Anti-Amyloid Monoclonal Antibodies for Alzheimer's

Identifying Candidates for Anti-Amyloid Treatments

  • Identify patients with mild cognitive impairment and early-stage Alzheimer's disease.
  • Consider amyloid quantification methods:
    • Serum tests
    • CSF analysis
    • Amyloid PET scans
    • Genetic testing for APOE alleles
  • Discuss risks with patients, especially ARIA (amyloid-related imaging abnormalities).

Differentiating Alzheimer's and Dementia

  • Dementia is an umbrella term for progressive neurologic decline.
  • Includes Alzheimer's, vascular dementia, frontotemporal dementia, Lewy body dementia, etc.
  • Alzheimer's is the most common type of dementia.
  • Conditions mimicking dementia: depression.

Screening for Cognitive Impairment

  • Medicare annual wellness visits require cognitive screening.
  • USPSTF does not currently recommend routine screening.
  • Screening may be beneficial due to new treatment options.

Alzheimer's Disease Statistics

  • Most common cause of dementia.
  • Sixth leading cause of death in the U.S.
  • Affects approximately six million Americans.
  • Prevalence increases with age: 10% over 65, 40% over 85.
  • Increasing cause of death compared to other diseases with effective treatments.

Historical Context of Alzheimer's

  • Alois Alzheimer studied Auguste Deter, who died in 1906.
  • Identified plaques and tangles (amyloid and tau) in her brain.
  • Plaques and tangles are primary targets of research.
  • Long presymptomatic phase; current research focusing on early identification.

Pathophysiology of Alzheimer's

  • Neurotoxicity leads to diffuse neuronal cell death.
  • Complex neuropathology with multiple mechanisms.
  • Genetics play a role but aren't the entire picture.
  • Amyloid's role is significant but not complete.
  • Effective amyloid removal doesn't fully arrest cognitive decline, suggesting additional factors.
  • Tau protein levels correlate with amyloid.

Future Drug Targets

  • Oxidative stress
  • Blood vessel architecture
  • Neuroinflammation
  • Mitochondrial dysfunction
  • Neurogenesis
  • Addressing the blood-brain barrier to improve drug delivery; targeted ultrasound.

Modifiable Risk Factors

  • Approximately 40% of dementia cases are linked to modifiable risk factors (according to The Lancet).
  • Early life: lack of education.
  • Midlife: hearing loss, hypertension, excessive alcohol use, obesity
  • Later life: smoking, depression, social isolation, physical inactivity, air pollution, diabetes.

Genetic Factors

  • ApoE alleles: numbered 2, 3, or 4.
  • APOE2: protective.
  • APOE4: increased risk.
  • 25% of people have one copy of APOE4, 2-3% have two copies.
  • One copy: 3x increased risk.
  • Two copies: 10-30x increased risk by age 75.
  • APOE4 increases ARIA risk with monoclonal antibody treatments.
  • APOE4 is not deterministic, it only means there is increased risk.
  • Rare familial genetic patterns (autosomal dominant) account for <1% of cases.
  • Down syndrome (trisomy 21) patients have a higher risk due to the amyloid precursor protein gene on chromosome 21.

Lab Testing

  • Recommended for patients with cognitive decline, not for presymptomatic identification (though this may change).
  • Serum testing:
    • Amyloid beta 42/40 ratio: a low ratio indicates high amyloid.
    • PTau217: rising serum biomarker.
  • Serum biomarkers correlate with CSF and amyloid PET scans.
  • Labs aren't FDA approved and may not be covered by insurance.

Amyloid PET Scans

  • Radio-labeled amyloid isotope.
  • Unstable and requires quick administration.
  • Limited availability in specialized imaging centers.
  • Coverage varies; requires justification and pre-approval.

Terminology Shift

  • Alzheimer's Association proposes identifying patients with biomarkers as "persons with Alzheimer's disease" and those with cognitive impairment as "Alzheimer's dementia”.
  • Concerns about insurance, stigma, and emotional impact.
  • Accuracy of clinical diagnosis is 30-50% compared to autopsy.
  • Amyloid PET scans can show positive results in asymptomatic individuals.

Cognitive Rating Scales

  • Montreal Cognitive Assessment (MoCA):
    • Takes 10-15 minutes.
    • More sensitive than MMSE.
    • Not copyrighted.
    • Requires training for proper administration.
  • Clinical Dementia Rating (CDR) scale:
    • Used in monoclonal antibody studies.
    • Studies included patients with CDR scores of 0 to 0.5 (no or questionable cognitive impairment).

Alzheimer's Treatments

  • Cholinesterase inhibitors (since mid-90s).
  • Memantine.
  • Anti-amyloid monoclonal antibodies (new).
  • Off-label medications for symptom management such as antidepressants, mood stabilizers, anxiolytics and antipsychotics.

Cholinesterase Inhibitors

  • Relatively safe and well-tolerated with GI side effects.
  • Mild slowing of cognitive impairment.
  • Example: Donepezil: patients tested about three points better than those on placebo.
  • Adverse effects include bradycardia, falls, fractures, syncope, pacemaker insertion.
  • Weight loss is also a consideration.
  • Effectiveness decreases over time.

Memantine

  • Similar effectiveness to donepezil.
  • Available as a combination pill for convenience.
  • Fairly well-tolerated but minimally effective.

Anti-Amyloid Monoclonal Antibodies

  • Aducanumab (ADUHELM):
    • Approved in 2021, controversial due to limited evidence of effectiveness.
    • FDA’s neurology subgroup voted against approval.
    • Trials stopped early; re-analyzed data showed slight benefit in early-stage patients at high doses.
    • Accelerated approval pathway required ongoing studies.
    • Biogen pulled it from the market; no longer available.
    • Provided early data on ARIA (amyloid-related imaging abnormalities), including edema and microhemorrhages.
    • 40% of patients experienced ARIA; higher risk with APOE4 alleles.
  • Studies showed limited eligibility based on trial criteria: 8% of Medicare patients, <1% in an Italian geriatric clinic.

