Alzheimer’s: disease modifying treatments

Case

John is 72 years old and presenting to the geriatric outpatient department with a two-year history of memory change. In the last six months he has forgotten to take his medications and missed paying his power bill. He is remarkably healthy excepting a history of dyslipidemia (treated with atorvastatin) and GERD (treated with hydrochlorothiazide). He has a family history of Alzheimer’s dementia affecting his brother, father and paternal grandfather.

Issue

Alzheimer’s dementia is the most common cause of dementia with significant effects on function and living independently.

Background

There will be 50 million people with Alzheimer’s dementia (AD) worldwide by 2030 with one million in Canada, and there are an equal number of people who have mild cognitive impairment (MCI).^{1, 2} This costs the Canadian health care system $10.4 billion,² and this is despite most care for AD being provided by unpaid caregivers to the amount of $7.3 billion.² Treatments that prevent onset, delay progression and improve symptoms are desperately needed.

Disease modifying treatments (DMTs) are an intervention that produces enduring change in clinical progression of AD. Cholinesterase inhibitors have been the mainstay of pharmacological management of AD for the past three decades. They offer – at best – symptomatic benefit but are associated with gastrointestinal and cardiovascular side effects leading to discontinuation in up to one-third of patients.³ 

Emerging medications that centre around decreasing amyloid in the brain are:

• Lecanemab (produced by Eisai in Tokyo and Biogen in Cambridge) is approved by the United States Food and Drug Administration (US FDA) but is pending approval by Health Canada (HC).
• Aducanumab (also produced by Eisai and Biogen) is approved by the US FDA but has been rejected by the European Union and Canada as not showing major improvements.⁴
• Donanemab (produced by Eli Lilly) is approved the US FDA but is again pending approval by Health Canada (HC). It is available in Canada but not available outside of experimental drug trials. ⁴

Many more treatments are being trialed. They decelerate the decline but do not stop the progression of AD completely or improve its symptoms.

Evidence for Lecanemab

Lecanemab is the first to be considered for approval in Canada based on the Clarity trial. The Clarity trial was a phase three, placebo-controlled, double-blind, parallel-group, 18-month study evaluating lecanemab in mild Alzheimer's disease and MCI due to AD. They looked at 1,795 patients with amyloid pathology (confirmed by amyloid positron emission tomography [PET] or cerebrospinal fluid [CSF]), and a mini–mental state examination (MMSE) score between 22 and 30 at screening and baseline.⁵ They found a -0.451 decrease on the primary endpoint of the Clinical Dementia Rating - sum of boxes (CDR SB) which represented decreasing clinical decline by 27%. They also improved the secondary endpoints, decreased amyloid burden and found similar cognitive and functional loss to CDR SB on other scales.⁵  

These DMTs show promise that needs to be looked at over a longer timeframe and balanced with safety. The main safety issues are infusion reactions and the development of amyloid related imaging abnormalities edema and hemorrhages (ARIA-E/H).⁵ 

Infusion reactions present with fever, chills, headache, rash, nausea, vomiting, abdominal discomfort and elevated blood pressure. Infusion reactions usually occurred during the first two treatments and were seen during the infusion or up to several hours after it. Infusion reaction symptoms typically resolve within 24 hours and can usually be managed at home.⁶ 

ARIA-E most occurred within the first three months of treatment (71%) and resolved within four months of detection (81%).⁵ Symptoms of ARIA include headache, confusion, visual changes, dizziness, nausea and gait difficulty. More serious ARIA symptoms include seizures, status epilepticus, encephalopathy, stupor and focal neurological deficits. Isolated ARIA-H events (microhemorrhages, superficial siderosis and intracerebral hemorrhages) in both the placebo and lecanemab groups were infrequent and distributed at a steady rate over 18 months of treatment. Excess ARIA-H appears to be due to concurrent ARIA-E + ARIA-H. ApoE4 carriers had higher incidence of ARIA-H.⁵ 

As these treatments are new, appropriate use recommendations (AUR) have been developed.⁶ To qualify for lecanemab the following are required: 

• Biomarker confirmation – CSF (elevated phosphorylated tau and low Aβ42 level) or amyloid increased on PET. 
  • A definite barrier. The introduction of sensitive blood biomarkers might mitigate some of these challenges. Tests that evaluate markers like amyloid beta ratios and p-Tau levels have, in some instances, indicated a higher precision in predicting Alzheimer’s onset compared to PET scans. 
• Baseline MRI (specific criteria excluding micro hemorrhages) – radiologists trained to detect ARIA. 
• ApoE4 typing given at increased risk of ARIA to guide risk-benefit discussions. 
• MMSE score of 22-30 
• Diagnosis of mild AD or MCI due to AD.⁶

The other factor that must be considered is cost. This includes diagnosis, initial work up, drug, IV infusion centre and staff, and monitoring. There needs to be baseline MRI and regular scanning after the fifth, seventh and 14th infusion, and week 52 (pre 26th infusion). After 12 months of treatment, obtaining MRIs should be guided by patient symptoms and prior MRI findings. Those unable to undergo MRI should be excluded. CT is inadequate.⁶ 

If ARIA is found on MRI and the patient is symptomatic, hold their treatment, scan with MRI monthly. Resume treatment when ARIA-E resolves/ARIA-H stabilizes, symptoms resolve and if the patient wishes. If the patient is asymptomatic with mild ARIA-E or ARIA-H, continue their treatment with monthly MRI until ARIA-E resolves/ARIA-H stabilizes. If ARIA-E or ARIA-H is moderate or severe, follow the same protocol as if the patient is symptomatic.⁶ 

When should lecanemab be discontinued?  

