Treatment Advances in Early Alzheimer Disease: Insights From AAIC 2024

The 24th Alzheimer’s Association International Conference (AAIC) — which was held in Philadelphia, Pennsylvania, and online from July 28 to August 1, 2024 — highlighted new developments in early diagnosis and treatment of AD. Strategies targeting Aβ and tau in the preclinical stage of AD, along with the exploration of novel therapeutic targets, demonstrate the potential to slow disease progression before the onset of irreversible late-stage pathology that is largely untreatable.
 
Erik C.B. Johnson, MD, PhD, is an assistant professor in the Department of Neurology and a member of the Goizueta Alzheimer’s Disease Research Center for Neurodegenerative Disease at Emory University School of Medicine in Atlanta, Georgia. In this article, Dr Johnson provides clinical insights into the implications of the new developments in early treatment for AD.

What is the rationale for differentiating therapeutic strategies between early and advanced AD? Why are different therapies needed?

Research over the past 5 to 10 years, using unbiased discovery methods involving brain tissues and biofluids from patients with AD, has revealed the complex pathological changes that evolve over the decades-long course of the disease. One of the earliest changes is the aggregation of Aβ protein into amyloid plaques. However, by the time patients seek medical attention for AD-related memory problems, most have experienced Aβ deposition in their brains for 15 to 20 years; multiple other pathological processes have subsequently developed, contributing to their cognitive impairment. This may explain why Aβ plaque removal in symptomatic individuals provides only a modest clinical benefit — other pathological processes downstream of Aβ accumulation may be more important drivers of symptomatic disease.
 
If we can better understand the pathological cascade in AD, it is likely that therapies specific to a particular pathological process will be most effective when administered near the onset of that process; this view is similar to the treatment of other diseases (eg, cardiovascular disease). For instance, we know that inflammation is a key pathological process associated with cognitive decline in early AD. A therapeutic approach to achieve a more favorable peripheral and central immune system response in AD, using low-dose interleukin (IL)-2, was explored by Sarazin and colleagues at multiple sites in France.¹ Immune system modulation has been successfully used in other neurological diseases (eg, multiple sclerosis). Safe and effective implementation in AD would represent a promising therapeutic advance.

What are the primary mechanisms researchers are exploring in AD development, and what implications do those mechanisms have regarding current clinical approaches to early AD?

The 2 primary mechanisms under ongoing investigation in AD are the aggregation of Aβ into plaques and the aggregation of tau into NFTs. Both are hallmark pathologies of the disease. In most individuals, Aβ plaques form prior to changes in tau phosphorylation and aggregation into NFTs, which occur in brain regions critical for cognition. Therefore, if Aβ plaques can be removed sufficiently early, subsequent changes in tau might be slowed or even prevented. Data from the Clarity AD trial (ClinicalTrials.gov identifier: NCT03887455), presented at the conference, examined the effect of Aβ plaque removal on biomarkers of NFT pathology. The results showed that removal of Aβ plaque using lecanemab slowed the rate of NFT accumulation in patients with early AD.² This is an important observation because the long-term goal is to prevent NFT accumulation, considering its strong correlation with cognitive decline in AD.
 
Because many older individuals have what is called preclinical AD (evidence of AD pathology in the brain without clinical symptoms), targeting Aβ plaque for removal in this stage of the disease — before substantial tau accumulation — may demonstrate greater efficacy in preventing the onset and progression of AD-related cognitive symptoms.³

The therapeutic landscape for early AD is rapidly evolving with the approval of 2 anti-amyloid monoclonal antibodies, donanemab and lecanemab. Aducanumab, the first anti-amyloid therapy, will soon be discontinued. Given this shift, what is the suggested role of amyloid removal therapy in early AD? How do these new treatments fit into the broader strategy for managing early AD, and what are the potential benefits and limitations of amyloid removal at this stage of the disease?

Multiple lines of research now suggest that earlier removal of amyloid pathology is more likely to provide a clinically significant benefit. Clinical trials currently underway are testing this hypothesis in people with preclinical AD, and the results of these trials will be available over the next few years. One completed trial tested this hypothesis in a unique population of individuals carrying genetic mutations that cause early-onset AD at a predictable age. These individuals were treated with gantenerumab, an anti-amyloid immunotherapy, before symptom onset.
 
