Everything You Need to Know About Amyloid Presence and Alzheimer’s Disease-modifying Therapies

Confirming amyloid pathology before administering Alzheimer’s disease-modifying therapies.

Approximately seven million Americans are currently living with Alzheimer’s disease (AD).¹  Clinicians must confirm amyloid pathology and rule out other potential causes of cognitive impairment before determining the best course of treatment. Once Alzheimer’s disease is established, clinicians have a new generation of treatments to consider: An estimated 2.2 million of those diagnosed with AD may be eligible for one of two newly approved disease-modifying therapies (DMTs). This new class of anti-amyloid drugs is designed to reduce AD-related amyloid pathology in the disease’s earliest symptomatic stages.²   

Some patients may be at a higher risk of adverse side effects depending on factors such as genetic status.^2,3 Here’s what you need to know about confirming Alzheimer's disease pathology and prescribing these new DMTs.  

3 ways to confirm Alzheimer’s amyloid pathology 

After a clinical evaluation that rules out other causes of cognitive decline — e.g., vitamin B12 deficiency, thyroid dysfunction, medications, long COVID, depression, or other neurodegenerative diseases⁴ — one or more of the following tests is typically used to confirm AD pathology: 

PET imaging 

• PET brain imaging utilizes a radioactive tracer that binds to beta-amyloid (β-Amyloid) plaques or tau neurofibrillary tangles in the brain. 
• There are three FDA-approved fluorine-18 radiotracers available: ¹⁸F-florbetapir, ¹⁸F-flutemetamol, ¹⁸F-florbetaben. Each is visually interpreted, with slight differences in color scale and positivity criteria depending on the agent used.⁵  
• A tau PET tracer, 18F-flortaucipir, was approved by the FDA in 2020. ⁶ While not used to confirm Alzheimer’s pathology for diagnostic purposes, tau PET may support disease staging and prognosis, as outlined in the 2024 revised diagnostic criteria.⁷ Additionally, its use to determine treatment eligibility is not addressed in the FDA prescribing information for current DMTs. ⁵ 
• Medicare covers amyloid and tau PET scans. ⁵

Cerebrospinal fluid testing  

• Measures key biomarker ratios in CSF, including: pTau 181/β-Amyloid 1-42, β-Amyloid 1-42/40, and tTau/Aβ42⁸   
• May be covered by Medicare in certain clinical contexts ⁹ 

Blood-based biomarker testing 

• Several blood tests are available in the U.S. as laboratory-developed tests (LDTs). 
• On May 16, 2025, the FDA cleared the first plasma-based in vitro diagnostic (IVD) test, the Lumipulse^® G pTau 217/ β-Amyloid 1-42 Plasma Ratio.¹¹
  • Test results are reported as a quantitative value, which is compared to pre-defined cutoffs to determine a positive, negative, or indeterminate result.
  • Medicare reimbursement via specific billing codes for many of these tests is being developed and should be available by January 2026.

Some blood-based Alzheimer’s biomarker tests are intended for triage use: meaning they are designed to only rule out Alzheimer’s disease. A negative result suggests the individual is unlikely to have amyloid pathology. However, a positive or inconclusive result requires follow-up testing with either CSF analysis or amyloid PET imaging.  

In this case, the Blood Biomarker Workgroup for the Global CEO Initiative on Alzheimer’s Disease recommends using a test with a sensitivity of≥90%, and a specificity of≥85% in primary care settings or 75–85% in specialist settings.¹⁰ 

Other blood-based tests are intended as confirmatory use, offering sufficient precision and accuracy to confirm amyloid pathology without additional testing. For this purpose, guidelines recommend that these tests have a sensitivity and specificity of approximately ≥ 90%.¹⁰  

Fujirebio’s blood-based biomarker test

In May, the FDA approved Fujirebio’s Lumipulse^® G pTau 217/β-Amyloid 1-42 Plasma Ratio blood test for use in adults aged 50 and older presenting in a specialist setting with cognitive complaints.¹¹ 

The test measures the levels of pTau-217, a phosphorylated form of the tau protein that increases in the presence of amyloid pathology associated with Alzheimer’s disease, and β-Amyloid 1-42, which is a proteolytic fragment of the amyloid precursor protein (APP) and a major component of amyloid plaques. A decrease in soluble Aβ42 levels reflects its aggregation in plaques, indicating underlying amyloid pathology. An elevated pTau 217/ β-Amyloid 1-42 plasma ratio is associated with the presence of amyloid plaques in the brain, and correlates strongly with amyloid pathology in the brain. 

