News
27/12/2024
2024 Wrapped: Key Advancements in Neurodegenerative Disease Research and Clinical Impact
As the year draws to a close, 2024 has proven to be an eventful period for neurodegenerative disease research. From notable advancements in understanding the mechanisms of diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) to the development of new therapeutic approaches, the scientific community has made significant strides. However, this progress has not come without its challenges. Long-standing hypotheses, such as the amyloid cascade hypothesis in Alzheimer’s disease, have sparked renewed debates, following the rapid market access of amyloid-targeted antibody therapies. Amidst the progress and controversy, we’ve created a timeline to highlight some of the most pivotal developments and discussions in the field over the past year.
January 2024
Alzheimer’s disease Therapy: 164 active trials (Phase 1-3) assessing 127 drugs aimed at preventing or treating Alzheimer’s disease. The majority (76%) focus on disease-modifying therapies (DMTs).[1]
Parkinson’s disease Therapy: 136 clinical trials in Parkinson’s research, mostly in Phase 1-2. More than half of the studies (56%) focus on symptomatic treatments rather than DMTs.[2]
February 2024
Memory-associated protein KIdney/BRAin (KIBRA) is revealed to repair synaptic plasticity in neurons of human tau transgenic mice.[3]
Amos Korczyn and Lea Grinberg openly discuss the very definition of Alzheimer’s disease and raise the question, whether AD should be reconsidered as a syndrome caused by a “convergence of pathogenic pathways” rather than a defined disease.[4] (featured article)
March 2024
The AD/PDTM Conference 2024 puts emphasis on the importance of early AD/PD diagnosis to enhance DMT effectiveness.[5]
Ultrasound treatment of APP23 mice shows cognitive improvements independent of amyloid and tau reduction.[6] (featured article)
April 2024
Diabetes medication lixisenatide (Lyxumia/Adlyxin) shown to slow progression of PD-related motor deficiencies in a 12-month Phase 2 trial.[7]
C-terminal fragments of APP discovered to reduce lysosomal Ca2+ influx and cause cholesterol accumulation, culminating in an endolysosomal collapse in mouse embryonic fibroblasts and hippocampal neurons.[8]
May 2024
APOE4 homozygosity proposed as another form of distinct genetically determined AD, such as early-onset ADAD and DSAD.[9]
June 2024
Revised criteria for the diagnosis and staging of Alzheimer’s disease by the AAW sparks controversial debates and dispute among AD experts concerning AD diagnosis, reliability of biomarkers, and conflicts of interest in clinical advances.[10] (featured article)
July 2024
The U.S. Food and Drug Administration (FDA) approves Eli Lilly’s anti-amyloid drug Kinsula (donanemab), which was shown to slow clinical decline but is also associated with risk of ARIA. The drug is approved for patients with mild cognitive impairment or mild dementia stage of AD.[11]
The Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMA) advises against marketing authorization for Leqembi (lecanemab) due to an unfavorable risk-to-benefit ratio.[12] (featured article)
August 2024
Ralph Nixon and David Rubinsztein highlight the critical role of the autophagic-endolysosomal trafficking system for maintaining neuronal health.[13] (featured article)
The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) approves Leqembi for early-stage AD treatment.[14]
National Institute for Health and Care Excellence (NICE) denies access through the National Health Service (NHS), deeming lecanemab’s benefits too small to justify the cost to the NHS.[15]
The FDA approves Amneal Pharmaceuticals’ Crexont (IPX203) and Medtronic’s Deep Brain Stimulation technology for the treatment of PD or essential tremors.[16][17]
September 2024
CSF and plasma proteomic analyses of participants in the Dominantly Inherited Alzheimer’s Network (DIAN) reveal 137 proteins associated with AD development, some of which show alterations even before long-established biomarkers, such as tau and Aβ42.[18]
October 2024
GWAS of multiple neuropathology endophenotypes finds four new genes linked to dementia and connects 19 known AD-related loci to specific neuropathologies, further supporting the view of dementias as multigenetic and multifactorial diseases.[19]
The Australian Therapeutic Goods Administration (TGA) decides against registering Leqembi for the treatment of patients with Mild Cognitive Impairment (MCI) due to AD and Mild Alzheimer’s dementia (early AD) on the basis that the drug’s demonstrated efficacy does not outweigh the safety risks associated with its use.[20]
November 2024
The FDA clears the AI tool icobrain aria by icometrix, designed to detect ARIA buildup in anti-amyloid therapies.[21]
The EMA’s human medicines committee (CHMP) issues a recommendation for granting a conditional marketing authorization of Leqembi after re-evaluation of the decision in July 2024. The recommendation is limited to patients with less than two copies of the APOE4 gene; additional restrictions apply.[22]
December 2024
The National Academies of Sciences, Engineering, and Medicine release report identifying “Research Priorities for Preventing and Treating Alzheimer’s Disease and Related Dementias” as a guideline the National Institutes of Health should pursue over the next three to 10 years to advance the prevention and treatment of AD and related dementias.