At the conference, Ibanez et al revealed that treatment with gantenerumab had a positive effect on multiple AD biomarkers; higher doses exhibited more favorable effects.⁴ Additionally, Bateman et al reported that the onset of cognitive symptoms was potentially delayed by 3 to 6 years in patients who received gantenerumab for the longest period of time (an average of 8 years).⁵ There are multiple caveats to these findings, including the small number of patients and the fact that the control group was not part of the actual study. However, the evidence suggests that early amyloid removal can delay AD onset.
 
Notably, despite the amyloid removal achieved in this trial, participants developed tau accumulation and cognitive symptoms. This finding underscores the growing recognition that multiple therapeutic interventions may be necessary to prevent AD. A new National Institutes of Health (NIH)-funded phase 2 clinical trial is launching soon to test anti-amyloid and anti-tau immunotherapies, both individually and in combination. This trial will explore whether simultaneous targeting of both pathologies is more effective than the targeting of either pathology alone.⁶

Researchers have encountered multiple challenges in designing new clinical trials for early AD, including the identification of highly accurate methods to measure therapeutic response. What measures demonstrate the best utility for evaluating effects on tau pathology?

A key challenge when designing clinical trials focused on early AD is the large number of patients that must be enrolled. Many people will not develop symptoms or experience clinically significant symptom progression, even on placebo, during the course of the trial. However, if a trial cohort can be enriched with individuals more likely to experience short-term progression, the number of participants can be substantially reduced. Various strategies can be used to enrich trial cohorts with people likely to experience progression, such as the inclusion of older individuals and those who exhibit genetic risk for AD.⁷
 
Another challenge with trials focused on early AD is the measurement of a clinical benefit in people who are, by definition, either unimpaired or very mildly impaired. Historically, US Food and Drug Administration (FDA) approval for an AD medication has required the detection of benefits regarding cognitive and functional statuses. However, the field is now shifting towards surrogate biomarkers of a beneficial treatment response, such as markers of tau pathology that are more closely associated with disease risk and clinical symptoms. The results of tau-positron emission tomography (PET) imaging comprise 1 such biomarker. Unfortunately, this imaging-based test is not widely available in clinical practice, is quite expensive, and is unlikely to be scalable for large-scale implementation in primary care settings.
 
Another surrogate biomarker is microtubule-binding region (MTBR)-tau 243, a tau protein isoform measurable in cerebrospinal fluid (CSF) that displays a strong correlation with the tau-PET signal. Thus far, this marker is only used in research settings and has mainly been studied in CSF samples. Markers of phosphorylated forms of tau (eg, pTau217 and pTau181) can be measured in blood and have demonstrated associations with brain pathology in AD. Analyses presented at the conference indicate that some of these pTau assays, such as the Lilly pTau217 assay, are more strongly associated with tau pathology in the brain, compared with other markers.⁸ However, additional work is needed to determine whether plasma pTau assays can be used to assess therapeutic effects on tau pathology in the brain.

Considering the diverse range of therapies under development for AD, including gantenerumab, IL-2 therapies, and monoclonal antibodies such as donanemab and lecanemab, what are the potential benefits of combining these treatments? How might donanemab’s mechanism of action complement other therapeutic strategies to enhance overall efficacy and patient outcomes?

It is highly likely that combinations of therapeutic modalities will be needed to achieve a substantial impact on AD. The therapeutic pipeline is expanding beyond anti-amyloid treatments to include anti-tau immunotherapy and other approaches. Although this is a positive development in the AD field, it also creates challenges in designing clinical trials to test the therapeutic benefits of drug combinations. Clinical trial design, a scientific discipline in its own right, will need to evolve in the AD field along with drug development to make combination therapy a reality for patients with AD. Combination therapy for AD is feasible; this approach has been successfully implemented in the cancer and HIV fields, where combination therapies are quite common. The NIH-funded combination clinical trial of anti-amyloid and anti-tau immunotherapies mentioned above is an excellent example of how publicly funded research can help to accelerate the testing and implementation of combination therapies.⁶
 
The hope is that simultaneous use of multiple therapeutic approaches, each with a different mechanism of action, leads to synergistic effects that cannot be achieved with a single therapeutic approach in isolation.⁹ For instance, aggressive amyloid removal with donanemab could complement tau removal and immunomodulation with IL-2 therapy in a cocktail approach to treating AD, potentially providing substantial therapeutic benefit. Larger disease-modifying effects are needed to reduce clinical trial time and cost while incentivizing pharmaceutical and biotech companies to invest in AD drug research.

