Diagnosis and Treatment Strategies for Early Alzheimer Disease: Highlights From AAN 2025

Several abstracts from AAN 2025 focused on the use of plasma biomarkers for the diagnosis and prognosis of AD.^1,2 How close are we to blood tests becoming standard of care rather than requiring PET or cerebrospinal fluid (CSF)?

That is a really good question, and one that is very high on many people’s lists for understanding. The issue is that we do not really have a gold standard. PET itself will, in many cases, reveal a positive amyloid scan in older adults who are cognitively normal.³ CSF is quite good at predicting AD pathology but, similarly, CSF positivity can occur some years before an individual develops symptoms.⁴ The question, then, is how do blood tests fit into this, and what do we judge blood tests against?
 
At the moment, there is a wide variety of abstracts and work covering the basic AD biomarkers, most notably phosphorylated tau217 (p-tau217) and ratios using this analyte, such as ratios with amyloid-β42. Using such measures, a number of groups have shown that the sensitivity and specificity are somewhere on the order of 90%.^1,2,5 These metrics are examined against amyloid PET scan, which is not necessarily a perfect gold standard either, as we mentioned.
 
Blood testing is still tantalizingly close to being of use for the definitive diagnosis of AD, but I would not say it is quite there. I am not sure many practitioners would be willing to either give a firm diagnosis or embark on treatment protocols for AD, which might go on for many years, simply on the basis of the current blood tests. Blood tests do show a lot of promise, and they are getting quite accurate. But it does seem that CSF is the most accurate way to diagnose the AD process at this point in time.

Multiple studies reported that real-world treatment outcomes of anti-amyloid mAbs are comparable with those seen in the clinical trials for AD.^6-8 How do these post-approval data impact your treatment decisions?

It is very gratifying to see that we have 2 US Food and Drug Administration (FDA)-approved therapies that clearly have proven to slow down the progression of disease.^9,10 And now that they are more widely used, it is good news that practitioners’ experience with them has not been too troublesome.^6-8 These are all relatively early reports, as lecanemab has been on the market for only a little over 2 years and covered by Medicare for less than 2 years. Donanemab is even newer. Some neurologists were early adopters of these new therapies, while others only recently started using these treatments.
 
It is certainly informative to note that practitioners across the country are using these agents without finding unusual or new safety signals, and also that they are not having marked difficulties in ascertaining eligibility, providing the required magnetic resonance imaging monitoring, or administering the necessary infusions. It is a revolution in neurology to have treatments for AD that slow down the disease, beyond the effects of the symptomatic treatments we have had for the last several decades. The early adoption of any new medication is never immediate, and there was a lot of fear about the known brain side effects of edema and bleeding in the brain.

A subcohort of the phase 3 TRAILBLAZER-ALZ 2 trial (ClinicalTrials.gov identifier: NCT04437511) showed the benefit of donanemab in patients with AD who have a Mini-Mental State Examination (MMSE) score of 27 or higher and low-medium tau PET burden.¹¹ What is the clinical significance of this data?

There are a variety of filters, if you will, that have been applied to both donanemab and lecanemab studies. These data, like that for lecanemab, are suggestive that treating people relatively early in the AD disease process is beneficial.^11,12 We all know that people with MMSE of 27 to 30 may still have AD and may still be symptomatic, and that just because they perform quite well on a basic screening test does not mean that their brain is “normal.” If a person has AD pathology, as best as we can tell, and has early AD, so far, all studies have indicated that such individuals show a benefit with treatment, as this subpopulation showed.^6-8,11

The Alzheimer’s Association recently released new clinical practice guidelines for the diagnostic evaluation and testing of suspected AD.^13,14 How do these new guidelines impact clinical practice?

I think they are actually more research practice guidelines than clinical practice guidelines. But they are gradually infiltrating the overall neurology landscape. The main controversy regarding these criteria has been what to call people who have clear biochemical signs — either in CSF, PET scan, blood testing, or any or all of the above — of the beginnings of AD, yet who have no symptoms. The Alzheimer’s Association guideline criteria do suggest that we classify these people as having AD, whereas other groups and individuals resist that categorization and would rather say that such persons are at risk for AD. It is a little bit of semantics, but clearly of import, as it really affects how you talk to patients as a practitioner, whether you inform them that they “have the beginning of AD” or that they “may end up having AD.”
 
The other big issue is that the criteria are very elaborate, but a number of the criteria are really not clinically executable in the current clinical practice world. That is because many of the biomarkers that are referred to are either only available on a research basis or are not widely available. It is great to have criteria, but when they involve markers that are not commonly available, that means people will be unable to utilize the criteria.

Barriers to initiation of anti-amyloid mAb treatment may be present, especially in more rural areas.¹² What are some ways that clinicians can try to remove roadblocks and expedite treatment access?

This is always an issue; the United States is a big country, and some places have portions of the populace that are far from big medical centers or medical care. For diagnosis, you may have to travel 300 miles, but we are talking about just 1 or 2 visits, and most people do that, whether it is for cancer or something else, and they should do that for memory problems too. Treatment and monitoring can be a bit more burdensome because they are more frequent.
 
Some of our anti-amyloid therapies may become available by subcutaneous injection. If we can deliver the medication through the skin in the privacy of the home, then patients would not have to travel to an infusion center every 2 or 4 weeks. That would be another advance, and indeed the FDA may approve subcutaneous anti-amyloid lecanemab therapy, but we do not know how such approval, if it happens, might look. There may be constraints on this approval, such that subcutaneous administration might only be approved after an initial 18 months of intravenous therapy. The FDA announced it will make a decision on the drug application to deliver lecanemab through the subcutaneous route before the end of August 2025.¹⁵ Again, while such administration might not be for initial therapy, it would certainly be a dramatic change regarding travel barriers.
 
