#511 Alzheimer’s Disease: Updates in Diagnosis and Treatment

January 12, 2026 | By Leah Witt

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Video

Transcript available via YouTube

Blood-based Biomarkers, Anti-Amyloid Therapies and Beyond

From blood-based biomarkers to anti-amyloid treatments, join us as we explore the latest in Alzheimer’s disease diagnosis and treatment with Dr. Halima Amjad. This episode will equip you to guide your patients about the latest Alzheimer’s diagnostics as well as eligibility, risks and monitoring for anti-amyloid therapies.

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Show Segments

Intro

Case

Cognitive and functional history reminders

Diagnosing Alzheimer’s Disease

Blood-based biomarkers

Anti-amyloid therapy indications, eligibility and contraindications

Patient counseling and treatment decisions

ARIA

Key takeaways

Outro

Disclosures

Dr. Amjad reports financial relationships with Centene (Advisor) and Craniometrix (Advisor). Relationships have not ended. The Curbsiders report no relevant financial disclosures. 

The production of this episode was supported by the Penn Geriatrics AGE-SMART Geriatric Workforce Enhancement Grant. This podcast content is solely the responsibility of the authors and does not necessarily represent the official views of the Health Resources and Services Administration or the U.S. Department of Health and Human Services. 

Alzheimer’s Disease: Updates in Diagnosis and Treatment Pearls

1. In order to make a diagnosis of dementia, new functional impairment must be present.
2. Alzheimer’s disease (AD) (a subtype of dementia) is characterized by impaired short term memory on cognitive testing. 
3. Blood-based biomarkers are a screening test for AD and only indicated for patients with objective evidence of cognitive impairment.  
4. Chronic kidney disease (CKD) can affect blood-based biomarker levels so amyloid PET scan is preferred.
5. If you order blood-based biomarkers blood-based biomarkers, know what you are going to do with the results! It is OK to defer these tests to an Alzheimer’s Disease specialist.  
6. Primary care doctors should be familiar with anti-amyloid therapy eligibility criteria to better screen for patients who would benefit from biomarker testing and/or treatment. 
7. Anti-amyloid therapies provide a modest clinical benefit for patients with mild cognitive impairment (MCI) or mild dementia by slowing cognitive and functional decline by 25-35% over 1.5 years. 
8. Amyloid-related imaging abnormalities (ARIA) are the primary risks of anti-amyloid therapy, and patients should be counseled about these before starting. 
9. While most patients are asymptomatic from ARIA, when clinically significant its impacts can be devastating (e.g. intracranial hemorrhage or edema). Have a low threshold to obtain brain MRI for new neurologic symptoms. 

Diagnosing Dementia

A quick review dementia diagnostic criteria (for more, see previous Curbsiders episodes for a refresher: #268 Dementia Made Simple with Dr. Josh Uy and #478 Dementia 2.0 with Dr. Anna Chodos).

• Normal cognitive aging involves subjective mild memory and attention deficits that are a nuisance to the affected person but do not impact others around them or their ability to function independently. 
• The diagnosis of dementia (also called major neurocognitive disorder) requires cognitive symptoms to interfere with one’s ability to function independently (Arvanitakis 2019, American Psychiatric Association 2013).
• The diagnosis of mild cognitive impairment (or mild neurocognitive disorder) falls in the middle of this spectrum with evidence of cognitive impairment on testing but preserved functional independence (Petersen 2011, Langa 2014).

*Remember: FUNCTIONAL IMPAIRMENT is what differentiates mild cognitive impairment vs. early-stage dementia 

Diagnosing Alzheimer’s Disease 

Remember that Alzheimer’s Disease (AD) is one of many possible causes of dementia (others include vascular disease and frontotemporal dementia)..

By History: people with Alzheimer’s Disease classically present with impaired short-term memory. They may frequently repeat themselves (e.g. by telling the same story over again), misplace items, and forget conversations (e.g. repeat the same questions). Collateral information from partners and friends can be helpful.

Cognitive Testing: Cognitive testing (e.g. a MOCA < 26 or MMSE < 24 depending on education level) is the first step. The Alzheimer’s Disease pattern of cognitive testing typically follows an “amnestic profile”, which means it displays significant difficulty with delayed recall and learning. 

On Imaging: Hallmark AD imaging findings  include bilateral atrophy of the hippocampal and mesial (or medial) temporal lobes. It is important to establish a lack of vascular disease burden as vascular dementia can mimic AD, or the two causes can co-occur (which impacts treatment options, see the anti-amyloid therapy section below for more info!).. 

What you need to know about Blood-Based Biomarkers (BBM) 

Phosphorylated tau 217 (pTau217) | High serum levels correlate to pTau and AB in the brain. This test is the most sensitive and specific for AD (approx 88%). (Therriault 2025, Hansson 2023).