Several novel targets for early AD therapy have been identified. What do you see as the most promising targets of therapy for this population, and what are the goals?

Immunotherapy for AD is increasingly shifting towards tau-targeting approaches. Similar to Aβ, many different forms of tau can serve as therapeutic targets. One of the more promising forms of tau is the MTBR, which forms the core of NFTs and is suspected to act as a seed that catalyzes NFT formation in connected brain regions where tau spreading occurs during disease progression. If MTBR-tau can be removed from the extracellular space, then perhaps NFT progression can be slowed.¹⁰
 
Immunotherapy presents challenges for drug delivery, and oral disease-modifying therapies for AD remain an unmet need. Several oral therapies currently in development target non-amyloid pathways; for example, histone deacetylase (HDAC) inhibitors target the regulation of gene expression to modulate signaling pathways with known implications in AD.¹¹ This class of medications is surprisingly well-tolerated and does not seem to have major off-target effects or toxicity. Although they have primarily been tested in cancer, HDAC inhibitors show promise as a new class of therapeutics for AD.
 
Another promising class of oral medications enhances the ability of brain cells to clear abnormally folded proteins, such as the NFTs that accumulate in the course of AD, through a process called autophagy. An oral medication in this class, called blarcamesine, showed very promising results in terms of cognitive and functional outcome measures after approximately 1 year of treatment without major side effects.¹² These types of oral medications could potentially be used in combination with immunotherapy to treat multiple pathological processes that occur in early AD.
 
This Q&A was edited for clarity and length.

Disclosures

Erik C.B. Johnson, MD, PhD, reported an affiliation with Eli Lilly and Company.

References

1. Sarazin M, Lagarde J, Olivieri P, et al. Therapeutic evaluation of low-dose IL-2-based immunomodulatory approach in patients with early AD. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 92047.
 
2. Wildsmith KR, Sacdev P, Horie K, et al. Lecanemab slows amyloid-induced tau pathology as supported by CSF MTBR-tau243 in Clarity AD. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 95507.
 
3. McKay NS, Millar PR, Barthélemy NR, et al. Preclinical Alzheimer disease pathology in studies of memory and aging. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 94151.
 
4. Ibanez L, Li Y, McDade E, et al. Impact of gantenerumab amyloid removal therapy on established Alzheimer disease fluid biomarkers.Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 94831.
 
5. Bateman RJ, Li Y, McDade E, et al. Delaying symptom onset in dominantly inherited Alzheimer’s disease: long-term gantenerumab treatment results from the DIAN-TU trial. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 94602.
 
6. Boxer AL, Sperling RA, Aisen PS, et al. The Alzheimer’s tau platform (ATP): a phase 2, combination amyloid and tau therapy clinical trial for early AD. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 85111.
 
7. Dickson SP. Study design considerations for strategies in early interventions in Alzheimer’s disease. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 88984.
 
8. Bali D, Janelidze S, SalvadóG, et al. Comparison of plasma ALZpath p-Tau217 with Lilly p-Tau217 and p-Tau181. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 94707.
 
9. Dickson SP, Mallinckrodt C, Burstein AH, Nisenbaum L, Fillit HM, Hendrix SB. The impact of lecanemab and donanemab on future Alzheimer’s disease clinical development.Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 93476.
 
10. van Dyck CH, Kahl A, Abelian G, et al. TargetTau-1: design of a phase 2 trial to evaluate the efficacy, safety, and tolerability of BMS-986446, an anti-MTBR tau monoclonal antibody, in patients with early Alzheimer’s disease. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 94677.
 
11. Lu W, Kawatani K, Jeevaratnam S, Bu G, Kanekiyo T, Li Y. Therapeutic effects of class I HDAC inhibitor CI-994 in Alzheimer’s disease. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 84770.
 
12. Sabbagh MN, Chezem WR, Jin K, Missling CU. Blarcamesine in early Alzheimer disease phase 2b/3 randomized clinical trial. Abstract presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA. Abstract 90729.