ARIA (Amyloid Related Imaging Abnormalities)

  • APOE4 carriers have a higher risk.
  • Edema: 24% on treatment
    • 0 APOE4 alleles: 15%
    • 1 APOE4 allele: 23%
    • 2 APOE4 alleles: >40%
  • Microhemorrhages are potentially more dangerous.
  • More common early in treatment; requires scheduled MRIs.
  • 70% are asymptomatic, detected by surveillance MRIs.
  • Symptoms: headache, confusion, visual changes, dizziness, nausea, gait impairment.
  • Severe symptoms: seizures, focal neurologic deficits, hemorrhages (fatal in some cases).

Lecanemab (Leqembi)

  • Full FDA approval.
  • Targets soluble amyloid protofibrils.
  • Minimum MMSE score of 22.
  • IV infusion every two weeks for 18 months.
  • Approximately $26,000 cost for drugs alone (not including MRIs, testing, monitoring).
  • 27% reduction in cognitive decline (5-month delay over 18 months).
  • ARIA occurred in 26% of patients
  • Brain MRIs of patients receiving placebo showed is about seven point four percent had some edema or microhemorrhages.
  • Some deaths related to intracranial hemorrhage (often in patients on anticoagulation).
  • Exclusion criteria: patients needing DOAC or strong anticoagulation.

Lecanemab Study Visual

  • The blue line (placebo) and the yellow line (lucanumab) indicating cognitive decline from baseline. These are for 18 months.
  • Unclear if lines will continue to diverge long-term.

Lecanemab Required Monitoring

  • Baseline MRI (exclude significant underlying conditions).
  • MRI prior to 5th, 7th, and 14th infusions.
  • Clinical monitoring for ARIA during the first 14 weeks.
  • Additional MRI if clinical symptoms occur.
  • If edema or microhemorrhage is present, holding off on the next treatment until clinically improves.

Donanemab (Kisunla)

  • FDA approved.
  • Monthly IV treatment.
  • Targets soluble amyloid, more mature plaques.
  • MMSE of 20-28.
  • All patients were amyloid PET and tau PET positive.
  • Treatment to amyloid negative; IV infusions of saline after clearance.
  • 52% of participants finished treatment in <12 months.
  • Clinically treating to amyloid negative.

Donanemab Benefits

  • Patients in earliest stages of disease had greater benefit (60% slowing of decline).
  • Rates of ARIA similar to other monoclonal antibody drugs; higher in APOE4 carriers.
  • Three deaths on drug (1.9% in the Donanemab group versus 1.1% in the placebo group).
  • Patients with low to medium tau showed higher benefit and the earlier stages of the disease.

Anti-Amyloid Antibodies Available

  • Adjelm: Off the market.
  • Leukembi and Kasunla: currently available.
  • Solanezumab: Not being pursued for FDA approval.
  • Ganterenumab: Promising for subcutaneous dosing.

CMS (Centers for Medicare & Medicaid Services) Coverage

  • Requirements for coverage:
    • Logging patients into a database.
    • Tracking diagnosis and amyloid quantification (PET scan, CSF, or blood tests).
    • Reporting clinical outcomes every six months.
  • Appropriate use criteria aligned with clinical trial inclusion/exclusion criteria such as only for patients aged 50 to 90, in MSE 22 to 30, BMI 17 to 35, patients with two or less lacunar infarcts and no major strokes..

Implementing Prescribing in Primary Care

  • Difficult and impractical due to infrastructure requirements.

Summary

  • Drugs are expensive.
  • Challenging to select appropriate patients and perform testing.
  • IV infusions are required every two to four weeks.
  • About a 30% reduction in cognitive decline.
  • Monoclonal antibodies are breakthroughs and resource drains. They are not as effective as hoped, very expensive, and difficult to manage.

Analogy

  • Treatment is similar to chemo for cancer patients: modest survival improvement, modest benefit, significant toxicity.

Real-World Experience

  • Patient on lecanemab experienced significant ARIA and was placed in assisted living memory care.
  • The clear future is to treat to the amyloid clearance and better diagnose patients based on genetic test.

Non-Drug Interventions

  • Effective such as mental activity, socialization, physical activity.
  • It can be done like lifestyle interventions make a difference such as intensive lifestyle interventions; Vegan diet, meditation and we should be recommending that for everybody and practicing it ourselves.
  • Patient and care partner support is crucial.

Additional Resources

  • Alzheimer's Association (helpline, website).
  • NIH, CDC, Alzheimer's Foundation of America.
  • AFP Cognitive Care Kit.

Serum Amyloid Information

  • APOE4 testing available through direct-to-consumer services (e.g., 23andMe).
  • Serum markers for amyloid inform treatment options for those pursuing newer medications.

Lifestyle Changes

  • Benefits of drugs vs. Lifestyle changes: there is no good data on how effective lifestyle changes are.

Alternative Treatments

  • Patients often ask about Prevagen or Niriva with data not being impressive.

Treatment Cost Estimate

  • Estimating treatment costs is difficult given insurance variables.
  • Drugs average $26,000-$28,000 for one year.
  • Most of these drugs are coming out for the drug alone around 26,00026,000 to 28,00028,000 for one year

Serial PET Scan Need

  • Studies have done serial PETs.
  • Hoping serum biomarkers are reliable, Repeat pets is done in the studies.