Amyloid-Beta 42:40 ratio (AB42:40) | Low serum levels correlate to plaques in the brain. 

Neurofilament light chain (NfL) | Non-specific marker of neurodegeneration. Seen in advanced AD but can be seen in frontotemporal Dementia 

LumiPulse | FDA-approved blood test for diagnosis of AD which includes pTau217 / AB42 ratio 

Remember: Chronic kidney disease (CKD) can affect plasma levels of the blood-based biomarkers, making the result unreliable. 

Where are these tests being ordered? 

Initial FDA and Alzheimer’s association clinical practice guidelines recommend receiving testing in a specialty care setting.  More recent FDA approvals for blood-based biomarkers indicate that primary care is an appropriate setting for ruling out Alzheimer’s Disease with blood-based biomarkers.

Dr. Amjad reminds us that it is important to remember these tests are still new. It is exciting to have these tests available, but we are all still learning. If you are going to order these biomarkers, know what you are going to do with the results. It is OK to defer testing to an AD specialist! 

Who should we order blood-based biomarkers for? 

Patients with subjective and objective evidence of cognitive deficits and patients for whom you want to rule in or rule out Alzheimer’s disease.

Remember: This is a screening test for risk stratification, not diagnosis or treatment. Patients must be counseled carefully about the purpose of testing.

When should I order these tests? 

If considering your patient for anti-amyloid treatment:

1. Stage their disease.  Patients must have mild cognitive impairment or mild dementia to be considered for treatment. Treatment for moderate or severe dementia is not appropriate.
2. Establish amyloid presence in the brain.  Remember, blood-based biomarkers are screening tests. Patients must undergo Amyloid PET or CSF testing to confirm amyloid presence in the brain. 
3. Rule out severe microvascular disease. Obtain a brain MRI to exclude vascular disease as the cause of cognitive impairment. Significant brain pathology/vascular disease will exclude patients from anti-amyloid treatment as patients with >4 microhemorrhages, cerebral amyloid angiopathy (CAA), a history of large ischemic stroke, multiple lacunar infarcts, or severe small vessel disease were excluded from the initial studies.  
4. Perform APOE genotype testing. APOE4 homozygotes are at increased risk for amyloid-related imaging abnormalities (ARIA).
5. Assess other medical comorbidities and relative contraindications.  Consider your patient’s life expectancy and other medical comorbidities which impact their health and ability to undergo frequent MRI monitoring.  Other relative contraindications include primary diagnosis of vascular, Lewy body or frontotemporal dementia; anticoagulation use; hx TIA/CVA or seizure within the last year; other immunosuppressant or monoclonal antibody use.  

Let’s talk about APOE 

Apolipoprotein E gene-allele 4 (APOE4) is one of the strongest known genetic risk factors for Alzheimer’s disease.  There are three variants (APOE2/APOE3/APOE4) and every human has two copies of the gene (one inherited from each parent). Each copy of the APOE4 allele increases one’s relative risk of developing Alzheimer’s disease. Due to the increased risk of disease development, these patients are often a large target population for treatment studies (Belloy 2023). 

APOE genetic testing is recommended prior to anti-amyloid treatment due to the increased risk of ARIA associated with APOE4 homozygotes.  

Remember: APOE4 allele is a genetic risk factor for Alzheimer’s disease – inheritance of the gene does NOT indicate the disease will present.

Anti-amyloid Therapies and Monitoring 

Lecanemab 

CLARITY-AD showed slowing of cognitive and functional decline on the Clinical Dementia Rating (CDR) scale. There was an approximately 25% reduction in clinical decline, equating to 4-5 months of delay in disease-related progression over 18 months. 

• Maintenance dosing: IV infusions every 2 weeks or subcutaneous injections every 4 weeks for 18 months.
• MRI at start of treatment and prior to 5^th, 7^th, and 14^th infusions 
• Most common side effects:  Infusion reactions (27%) and ARIA (22%). 
• If a patient develops ARIA, MRI monitoring and treatment dosing schedules are adjusted based on symptoms and severity. 

Donanemab  

TRAILBLAZER-ALZ 2 showed slowing of cognitive and functional decline on integrated Alzheimer’s Disease Rating Scale (iADRS).  There was approximately 35% reduction in decline with treatment. Patients were evaluated with serial amyloid PET scans to determine treatment duration and 52% of treated patients had negative amyloid PET scans after 12 months. 

• Intravenous infusions every 4 weeks for 18 months or until minimal evidence of amyloid on PET imaging 
• MRI at start of treatment and prior to 2^nd, 3^rd, 4^th, and 7^th infusions 
• Rates of ARIA were 37% in the treatment group, compared to 15% in the placebo group. 
• If a patient develops ARIA, MRI monitoring and treatment dosing schedules are adjusted based on symptoms and severity. 

