Diagnosing, Preventing, & Treating Alzheimer’s Disease, & Life Lessons from Dementia Patients

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
• 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
• 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