This Q&A was edited for clarity and length.
 

Disclosures

Lawrence S. Honig, MD, PhD, reported affiliations with Acumen; Alector, Inc; APRINOIA Therapeutics; Biogen, Inc; Bristol-Myers Squibb Company; CervoMed, Inc/EIP Pharma, Inc; Cognition Therapeutics, Inc; Corium, LLC; Eisai, Inc; Ferrer; Genentech, Inc/Roche Holding AG; GemVax & KAEL Co, Ltd; GlaxoSmithKline, plc; Janssen Biotech, Inc; Johnson & Johnson Services, Inc; Medscape; NewAmsterdam Pharma, Co; PPD/Thermo Fisher Scientific, Inc; Transposon Therapeutics, Inc; UCB Pharma, Inc; Vaccinex, Inc; and Vigil Neuroscience, Inc.

References

1. Aubrecht J, Quadrini KJ, Johnson AD, et al. Accuracy of plasma biomarkers for detecting amyloid beta deposits in participants with Alzheimer’s disease in ASCENT-2 clinical trial of PRX012. Poster presented at: American Association of Neurology (AAN) Annual Meeting; April 5-9, 2025; San Diego, CA. Poster 10.1212/WNL.0000000000210621.
 
2. Chenna A, Yee B, Badal Y, Winslow J, Petropoulos C. Analytical and clinical assessment of plasma p-Tau217, BD-Tau, p-Tau181 and Aβ42/Aβ40 assays in Alzheimer’s disease (AD) subjects. Poster presented at: American Association of Neurology (AAN) Annual Meeting; April 5-9, 2025; San Diego, CA. Poster 10.1212/WNL.0000000000211350.
 
3. Noble JM, Scarmeas N. Application of PET imaging to diagnosis of Alzheimer’s disease and mild cognitive impairment. Int Rev Neurobiol. 2009;84:133-149. doi:10.1016/S0074-7742(09)00407-3
 
4. Gale SA. Language and meaning: asymptomatic Alzheimer’s disease in the clinic and society. J. Alzheimer’s Dis. 2024;99(2):489-492. doi:10.3233/JAD-240195
 
5. DeMarshall C, Viviano J, Krishnan A, Hutchison D, Sahin M, Nagele R. Clinical and analytical performance of DuritectTM: a novel blood-based autoantibody diagnostic screening platform for Alzheimer’s and Parkinson’s diseases. Poster presented at: American Association of Neurology (AAN) Annual Meeting; April 5-9, 2025; San Diego, CA. Poster 10.1212/WNL.0000000000212002.
 
6. Kuball P, Watkins K, Stobin I, et al. Early clinical outcomes following lecanemab therapy for mild cognitive impairment and mild dementia due to Alzheimer’s disease. Poster presented at: American Association of Neurology (AAN) Annual Meeting; April 5-9, 2025; San Diego, CA. Poster 10.1212/WNL.0000000000212315.
 
7. Weisman D, Nimma S, Lutz H, et al. Real-world experience with long-term lecanemab treatment: a retrospective chart review in early Alzheimer’s disease. Poster presented at: American Association of Neurology (AAN) Annual Meeting; April 5-9, 2025; San Diego, CA. Poster 10.1212/WNL.0000000000210905.
 
8. Moon J, Ferrer A. Lecanemab in clinical practice: real-world treatment outcomes from a retrospective neurological clinic case series review in early Alzheimer’s disease. Poster presented at: American Association of Neurology (AAN) Annual Meeting; April 5-9, 2025; San Diego, CA. Poster 10.1212/WNL.0000000000211951.
 
9. Lilly’s Kisunla™ (donanemab-azbt) approved by the FDA for the treatment of early symptomatic Alzheimer’s disease. News release. Eli Lilly and Company. July 2, 2024. Accessed March 24, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early
 
10. FDA converts novel Alzheimer’s disease treatment to traditional approval. News release. US Food and Drug Administration. July 6, 2023. Accessed March 24, 2025. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
 
11. Vasudeva R, Doty E, Yang F, et al. The importance of early recognition and treatment initiation for managing Alzheimer’s disease: subpopulation analysis of the TRAILBLAZER-ALZ 2 randomized trial. Poster presented at: American Association of Neurology (AAN) Annual Meeting; April 5-9, 2025; San Diego, CA. Poster 10.1212/WNL.0000000000210512
 
12. Eisai presents data on benefits of long-term administration of dual-acting lecanemab at the 17th Clinical Trials for Alzheimer’s Disease (CTAD) conference. News release. Eisai, Inc. October 31, 2024. Accessed March 24, 2025. https://www.eisai.com/news/2024/news202481.html
 
13. Atri A, Dickerson BC, Clevenger C, et al. The Alzheimer’s Association clinical practice guideline for the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer’s Disease and Related Disorders (DETeCD-ADRD): executive summary of recommendations for primary care. Alzheimers Dement. Published online December 23, 2024. doi:10.1002/alz.14333
 
14. Dickerson BC, Atri A, Clevenger C, et al. The Alzheimer’s Association clinical practice guideline for the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer’s Disease and Related Disorders (DETeCD-ADRD): executive summary of recommendations for specialty care. Alzheimers Dement. Published online December 23, 2024. doi:10.1002/alz.14337
 
15. FDA accepts Leqembri^® (lecanemab-irmb) biologics license application for subcutaneous maintenance dosing for the treatment of early Alzheimer’s disease. News release. Biogen, Inc. January 13, 2025. Accessed March 24, 2025. https://investors.biogen.com/news-releases/news-release-details/fda-accepts-leqembir-lecanemab-irmb-biologics-license