What are the newer drugs for treating Alzheimer's disease?

Newer Drugs for Treating Alzheimer's Disease

The newest FDA-approved drugs for treating Alzheimer's disease are the amyloid plaque-lowering monoclonal antibodies lecanemab (Leqembi) and donanemab (Kisunla), which received traditional FDA approval in 2023 and 2024 respectively for early-stage Alzheimer's disease. 1, 2

Current Treatment Options for Alzheimer's Disease

Established Medications

• Cholinesterase Inhibitors:

  • Donepezil (Aricept): For mild to moderate Alzheimer's disease 2
  • Rivastigmine (Exelon): For mild to moderate dementia of Alzheimer's type 3
  • Galantamine (Reminyl/Razadyne): For mild to moderate dementia of Alzheimer's type 4

• NMDA Receptor Antagonist:

  • Memantine: For moderate to severe Alzheimer's disease 2

These medications provide symptomatic relief but do not modify disease progression. They work by either inhibiting the breakdown of acetylcholine (cholinesterase inhibitors) or regulating glutamate activity (memantine).

Disease-Modifying Therapies (Newest Treatments)

1. Lecanemab (Leqembi):

   • Received traditional (full) FDA approval in July 2023 2
   • Amyloid-β directed monoclonal antibody that targets and removes amyloid plaques
   • Indicated for early Alzheimer's disease (mild cognitive impairment or mild dementia)
   • Requires biomarker confirmation of amyloid pathology before initiation 1

2. Donanemab (Kisunla):

   • Received traditional FDA approval in July 2024 2
   • Amyloid plaque-lowering monoclonal antibody
   • Indicated for early Alzheimer's disease 1

3. Aducanumab (Aduhelm):

   • Received accelerated FDA approval in June 2021 2
   • Development has been discontinued due to limited CMS reimbursement and controversial efficacy data 5, 6
   • Showed modest slowing of cognitive decline but significant concerns about amyloid-related imaging abnormalities (ARIA) 5

Key Considerations for Newer Treatments

Patient Selection

• Limited to patients with mild cognitive impairment (MCI) due to Alzheimer's disease or mild dementia 1
• Requires biomarker confirmation of amyloid pathology through:
  • Amyloid PET imaging
  • CSF biomarkers (elevated phosphorylated tau and low amyloid beta 42)
  • Validated blood biomarkers (emerging option) 2, 1

Safety Monitoring

• MRI monitoring is essential during treatment to detect ARIA 1
• Risk factors for adverse events include APOE4 genotype, autoimmune conditions, history of seizures, and extensive white matter pathology 1
• Regular cognitive and functional assessments are necessary to monitor efficacy 1

Emerging Diagnostic Tools

• Blood biomarker tests for amyloid pathology are being developed as more accessible alternatives to PET or CSF testing 2
• Recommended performance standards: sensitivity ≥90% with specificity ≥85% in primary care 2

Clinical Implications

The monoclonal antibody therapies represent a significant shift from purely symptomatic treatments to disease-modifying approaches. However, they come with important limitations:

1. They are only approved for early-stage disease, highlighting the importance of early diagnosis
2. They require specialized administration and monitoring protocols
3. They target amyloid pathology specifically, which is only one component of Alzheimer's disease pathophysiology 7, 8
4. Lecanemab appears to preferentially bind to smaller amyloid aggregates present in early Alzheimer's disease, explaining its greater efficacy in early stages 9

Access and Equity Considerations

Significant disparities exist in access to diagnosis and treatment, particularly for underrepresented populations 1. The development of more accessible diagnostic tools like blood biomarkers may help address these disparities.

These newer treatments represent an important advancement in Alzheimer's disease management, but their use requires careful patient selection, monitoring, and realistic expectations about their benefits and limitations.