What you need to know about ARIA 

Amyloid-related imaging abnormalities 

Amyloid-related imaging abnormalities (ARIA) are MRI findings associated with the removal of amyloid plaques from the brain due to anti-amyloid therapies.  As a result of amyloid plaque removal, there is focal edema (ARIA-E) or hemorrhagic changes (ARIA-H) (Hampel 2023, Jeong SY 2025).

ARIA-E can develop symptomatic manifestations and poses a risk of clinical worsening, whereas ARIA-H are often incidentally detected. Therefore, ARIA-E receives greater clinical attention and may warrant treatment modification. 

Most ARIA is asymptomatic and resolved in about 4 months in CLARITY-AD and 10 weeks in TRAILBLAZER-ALZ. Nearly 90% of ARIA-E occurred within the first 6 months of treatment (Wang 2025). About 3% of patients who develop ARIA are symptomatic. Symptoms are usually mild, consisting of headache or confusion, but some can be more severe like seizures and even death. For symptomatic or severe radiologic evidence of ARIA, treatment with high-dose steroids may be warranted. As of now, mild to moderate ARIA is thought to have no long-term effects after treatment with steroids. More data is needed to monitor the long-term adverse effects. 

As mentioned previously, there is a significant increased risk associated with ARIA for APOE4 homozygotes. Meta-analysis also showed significant increased risk for APOE4 heterozygote carriers compared to non-carriers (Jeong 2025). 

There were three deaths reported in each TRAILBLAZER-ALZ and CLARITY-AD trials, or open label extension.  The majority of deaths occurred in the context of anticoagulation use, with one patient having received tissue plasminogen activator (tPA) for acute ischemic stroke and died of extensive, multifocal cerebral hemorrhages (Reish 2023). 

What does this have to do with the “Amyloid Hypothesis”?  

Alzheimer’s disease is characterized by the accumulation of amyloid-B (AB) plaques, composed of AB40 and AB42, and neurofibrillary tangles, that contain tau protein  (Ramanan, 2023). The genetics associated with Alzheimer’s (ie. APOE) are genes associated with amyloid processing. It is also proposed that amyloid deposition begins many years before clinical symptoms emerge. All the above has made AB an enticing target for disease modifying therapies, which is why the development of blood-based biomarkers for early amyloid detection is a major advancement for the field. 

In 2021, aducanumab received accelerated FDA approval as an anti-amyloid therapy.  The drug effectively lowered levels of amyloid via PET, but failed to demonstrate a clinical benefit for patients and produced conflicting results in clinical trials. This has caused heightened awareness surrounding the efficacy and safety of other anti-amyloid therapies. 

Dr. Amjad reminds us that these therapies demonstrate effective removal of amyloid plaque in the brain – there is no controversy surrounding that.  All of these drugs have different mechanisms of plaque removal, therefore it is understandable why some drugs may be more effective, or have a different effect, than others.  

If amyloid is being effectively removed, why is it not stopping the disease? 

There must be other coexisting mechanisms involved in the neurodegeneration and cognitive and functional decline associated with Alzheimer’s Disease. The underlying disease mechanism is likely multifactorial.  All of this to say, amyloid is likely just one piece of Alzheimer’s puzzle. 

Remember: At age 80, about 30 to 40% of Amyloid PET scans are positive in cognitively normal adults.  

Links

1. Ramanan VK, Armstrong MJ, Choudhury P, Coerver KA, Hamilton RH, Klein BC, Wolk DA, Wessels SR, Jones Jr LK, AAN Quality Committee. Antiamyloid monoclonal antibody therapy for Alzheimer disease: emerging issues in neurology. Neurology. 2023 Nov 7;101(19):842-52.
2. AAFP: Blood Biomarkers and Early Detection of Alzheimer’s Disease and Related Dementias 

Goal

Listeners will develop a framework to approach the diagnosis and treatment of Alzheimer’s Disease, in the era of blood-based biomarkers and anti-amyloid therapies.

Learning objectives

After listening to this episode listeners will…  

1. Learn diagnostic criteria for dementia and Alzheimer’s disease (AD).  
2. Recognize notable features in patients’ history, functional and cognitive assessments specific to Alzheimer’s disease. 
3. Understand the significance of plasma-based biomarkers in the diagnosis of AD and eligibility for anti-amyloid therapy.   
4. Discuss the risks and benefits of anti-amyloid therapy and drug safety monitoring.  

Citation

Barrett NA, Miller RK, Witt LJ, Amjad H,, Williams PN, Watto MF. “#511 Alzheimer’s Disease: Updates in Diagnosis and Treatment ”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date January 12, 2026