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Published in final edited form as: Ageing Res Rev. 2024 Mar 19;96:102281. doi: 10.1016/j.arr.2024.102281

Alzheimer’s Drugs APPlication for Down syndrome?

Deborah K Sokol a, Debomoy K Lahiri b,c,*
PMCID: PMC11903029  NIHMSID: NIHMS1984352  PMID: 38513771

Abstract

Accumulation of the amyloid β (Aβ) peptide, derived from Aβ precursor protein (APP), is a trait of Down syndrome (DS), as is early development of dementia like Alzheimer’s disease (AD). Treatments for AD in DS simply do not exist. New drug therapies for AD, e.g., Lecanemab, are monoclonal antibodies designed to clear amyloid plaques composed of Aβ. The increasingly real ability to target and dispose of Aβ favors the use of these drugs in individuals with DS for AD, perhaps as earlier intervention for cognitive impairment. We present pertinent similarities between DS and AD in adult DS subjects, discuss challenges to target APP metabolites, and suggest that recently developed antibody treatments against Aβ may be worth investigating to treat AD in DS.

Keywords: Aging, Amyloid, Down, DYRK1, Trisomy 21

1.1. Introduction

Trisomy 21 (T21) or Down syndrome (DS), occurs in 1 in 700 newborns and is the most prevalent genetic cause of intellectual deficiency (ID). Presently, no medications are FDA approved for the lifelong ID associated with DS. Indeed, a recent, comprehensive review of over 70 interventions within the last 10 years (70% pharmacological) determined no effective therapeutic interventions for ID in DS individuals (Lorenzon et al., 2023). We must recognize the barriers and facilitators of people’s participation in DS research and learn lessons from other fields (Sokol and Lahiri, 2023a; Souto et al., 2024). Understanding the disease mechanisms and cross-disciplinary research that would lead to effective treatment are the moment’s needs, and here we present one such viewpoint (Becker et al., 2015).

The National Institutes of Health (NIH) continues to support research in DS (Becker et al., 2015). Following a 2018 congressional directive for a trans-NIH initiative to address medical issues in DS, NIH launched the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project. Notably, the three INCLUDE components are basic science research, cohort development, and clinical trials. The Project is geared towards addressing conditions such as immune disorders and Alzheimer’s disease (AD). Herein, we submit our opinion of testing recently approved AD drugs in preclinical trials using T21-derived cells, organoids, animal models, and finally, subjects with DS.

People with DS experience acceleration of the aging process, which particularly affects the immune and central nervous systems. Treatments for DS are limited, and pre-clinical research is evolving in various models, including DS animals. For example, EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a DS model (Delabar et al., 2024).

Amyloid-beta (Aβ) precursor protein (APP) localizes to Chromosome 21 and is abundant in T21. Further, Aβ accumulates over time, contributing to neuritic plaques and neurodegeneration seen in over 50% of older individuals with DS (Head et al., 2017). The new monoclonal antibody drug therapies for AD, e.g., Aducanumab, Lecanemab, and Donanemab, were intended to clear amyloid plaques. Their significant potential to target and dispose of Aβ favors potential use of these drugs in DS. However, individuals with DS were not included in clinical trials of these new medications (Head et al., 2017). The possibility that DS patients may benefit from anti- Aβ stems from our opinion that APP metabolites, such as Aβ, may be therapeutic targets for conditions other than AD (Westmark et al., 2016). We should note caution as the field of Aβ therapeutics is dynamic and future challenges are unknown. For example, Biogen stopped marketing Aducanumab. The company recently announced it would halt its post-market trial and stop selling the drug; its rights now revert to Swiss company Neurimmune (Rogers, 2024).

APP metabolites play a significant role in early neurodevelopmental disorders (Lahiri et al, 2013). Understanding when and how Aβ affects brain development (neurogenesis) and neurodegeneration in T21 may produce targets for Aβ therapeutics. In particular, Aβ peptide with 42 residue (Aβ−42) is abundant in fetal T21 brain tissue (Teller et al., 1996), and amyloid deposition exists in T21 brain samples from children ages 8–12 years (Leverenz and Raskind, 1998). Fifty percent of individuals younger than 30 years with DS show Aβ-positive plaques, before they demonstrate clinical signs of dementia (Lemere et al., 1996). These findings suggest that Aβ peptides or a few of the fragments contribute to the T21 phenotype, potentially during neurogenesis (Fig. 1). Aβ (specially the 42 fragment) also plays a role in DS neurodegeneration as those with DS frequently develop AD symptoms and brain pathology by age forty (Head et al., 2017).

Figure 1. Potential APPlication of anti-Aβ drugs in Down Syndrome.

Figure 1.

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Relative timing of AD-like pathology and symptoms in Down syndrome. Therapies developed for AD would require administration at earlier ages than for conventional AD. Use of Aducanumab, Lecanemab and Donanemab in DS are as shown. Lecanemab maybe advantageous as it is administered intravenously compared to Aducanumab which requires spinal infusion. Lecanemab is designed to target other forms of amyloid, though it also removes plaques. Donanemab is designed to target plaques specifically, and maybe more effective in removing disease-associated toxic protein clumps in the brain. All drugs appear to slow down the loss of memory and cognition, in patients with early AD.

