Recapping Research From 2023 Alzheimer's Association International Conference

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As a recap from AAIC 2023, get caught up on some of the latest news in neurology as the NeurologyLive® team shares some of our data updates.

In recent months, the NeurologyLive® team has been covering the news and conducting interviews with experts on the latest updates in the clinical care of patients with neurological diseases, such as dementia or Alzheimer, epilepsy, headache or migraine, movement disorders, multiple sclerosis, neuromuscular diseases, sleep medicine, and stroke.

To recap the 2023 Alzheimer’s Association International Conference (AAIC), July 16-20, in Amsterdam, the Netherlands, the team has culminated some of the biggest pieces of news to offer updates on new developments in the literature about Alzheimer disease (AD) to spread awareness on prevention and treatment approaches.

Click here for more coverage of AAIC 2023.

Latest Literature

Donanemab Demonstrates Slowing of Alzheimer Disease Progression in Phase 3 TRAILBLAZER-ALZ 2 Trial

At the 2023 AAIC, full data from the pivotal, phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511) highlighted donanemab’s (Eli Lilly) impact on disease progression in individuals with early symptomatic AD.1,2 The results, which were simultaneously published in JAMA, showed that donanemab, an antiamyloid therapy, was effective across all cognitive and functional secondary end points, and across multiple analysis methods.

TRAILBLAZER-ALZ-2, a multicenter trial, included 1736 patients who received donanemab (n = 860) or placebo (n = 876) administered intravenously every 4 weeks for up to 72 weeks. Spanning across 277 medical sites in 8 countries, the primary outcome of the study was least-squares mean (LSM) change in integrated Alzheimer Disease Rating Scale (iADRS) score, with lower scores indicating greater impairment. Among trial participants, 68.1% (n = 1182) had low/medium tau pathology and 31.8% (n = 552) had high tau pathology.

In the low/medium tau population, LSM change from baseline in the iADRS score at 76 weeks was –6.02 (95% CI, ­–7.01 to –5.03) in the donanemab group and ­–9.27 (95% CI, –10.23 to ­–8.31) in the placebo group, otherwise a 35.1% (95% CI, 19.90-50.23) slowing of disease progression. The impacts were less pronounced in the overall population, with between-group score differences of 2.92 (95% CI, 1.51-4.33; P <.001), representing a 22.3% (95% CI, 11.38-33.15) slowing of disease progression.

Mortality Risk Significantly Increased With New Opioid Use in Older Adults With Dementia

Among older patients with dementia, findings from a Danish nationwide study suggest that new opioid use is associated with excess mortality, with a nearly 11-fold increase observed for all opioids within the first few weeks. Investigators called for additional research to identify subgroups of patients with the highest excess mortality risk in efforts to ultimately create guidelines for appropriate prescription.3

The study, presented at 2023 AAIC, included 75,471 Danish residents aged 65 years and older diagnosed with dementia, 42% (n = 31,619) of which redeemed a prescription for an opioid after their diagnosis. Exposed participants were matched with up to 2 unexposed individuals based on age and sex (n = 63,235). Mortality risk was assessed within 180 days after the initiation of opioid treatment.

Among those exposed to opioids, 33.7% (n = 10,642) died within 180 days after initiating their first opioid prescription compared with 6.4% (n = 3980) of those unexposed, yielding a 4-fold increased excess mortality risk (HR, 4.13; 95% CI, 3.98-4.30). Strong opioids used in the study included morphine, oxycodone, ketobemidone, hydromorphone, pethidine, buprenorphine, and fentanyl. These medications were associated with a 6-fold increased mortality risk (HR, 6.34; 95% CI, 6.00-6.69) whereas the risk was lower for weak opioids (HR, 2.52; 95% CI, 2.38-2.67).

High Prevalence of CAA-Related Lesions in APOE ε4/4 Homozygotes With Early Alzheimer disease

Recent imaging results from the phase 3 APOLLOE4 trial (NCT04770220) investigating ALZ-801 (Alzheon), an investigational oral amyloid oligomer inhibitor, showed that patients with early-stage Alzheimer disease (AD) who are apolipoprotein ε4 allele (APOE4/4 homozygotes) carriers had a high prevalence of cerebral amyloid angiopathy (CAA)-related lesions at baseline.4 These findings suggest that these patients would be more susceptible to treatment-induced brain edema and microhemorrhage (MH), known as amyloid related imaging abnormalities (ARIA).

At least 1 lobar MH was present in about 32% of a 325-patient cohort, including 9% of patients with greater than 4 microhemorrhages (MH) and 9% of patients with superficial siderosis, with the most common locations of these lesions in the occipital and frontal lobes. Notably, 2 participants had macrohemorrahages and a majority of the participants had white matter disease. Presented at 2023 AAIC, the APOLLOE4 trial fully enrolled 325 APOE ε4/4 homozygotes patients with earlier AD who had a Mini-Mental State Exam score of at least 22 points. Abushakra and colleagues investigated the prevalence of MH and CAA lesions in this patient sample at the baseline (mean age 69 years; women, 51%; MMSE, 26; white, 82%; MCI, 65%). The baseline MRIs were obtained from 1.5T/3T scanners which were centrally evaluated by Clario, collecting reports on the number and locations of the CAA lesions.

ARIA-E was also reported in APOE e4/4 carriers treated with placebo in lecanemab (Leqembi; Eisai) & gantenerumab (Eli Lilly) trials (4%-6%). This background ARIA likely reflects spontaneous CAA-related inflammation commonly reported in APOE ε4 carriers.3 Oral ALZ-801 in the ongoing studies has not shown increased ARIA risk, and has safety advantage over amyloid antibodies especially for APOE ε4/4 homozygous patients.