In conjunction with other patient clinical information, the test has proven accurate enough to confirm amyloid pathology.¹¹ 

Leqembi vs. Kisunla   

• There are currently two FDA-approved DMTs, Eisai and Biogen’s Leqembi (lecanemab) and Eli Lilly’s Kisunla (donanemab). They are the only two FDA-approved monoclonal antibodies currently available to target and clear beta amyloid plaques in order to help slow the progression of Alzheimer’s cognitive and functional decline.^12,13
• Currently, both DMTs require intravenous infusion, although subcutaneous delivery systems are under review by the FDA for Leqembi.^12,13,14 

Mechanism of action 

• Leqembi primarily targets soluble beta-amyloid protofibrils and also binds to insoluble fibrils associated with plaques.¹⁵ Its epitope was first characterized in a Northern Swedish family with the Arctic mutation, a genetic variant linked to early-onset Alzheimer’s.¹⁶ 
• Kisunla binds to N-terminal pyroglutamate-modified β-Amyloid fibrils (pGlu3-Aβ), which are prone to aggregation.^17,18 

Although they bind to different conformations of β-Amyloid, both therapies promote microglia-mediated plaque clearance. ¹⁷ The resulting reduction in amyloid burden can be monitored via amyloid PET imaging.  

Effectiveness and limitations 

In Phase 3 trials, both drugs showed modest benefits in slowing cognitive decline, with stronger effects observed in patients treated during the mild cognitive impairment (MCI) stage: 

• Leqembi showed a 0.45-point reduction in the decline of the Clinical Dementia Rating – Sum of Boxes (CDR-SB) compared to placebo over 18 months¹²  
• Kisunla showed a 0.7-point reduction in CDR-SB over 76 weeks compared to placebo¹³ 

However, these effects fall below the minimal clinically important difference (MCID) established in prior studies.^19,20 Further, subgroup analyses suggest Leqembi had reduced efficacy in women and ApoE4 homozygotes.^21,22 

Regulatory notes: Leqembi received conditional approval in Europe for non-homozygote patients only. The European Medicines Agency has not recommended approval of Kisunla. ^23,24 

Adverse events: Risk of ARIA 

Both therapies are associated with amyloid-related imaging abnormalities (ARIA), which may include edema (ARIA-E) or microhemorrhage (ARIA-H). Most ARIA events are asymptomatic. About 0.7–6% of ARIA cases present with symptoms^.12,13 

• Leqembi: ARIA-E occurred in 12.6% of patients, and ARIA-H in 17.3%.¹²  
• Kisunla: ARIA-E occurred in 24% of patients, and ARIA-H in 31%.¹³  
• ApoE4 homozygotes had a higher incidence of ARIA, with risk approximately twofold greater than in non-carriers.^12,13 

Anticoagulant use can also increase a person’s risk of ARIA.²⁵ These therapies carry an increased risk in patients with certain MRI findings. In particular, pretreatment microhemorrhages and superficial siderosis have been associated with an increased risk of ARIA in clinical trials of Leqembi and Kisunla.^25,26,27

Severe complications were rare in both trials but included cases of intracerebral hemorrhage and fatal outcomes.

For a comprehensive list of ARIA risk factors and eligibility restrictions, refer to the FDA-approved prescribing information for each drug.^28,29

Administration and monitoring 

• Leqembi: administered at 10mg/kg via intravenous infusion every two weeks, over approximately 30–60 minutes.²⁸ While the pivotal trial followed patients for 18 months, the FDA label does not specify a treatment duration.^12,28 A subcutaneous maintenance formulation is currently under FDA review.¹⁴ 
• Kisunla: initiated with 700mg IV every four weeks for the first three doses, followed by 1400mg every four weeks.²⁹ Each dose is infused over approximately 30 minutes.²⁹ Treatment is discontinued once the amyloid plaque burden falls below a prespecified threshold, as determined by amyloid PET imaging.²⁹ Lilly is also studying reduced Kisunla dosing to lower ARIA risk while maintaining efficacy.³⁰  

MRI monitoring guidelines:  

• Leqembi: MRI scans are recommended after the 5th, 7th, and 14th infusion; For ApoE4 carriers, an additional MRI is advised prior to the 26th infusion.^26,28 
• Kisunla: MRI scans should be performed before the 2nd, 3rd, 4th, and 7^th infusions. High-risk patients require additional scans before infusion number 12th.^27,29 

Cost and coverage 

• Leqembi: List price is $26,500 per year for a patient weighing approximately 165 pounds (75kg), based on a biweekly 10mg/kg IV infusion regimen.³¹ 
• Kisunla: List price is approximately $32,000 per year; total cost depends on treatment duration.³² 

Currently, Medicare covers both therapies, although coverage criteria apply. Private insurer coverage varies and may depend on documentation of diagnostic confirmation.³³

A recap: Prescribing DMTs for Alzheimer’s  

Recent advances in biomarker testing will streamline the evaluation process for DMTs, enabling clinicians to confirm amyloid pathology more efficiently and identify appropriate candidates.³⁴ Currently, amyloid PET imaging and CSF testing remain the primary tools used to confirm amyloid pathology and meet the diagnostic eligibility criteria for Leqembi or Kisunla. However, with the emergence of validated blood-based biomarkers, plasma testing is expected to become a standard component of the clinical workup in the near future.