• If there is any macrohemorrhage. 
• >1 area affected by superficial siderosis. 
  • 10 microhemorrhages since starting treatment. 
  • Two episodes of ARIA. 
• Severe symptoms of ARIA. 
• Patient requires treatment with anticoagulant. 
• Grade 3 or higher infusion reactions. 
• Declining on cognitive test as would expect or beyond.

It can be seen that to manage AD patients taking lecanemab, there must be skilled clinicians to make the AD diagnosis and collect CSF; MRI availability and radiologists trained to look for ARIA; ApoE4 genotyping capability and data; and clinicians trained to deal with cerebral edema, ARIA and seizures.⁶ 

In addition to the exclusions above in the Clarity trial, the AUR added cerebral amyloid angiopathy (CAA) as it increases the risk of ARIA and should be excluded too. Patients with Down syndrome have an increased risk of CAA so should be excluded from treatment with lecanemab. Anticoagulation (warfarin, vitamin K antagonists, DOACs and heparin) increases the risk of hemorrhage. The AUR recommends that patients requiring anticoagulants not receive lecanemab until more data are available.⁶  

Detailed conversations need to be held with patients and caregivers to cover all of this information. Review the benefits versus the harms; administer a twice monthly infusion of the lecanemab, order baseline MRI and repeat four more times in first year (order additional MRI if the patient develops ARIA); confirm the presence of amyloid via PET or CSF; perform the ApoE4 genotyping test; and, importantly, explain that these interventions can slow the progression of AD, but patients and their families must have realistic expectations that it will not stop or improve it.⁶ 

Clinical relevance 

A one- to two-point increase/decrease in CDR SB equates to minimally clinically important difference (MCID). Expect the MCID to drop by one point per year in patients with AD. On lecanemab, you can expect less of a drop (trial found 0.45). 

The third factor is cost which will be significant. The cost of lecanemab was set by the sponsor at $26,500 USD per year. This was on the basis of a cost-effectiveness analysis concluding that lecanemab would deliver a fair societal value at this price. It is unknown how much it will cost in Canada. Even if approved by HC, provincial Alberta Blue Cross special authorization if successful would be at least one year. Some patients may have private coverage.^7,8 

DMTs will be part of a broad-based approach to treatment that will still include addressing vascular risk factors, diet and exercise, AChEI and memantine. We will need to balance access to DMTs for early Alzheimer's versus continued support for more advanced AD and other dementias. 

Recommendations 

After a long discussion and given John's preference and that he has private coverage and a strong family history of AD, he proceeded with lecamemab treatment.

References 

1. Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer's disease drug development pipeline: 2023. Alzheimer’s Dement. 2023; 9:e12385. doi.org/10.1002/trc2.12385 
2. Dementia numbers in Canada, Alzheimer Society alzheimer.ca/en/about-dementia/what-dementia/dementia-numbers-canada 
3. Dyer A, Dolphin H, Shenkin S et al. Emerging disease modifying therapies for older adults with Alzheimer disease: perspectives from the EuGMS special interest group in dementia. European Geriatric Medicine (2023) 14:919–923 doi.org/10.1007/s41999-023-00846-2 
4. Thomas G, Smith E, Ismail Z et al. Potential Eligibility for Disease Modifying Therapies Among Individuals Referred to A Tertiary Care Memory Clinic in Calgary, Alberta, Canada: Implications for AD Biomarker Testing. Alzeimers and Dementia 20(S7) 2025.  doi.org/10.1002/alz.091118 
5. Van Dyck CH, et al. Lecanemab in Early Alzheimer’s Disease New Engl J Med. 2022. nejm.org/doi/full/10.1056/NEJMoa2212948
6. Cummings, J., Apostolova, L., Rabinovici, G.D. et al. Lecanemab: Appropriate Use Recommendations. J Prev Alzheimers Dis 10, 362–377 (2023). doi.org/10.14283/jpad.2023.30 
7. Burke J, Kerber K, Langa K et al. Lecanemab – Looking before we leap. Neurology 2023;101:661-665. doi:10.1212/WNL.0000000000207505 
8. Knopman D, Hershey L. Implications of the Approval of Lecanemab for Alzheimer Disease Patient Care Incremental Step or Paradigm Shift? Neurology 2023;101:610-620. doi:10.1212/WNL.0000000000207438