Note: The Study was undertaken by the Ad hoc Committee of the National Academies of Sciences, Engineering, and Medicine, of which Christian Behl, founder of ni2n, is currently a member of (since 2023)
References:
[1] Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F (2024) Alzheimer’s disease drug development pipeline: 2024. Alzheimers Dement (N Y) 10:e12465. DOI: 10.1002/trc2.12465
[2] McFarthing K, Buff S, Rafaloff G, Pitzer K, Fiske B, Navangul A, Beissert K, Pilcicka A, Fuest R, Wyse RK, Stott SRW (2024) Parkinson’s disease drug therapies in the Clinical Trial Pipeline: 2024 update. J Parkinsons Dis 14:899–912. DOI: 10.3233/JPD-240272
[3] Kauwe G, Pareja-Navarro KA, Yao L, Chen JH, Wong I, Saloner R, Cifuentes H, Nana AL, Shah S, Li Y, Le D, Spina S, Grinberg LT, Seeley WW, Kramer JH, Sacktor TC, Schilling B, Gan L, Casaletto KB, Tracy TE (2024) KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss. J Clin Invest 134. DOI: 10.1172/JCI169064
[4] Korczyn AD, Grinberg LT (2024) Is Alzheimer disease a disease? Nat Rev Neurol 20:245–251. DOI: 10.1038/s41582-024-00940-4
[5] AD/PD 2024. Advances in science and therapy. Retrieved 25 December 2024.
[6] Leinenga G, To XV, Bodea L-G, Yousef J, Richter-Stretton G, Palliyaguru T, Chicoteau A, Dagley L, Nasrallah F, Götz J (2024) Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction. Mol Psychiatry 29:2408–2423. DOI: 10.1038/s41380-024-02509-5
[7] Meissner WG, Remy P, Giordana C, Maltête D, Derkinderen P, Houéto J-L, Anheim M, Benatru I, Boraud T, Brefel-Courbon C, Carrière N, Catala H, Colin O, Corvol J-C, Damier P, Dellapina E, Devos D, Drapier S, Fabbri M, Ferrier V, Foubert-Samier A, Frismand-Kryloff S, Georget A, Germain C, Grimaldi S, Hardy C, Hopes L, Krystkowiak P, Laurens B, Lefaucheur R, Mariani L-L, Marques A, Marse C, Ory-Magne F, Rigalleau V, Salhi H, Saubion A, Stott SRW, Thalamas C, Thiriez C, Tir M, Wyse RK, Benard A, Rascol O (2024) Trial of lixisenatide in early Parkinson’s disease. N Engl J Med 390:1176–1185. DOI: 10.1056/NEJMoa2312323
[8] Bretou M, Sannerud R, Escamilla-Ayala A, Leroy T, Vrancx C, van Acker ZP, Perdok A, Vermeire W, Vorsters I, van Keymolen S, Maxson M, Pavie B, Wierda K, Eskelinen E-L, Annaert W (2024) Accumulation of APP C-terminal fragments causes endolysosomal dysfunction through the dysregulation of late endosome to lysosome-ER contact sites. Dev Cell 59:1571-1592.e9. DOI: 10.1016/j.devcel.2024.03.030
[9] Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, Videla L, Gispert JD, [1] Suárez-Calvet M, Johnson SC, Sperling R, Bejanin A, Lleó A, Montal V (2024) APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Nat Med 30:1284–1291. DOI: 10.1038/s41591-024-02931-w
[10] Jack CR, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC (2024) Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimers Dement 20:5143–5169. DOI: 10.1002/alz.13859
[11] FDA (2 July 2024). FDA approves treatment for adults with Alzheimer’s disease. Retrieved 25 December 2024.
[12] EMA (26 July 2024). Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 22-25 July 2024. Negative opinion for one medicine. Retrieved 25 December 2024.
[13] Nixon RA, Rubinsztein DC (2024) Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases. Nat Rev Mol Cell Biol 25:926–946. DOI: 10.1038/s41580-024-00757-5
[14] Gov.uk (22 August 2024). Press release – Lecanemab licensed for adult patients in the early stages of Alzheimer’s disease. Retrieved 25 December 2024.
[15] NICE (22 August 2024). Benefits of new Alzheimer’s treatment lecanemab are too small to justify the cost to the NHS. Retrieved 25 December 2024.
[16] Michaeljfox.org (8 August 2024). FDA approves new levodopa/carbidopa formulation for use in Parkinson’s. Retrieved 25 December 2024.
[17] Medtronic (12 August 2024). Medtronic receives landmark FDA approval for Asleep Deep Brain Stimulation surgery. Retrieved 25 December 2024.
[18] Bretou M, Sannerud R, Escamilla-Ayala A, Leroy T, Vrancx C, van Acker ZP, Perdok A, Vermeire W, Vorsters I, van Keymolen S, Maxson M, Pavie B, Wierda K, Eskelinen E-L, Annaert W (2024) Accumulation of APP C-terminal fragments causes endolysosomal dysfunction through the dysregulation of late endosome to lysosome-ER contact sites. Dev Cell 59:1571-1592.e9. DOI: 10.1016/j.devcel.2024.03.030
[19] Shade LMP, Katsumata Y, Abner EL, Aung KZ, Claas SA, Qiao Q, Heberle BA, Brandon JA, Page ML, Hohman TJ, Mukherjee S, Mayeux RP, Farrer LA, Schellenberg GD, Haines JL, Kukull WA, Nho K, Saykin AJ, Bennett DA, Schneider JA, Ebbert MTW, Nelson PT, Fardo DW (2024) GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia. Nat Genet 56:2407–2421. DOI: 10.1038/s41588-024-01939-9
[20] TGA (16 October 2024). TGA’s decision to not register lecanemab (LEQEMBI). Retrieved 25 December 2024.
[21] Icometrix (14 November 2024). FDA authorizes the first AI-driven MRI solution for safer Alzheimer’s treatment. Retrieved 25 December 2024.
[22] EMA (14 November 2024). Leqembi recommended for treatment of early Alzheimer’s disease. Retrieved 25 December 2024.