Overlap exists between the genes and pathways that lead to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, adding to what is known about cognitive decline in adults with DS. By this example, an Alzheimer’s polygenic risk factor (i.e., APOE ε4) associates with a cognitive phenotype in DS (Gorijala et al., 2023).

The dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene localizes to the Chromosome 21 DS critical region (DSCR), a region comprising the most harmful triplicated T21 genes. DYRK1A and Wnt pathway participants, together with Aβ affect neurogenesis, all likely further contributing to microcephaly and other dysfunction in T21. Microcephaly is not associated with AD, and, paradoxically, increased DYRK1A during aging may be protective against neurodegeneration (Delabar et al., 2023), so use of AD therapies in T21 may not be equivalent to their use in AD. With this caveat in mind, we present our view in favor of testing recently approved AD drugs in preclinical trials employing T21 cells, organoid, and animal models, and ultimately individuals with DS.

2.1. APP in Neurogenesis and the Cell Cycle

Given the extra dose of APP in T21, we believe APP contributes to the small OFC and ID seen in T21. Recently, we have reviewed APP’s role in neurogenesis and the cell cycle (Sokol and Lahiri, 2023b). Fetal neurogenesis occurs near the ventricular lumen, the hippocampal dentate gyrus (HDG) and subventricular zone (SVZ) (Jurkowski et al., 2020). During fetal development, the neocortex undergoes an explosive increase in surface area due to increase in neural progenitor cells (NPCs) that undergo several rounds of mitosis, eventually forming neurons. There is a reduced number of proliferating cells in the HDG and SVZ found in T21 fetuses (Contestabile et al., 2007). This suggests a problem in neurogenesis rather than neurodegeneration (Contestabile et al., 2007).

In murine models of AD cell cycles, phosphorylated APP (P-APP) generates Aβ, and both appear to activate the neuronal cell cycle. This induces AD mouse brain cells to re-enter the cell cycle without the cells undergoing cell division, contributing to neurodegeneration in the AD mouse brain. This promotes differentiation into glia instead of post-mitotic neurons, favoring atrophy, or, potentially in the case of DS, a smaller brain. Additionally, P-APP localizes to centrosomes and P-APP-induced cell cycle activation causes chromosome mis-segregation. In AD mice, Aβ leads to increased tau disruption of the mitotic spindle during metaphase, again contributing to a disrupted cell cycle and reduced neuron production. By these mechanisms, and given their increased levels in T21, APP/Aβ may contribute to microcephaly during T21 neurogenesis. However, cell, organoid and animal T21 model research is necessary to confirm APP/Aβ’s role in T21 neurogenesis before the use of AD drugs in infants.

2.2. APPraising other actors in Neurogenesis in T21

The Wnt pathway may link APP to impaired neurogenesis in T21. A signal transduction pathway, Wnt signaling regulates neurogenic processes including cell proliferation, migration and differentiation (Liu et al., 2021). Genetic ablation of β-catenin, the signal transducer of canonical Wnt signaling in transcription, leads to increased cell exit of NPCs, premature neuronal differentiation, and favors reduction of brain development. Wnt signaling pathways, particularly the β-catenin canonical pathway, inhibits Aβ production and is downregulated in AD (Liu et al., 2021). The Wnt canonical pathway is downregulated in T21 hippocampus (Granno et al., 2019).

Overproduction of DYRK1A, as seen in T21, may also downregulate the Wnt canonical pathway (Granno et al., 2019). In some T21 mouse models and in humans with DS, DYRK1A appears to disrupt neuronal cell proliferation and differentiation which contributes to the reduced number of neurons produced in early brain development (Granno et al., 2019). Further, DYRK1A phosphorylates APP at Thr-668 which facilitates BACE1 and y-secretase cleavage, resulting in increased production of Aβ peptides (Ryoo et al., 2008), but, as noted DYRK1 upregulation may be protective in older people (Delabar et al., 2023).

3.1. Challenges in Use of AD Drugs in Adults with DS

To determine effectiveness of anti-Aβ drugs for adults with DS we need to identify the age-range of the ideal sample, understand the mechanism of action, and agree upon meaningful outcome measures (Rafii, 2020). Individuals with DS over the age of 30 years may begin to show AD, and by age 40 years, most people with DS have enough neuropathology for an AD diagnosis (Head et al., 2017). In both AD and DS, soluble, protofibrillar Aβ first appears throughout the brain, followed by fibrillar Aβ, resulting in Aβ plaques (Rafii, 2020). The anti-Aβ drugs appear to have different targets. While Solanezumab did not show improvement of AD or slowing of cognitive decline, it reduced soluble Aβ, which may be efficacious in DS. Donanemab slowed cognitive decline in AD. Donanemab has been used to identify Aβ plaques in DS and AS brain specimens (Bouter et al., 2022). Lecanemab (Leqembi) targets early amyloid protofibrils and amyloid plaque fibrils and has been used to identify Aβ protofibrils and insoluble Aβ deposits in DS and AD brain samples (Johannesson et al., 2021). Aducanumab (Aduhelm) reduces both fibrils and plaques (Rafii, 2020).

