adecanumab and Biogen
- Adecanumab is a monoclonal antibody to amyloid developed by Biogen
- Phase Three trials: Emerge and Engage
- Futility analysis initially showed no primary endpoints met
- Further analysis showed high-dose group met endpoints
- FDA decision on approval expected on June 7
Challenges in Alzheimer’s Drug Development
- Technical challenge: developing an effective drug
- Operational challenge: studying the drug and its effects
- Subjective evaluation plays a significant role in Alzheimer’s disease
- Biomarkers predictive of clinical outcomes are needed
- Long-term studies for hard outcomes are difficult to conduct
Adecanumab and Future Trials
- If FDA does not approve Adecanumab, Biogen could conduct another Phase Three trial
- Different primary outcome measures could be used in future trials
- Operational challenges in studying Alzheimer’s drugs remain a significant hurdle
Cognitive Composite and Aging - Cognitive composite: thoughtful way of rethinking and getting good data
- Useful for drugs moving forward
- Healthy aging: how people see themselves, interact with the world, relationships, letting go of losses, focusing on the positive
- Struggle with depression when focusing too much on the future or what might happen
- Successful aging: focusing on what can still be done, making the most of each day
Three Dimensions of Health Span
- Physical
- Cognitive
- Emotional
- Physical and cognitive decline with age, emotional health does not
- Emotional health tied to quality of relationships
- Most miserable people have identity wrapped up in things that decline with age
- Importance of focusing on emotional health and relationships
Regret and Aging
- Regret can contribute to quality of life
- Don’t wait to do things you enjoy, make adjustments as needed
- Prevention is the best medicine for chronic diseases like Alzheimer’s
- Monoclonal antibodies targeting amyloid beta or tau could be a step in the right direction
Exercise and Cognitive Health
- Aerobic activity can improve cognitive testing scores even in those with cognitive impairment or dementia
- Importance of exercise for overall cognitive health
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