Positive Progress Reported in ANeND Study of Ambroxol in Dementia With Lewy Bodies

At 2023 AAIC investigators gave a positive progress report on the phase 2a ANeND study (NCT04588285) assessing ambroxol as a potential therapy for new and early dementia with Lewy bodies (DLB).5 There 38 of the 47 included patients started treatment with compliance that was greater than 90%. Initiated in May 2021, 5 patients thus far have completed the blinded phase after 18 months and have continued on to the open-label phase for an additional 12 months.

The goal for the multicenter, placebo-controlled trial is to include 180 participants who are randomly assigned 1:1 to either ambroxol 1260 mg/d or placebo for an 18-month period. As of February 2023, 6 of the 7 sites have started recruitment. In the 47 patients with available data, the mean Mini-Mental State Examination (MMSE) scores at baseline were 23.5 (SD, 4.4) and mean Unified Parkinson’s Disease Rating Scale Part III scores were 21.2 (SD, 12.7). The mean age of those included was 71.3 (SD, 6.1) years with a mean disease duration of 9.9 (SD, 9.2) months. Thus far, the reported adverse events included falls, nausea, and sleep disturbances; however, the relationship of these with ambroxol remains uncertain.

Ambroxol is a mucolytic compound and the main ingredient of over-the-counter cough medicines sold in many countries. The hypothesis that ambroxol could potentially be useful in DLB originated in studies in Gaucher disease, a lysosomal storage disorder, caused by a mutation in the glucocerebrosidase (GCase) gene and resulting in the development of parkinsonism in some patients. This has led researchers to discover that mutations in the GBA1 are a genetic risk factor for synucleinopathies similar to Parkinson disease and DLB.6

Epigenetic Therapy Demonstrates Efficacy in APOE Reduction for Alzheimer Disease

In a recent study using an epigenome therapy strategy, the candidate demonstrated efficacy in editing of apolipoprotein (APOE) and APOE e4 expressions in human induced pluripotent stem cells (hiPSC) -derived neurons and the human isogenic APOEe4 organoids, ultimately reducing the levels of APOE-mRNA and the protein in both models.7 These findings provided in vitro and in vivo proof-of-concept of the therapy’s efficacy and suggests the candidate's ability to fine-tune APOE expression is translational toward the development of a therapeutic approaches to prevent or delay late-onset AD.

Using this therapy approach there were no detectable editing of the e3 allele in the isogeneic hiPSC-derived neurons, and organoids homozygous for the e3 allele. Adeno-associated- dCas9-KRAB-MeCP2 vector injected into the hippocampus of APOEe4 and APOEe3 mice, performed in vivo studies, demonstrated between a 50-70% decrease in the mRNA and protein. Researchers noted a similar effect using the lentivirus- CRISPR/Cas system to target ApoEe4 in the same allele-specific way.

In the study, an epigenome therapy platform was developed to reduce APOE and APOE e4 alleles specifically by targeting modification of the epigenome landscape in APOE locus, based on the CRISPR/dCas9-editing strategy. Presented at 2023 AAIC, investigators designed the therapy candidate to target the APOE e4 in an allele-discriminatory approach, making the editing allele specific and precise.

A similar approach was developed for targeting the regulatory elements in the APOE promoter. The platform was then evaluated in vitro using human hiPSC-derived neurons and organoids, as well as in vivo through stereotactic injection of the developed system in the hippocampus of the APOE-humanized mice, fostering the human APOE loci substituted the mouse ortholog. All told, the system technology also provides the opportunity for refining the platform to the development of gene-specific and even allele- and cell-type- specific therapies. Thus, this approach could potentially enable the advancement of strategies for precision medicine in late-onset AD.

REFERENCES
1. Mintun M, Solomon P, Sims JR, Salloway S. Donanemab in early symptomatic Alzheiemr’s disease: efficacy and safety in TRAILBLAZER-ALZ 2, a phase 3 randomized clinical trial.
2. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239
3. New use of opioids increases risk of death elevenfold in older adults with dementia. News release. Alzheimer’s Association. July 18, 2023. Accessed August 3, 2023. https://www.prnewswire.com/news-releases/new-use-of-opioids-increases-risk-of-death-elevenfold-in-older-adults-with-dementia-301879360.html
4. Abushakra S, McLaine R, Barakos J, et al. Prevalence of Cerebral Microhemorrhages and Cortical Superficial Siderosis in APOE4/4 Homozygotes with Early Alzheimer's disease: Baseline Findings from Phase 3 Trial of Oral ALZ-801 in APOE4/4 Homozygotes (APOLLOE4). Presented at: 2022 Alzheimer’s Association International Conference; July 16 to July 20; Amsterdam, the Netherlands. Abstract 82916.
5. Chwiszczuk LJ, Rongve A. The ANeND study: Ambroxol in new and early dementia with Lewy bodies. Presented at: AAIC 2023; June 16-20; Amsterdam, the Netherlands. Abstract 77803
6. Tayembi N, Walker J, Stubblefield B, et al. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab. 2003;79(2):104-9. doi:10.1016/s1096-7192(03)00071-4.
7. Kantor B, Rittiner J, Odonovan B, Chiba-Falek O. APOE-targeted epigenome therapy for late onset Alzheimer’s disease. Presented at: 2022 Alzheimer’s Association International Conference; July 16 to July 20; Amsterdam, the Netherlands. Abstract 80698.
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