AD comprises early, middle and late stages. The new AD drugs are most efficacious for early-stage disease. Unfortunately, there are no standardized methods to measure changes in patients with DS in minimally symptomatic early stage AD (Rafii, 2020). Typical cognitive instruments, useful for individuals who at one time had normal intelligence, have limited use for those with DS due to floor effects. Recent efforts to produce standardized measurements to identify cognitive deficits specific to AD in patients with DS produced the DS Mental Status Examination and the Dementia Scale for DS. Despite these challenges, drug trials for AD in DS, other than the new anti-Aβ, are underway (Lorenzon et al., 2023; Rafii, 2020). Recently, two randomized clinical studies reported that donepezil produces some improvement in general function in adults with DS dementia while the majority of pharmacological therapies showed no impact on memory or general function within this population (de Oliveira and de Paula Faria, 2022). Memantine was also tested in young adults with DS, but dosage typical for AD did not produce differences in cognitive measures vs. placebo group; however, further testing is needed (Costa et al., 2022).

4.1. Are AD and T21 Targets the Same?

We can speculate that AD in DS likely involves lifelong amyloid over-production compared to late onset sporadic AD that results from abnormality in amyloid processing and clearance (Hanney et al., 2012). Evidence supports APP metabolite/Aβ influence on neurogenesis and neurodegeneration in DS. Both processes may provide targets for Aβ therapeutics. However, Aβ in neurogenesis may serve a different purpose than Aβ accumulation during neurodegeneration, and its blockade or removal may generate unexpected results. This raises the importance of cell, organoid and animal T21 model research to confirm APP/Aβ’s role in T21 neurogenesis.

Amyloid related imaging abnormalities (ARIA) with edema (E) or microhemorrhage (H) are MRI changes associated with use of AD monoclonal antibody drugs (Alves et al., 2023). AD patients with these MRI changes largely show no clinical sequala, and while microhemorrhage remains, edema disappears once treatment is discontinued. CAA, which occurs in about 48% of AD, and 31% of symptomatic DS is the accumulation of Aβ in the vascular wall that can also cause microhemorrhage (Head et al., 2017). Lifelong accumulation of CAA may prove more intractable in DS than more recently acquired CAA in late onset, sporadic AD. CAA is a risk factor for the use of AD monoclonal antibody drugs (Alves et al., 2023). APOE ε4 increases risk for CAA (Rannikmäe et al., 2014), and together with risk for increased APOE ε4 in DS with dementia, older individuals with DS may be of increased risk for ARIA-H when prescribed anti-amyloid drugs. Therefore, use of these drugs may be safer for younger individuals with DS before CAA accumulates. Nevertheless, direct parallels between DS and AD need to be fully elucidated. Fortunately, two clinical trials are under way to explicitly trace AD pathogenesis and progression in DS (Dewey, 2019; Institut Jerome Lejeune, 2023).

It follows that the drug Lecanemab. that targets early, soluble Aβ protofibrils preceding plaques, may be best suited for younger T21 patients before CAA develops. Changes in the brain size of individuals with inherent microcephaly such as those with DS, may not be so benign. Therefore, the successful use of AD drugs in individuals with DS may be influenced by developmental stage (neurogenesis vs neurodegeneration) and age of the patient. We propose further research and testing of recently approved AD drugs first in animal models of T21, for potential use in individuals with DS.

5.1. Conclusion

There are no available FDA approved medications targeting the lifelong ID associated with T21. APP proteolytic metabolite Aβ affects brain development (neurogenesis) and neurodegeneration in T21, producing targets for Aβ therapeutics. New drug therapies for AD, e.g., Aducanumab, Lecanemab and Donanemab, are monoclonal antibodies designed to clear amyloid plaques, composed of Aβ. The increasingly real potential to target and dispose of Aβ favors use of these drugs in individuals with DS. However, preclinical research is needed to determine the effect of Aβ therapeutics, particularly considering Aβ’s role in prenatal T21 neurogenesis which is likely different than that for individuals with AD.

Highlights.

  • Accumulation of the amyloid β (Aβ) peptide is a trait of Down syndrome (DS), like Alzheimer’s disease (AD).

  • Treatments of AD in DS are lacking and urgently needed.

  • New antibody treatments for AD to clear amyloid plaques composed of Aβ, are worth investigation to treat DS.

  • Further research is needed to determine the effect of Aβ therapeutics, for individuals with DS.

Acknowledgements.

We sincerely thank Bryan Maloney for critically reading the manuscript.

Funding.

DKL is partially supported by grants from the US National Institute on Aging/NIH (P30AG10133, P01AG014449, R56AG072810, R21AG056007, R21AG074539, and R21AG076202).

Footnotes

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Declarations of Interest.

none

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