Experts’ feedback

Our first approach was to engineer a single enzyme to directly cleave misfolded proteins linked to Alzheimer’s disease.This design would primarily target anti-amyloid beta and secondarily tau. After build and test phase, we discussed our findings with the group of researchers from the Institute of Biochemistry, who later became our instructors. They flagged the risk of protein misfolding and suggested we investigate a modular architecture for the therapeutic platform. Discussions with pharmacology experts uncovered that the lack of modularity of the system would lead to high manufacturing costs. As a result, we abandoned the single enzyme approach and shifted towards a modular system.

Confirmation from clinical experts and conclusions from our own background research pointed to the failure of anti-amyloid drugs in recent trials. We thus decided to focus on tau. Whilst tau therapies, too, failed in clinical trials, recent research showed a new part of tau pathology, not explored before, as a possible therapeutic target: extracellular tau seeds. Tau seeds, or p-tau seeds, are extracellular tau oligomers which spread Alzheimer’s disease pathology throughout the brain, by acting as a template for tau to misfold and aggregate. The input of researchers from the Institute of Biochemistry was invaluable – it directed us towards the use of LYsosome TArgeting Chimeras (LYTAC) to degrade the tau seeds. LYsomome TArgeting Chimeras are bifunctional proteins, consisting of two parts: an internalising receptor binder and a Target binder (usually an antibody specific to the protein of interest). The LYTAC approach would also avoid genome editing.

Further feedback from pharmacology experts emphasized BBB delivery as crucial. Therefore we needed to include an element – a binding peptide – to allow for BBB delivery. This was added to the existing tau-binding peptide, and we still had to address the problem of routing the toxic “cargo” to the lysosomes – through a dimeric IGF-2R binder. These three elements are the components of our TRI-LYTAC structure: (1) the tau binding scFv; (2) a TfR binding peptide to allow for BBB transport; and (3) dimeric IGF-2R binder to route internalised cargo to the lysosomes.

The initial delivery strategy envisaged was through PEGylated vesicles that could also do the task of BBB transcytosis. Feedback from the Institute of Biochemistry researchers and our modeling revealed that manufacturing vesicles with constant size and ligand density is costly, slow, and thus an ineffective delivery strategy. The alternative suggested was mRNA/LNP - a scalable and already clinically validated (through COVID-19 vaccines) option.

Discussions with clinicians and researchers emphasized the importance of safety associated with our therapeutic platform. In order to address this, we developed a logic gate system for detection of disease and targeted therapeutic release, ensuring that our therapeutic would not be expressed and secreted in cells not affected by Alzheimer’s disease.

Healthcare practitioners’ feedback

Early in our project, we planned to discuss with doctors, nurses, therapists and other healthcare practitioners about Alzheimer’s patients, in order to understand the challenges faced by the medical profession in this area.

Diagnosis challenges. Neurologists must rule out a number of conditions before a diagnosis for Alzheimer’s can be declared, such as depression, thyroid disorders, vascular dementia or vitamin deficiencies. Early Alzheimer’s is difficult to distinguish from mild cognitive impairment, or minor memory loss due to stress or normal ageing. Neurologists rely on a combination of tests (cognitive questionnaires, imaging like PET or MRI, biomarkers) because there is no quick, standard test. The costs of investigations such as a PET scan further complicate the diagnosis process. Moreover, no two patients present identical rates of cognitive decline and response to treatments. Finally, families and patients often underreport memory loss, and seek consultation when symptoms are very severe, thus losing the chance of early intervention.

Treatment challenges. As expected, our discussions with neurologists identified the lack of curative therapies as the biggest challenge in the treatment of Alzheimer’s patients. The existing drugs only slow the progression of the disease, while new drugs, like anti-amyloid antibodies, produce limited effect and are accompanied by severe side effects, like brain swelling or bleeding. A second problem is the fact that many patients suffer from other diseases as well, like hypertension, diabetes, cardiovascular disease, or depression. This increases the risk of drug interactions and complicates the medication plan. There is generally low adherence to treatment, if family is not involved.

Nurses caring for Alzheimer’s patients signalled the communication difficulties encountered, combined with behavioural symptoms that must be managed, as some patients are aggressive, agitated or uncooperative, which makes care unpredictable. Constant supervision is needed, because as the disease progresses, the risks of falls, burns, choking or getting lost increase exponentially. Apart from medication management, the nutrition of patients must be supervised, because they would often forget to eat, eat too many times a day or refuse food altogether.

Patients and families

We are deeply grateful to the families of Alzheimer’s patients who agreed to talk to us. We were profoundly moved by their stories, their courage and resilience. They showed incredible generosity in sharing their experiences, and we can only hope that sharing them further would help other families. This is our attempt at a very short “family guide” - a list of steps and things to keep in mind after receiving and Alzheimer’s disease diagnosis.

Family Guide: After an Alzheimer’s Diagnosis

When a loved one is diagnosed with Alzheimer’s disease, life changes for the whole family. Understanding and planning for this change is important. Here is a start.

Medical & Practical

Establish a care plan with professionals and keep reliable records.

  • Discuss treatment options with the neurologist and develop an understanding of the disease stage your loved one is in.
  • Contact your family doctor for additional support and to ensure access to free medication, investigations, etc.
  • Keep a notebook or use an app for medications, appointments, and changes in behavior.


Daily Life at Home

Create gentle routines and reduce risks to support independence.

  • Simplify life. Create predictable routines: mealtimes, bedtime, activities.
  • Consider safety in the house: remove tripping hazards, ensure supervision to avoid accidents in the kitchen, etc.
  • Encourage gentle exercise and serve healthy food.
  • Try to incorporate activities in the daily routine that bring pleasure to the patient: music, storytelling, looking at photos.


Communication

Prioritize clarity, patience, and reassurance.

  • Use short sentences and speak slowly, trying to focus on one thing at a time.
  • Be patient, do not argue or correct harshly.
  • Offer kindness and reassurance when confusion or fear arises.


Caregiving

Share the load and care for the caregiver, too.

  • Share responsibilities with family members: one person handles meds, another appointments, etc.
  • Make an effort to take breaks — use adult day centers, help from relatives, etc.
  • Join a caregiver support group to avoid isolation.


Plan early to honor wishes and protect resources.

  • Talk early about wishes for future care: options for in-home help or memory care facilities.
  • Set up a power of attorney for health-related decisions and finances.
  • Review insurance, benefits, and savings for long-term care needs.

Whenever possible, focus on comfort and quality of life — celebrate small moments together.