Overcoming diagnosis delays in Alzheimer’s: Why the development of biomarkers is critical to the success of future treatments

Despite Alzheimer’s being discovered over 100 years ago, the complexity of the brain and limitations surrounding research/diagnostic methods have historically acted as barriers for Alzheimer's disease (AD) drug development. As a result, market authorisations for AD have been particularly low, with only four drugs treating the symptoms, rather than the causes, approved between 1996 and 2020.

Recently, however, this trend has shifted and advancements in AD therapeutics have accelerated dramatically. In 2021, the AD pipeline saw major advancements with the (controversial) FDA accelerated approval of Biogen’s Aduhelm (aducanumab), the first amyloid-targeting antibody for AD. Today, the recent FDA approval of Eisai’s Leqembi (lecanemab) and imminent approval of Lilly’s donanemab, both of which also target amyloid plaques formed from a protein known as amyloid-beta (Aβ), are receiving significant attention. Seen as a breakthrough for the disease, there is the belief that targeting and reducing amyloid deposition in the brain will slow/prevent AD pathology.  

While both treatments show significant efficacy in this area, with trials showing these drugs can slow the progression of memory loss by one-third when given in the early stages of Alzheimer’s, side effects known as amyloid-related imaging abnormalities (ARIA) have raised some questions about their suitability. Whilst currently not well understood, it is known ARIA have some safety implications including edema, and haemorrhagic propensities, with concerns also surrounding potential brain shrinkage. Comorbidities such as APOE4, microhaemorrhages and cerebral amyloid angiopathy are also likely to start precluding patients given their significant association with ARIA and other serious side effects.

Side effects aside, despite their benefits, disease progression still occurs when using these drugs, indicating other mechanisms are likely at play. These limitations in current amyloid therapeutics and advances in our understanding of other AD-related pathologies continue to influence the expansion of the AD pipeline beyond just amyloid. New drugs targeting tau, an intraneuronal protein associated with maintaining the stability of neuronal structures and forms tangles during AD have seen a significant growth in interest. Whilst inflammatory pathway and the innate immune system modulators are also contributing to the growing diversity of AD therapeutics.

Overcoming the roadblocks

Whilst we are certainly entering an exciting phase of development and innovation for AD treatment, the efficacy of current drugs hinge on early diagnosis/treatment with delays known to have major impacts on their effectiveness. In fact, recent reports claim that tens of thousands of patient’s face missing out on the new Alzheimer’s drugs in the UK due to the NHS not having the capabilities to diagnose the disease early enough. This is largely due to a cost and benefits assessment determining that the drug effectiveness is linked to early treatment with only a few people having access to the required diagnostic tools, which include amyloid and tau PET scanning or CSF biomarker assays (2% estimated by the BBC). However, with the disease taking 10 years or more from the onset of pathology to start presenting clinically, patients and doctors have been less likely to implement time consuming and costly diagnostics. Meanwhile, significant delays within the NHS diagnostic pathway has often meant the damage has already been done by the time a formal diagnosis and treatment become available– emphasising the requirement for better and earlier diagnostics.

Fortunately, the development of novel biomarker assays is playing a part in optimising the treatment of AD.  Biomarkers are naturally occurring molecules, genes, or characteristics that allow for a pathological or physiological process to be measured. In AD, biomarkers are used to diagnose and measure disease progression and include the detection of risk-associated genetic mutations, variable Aβ_40/42 ratios, p-Tau, neurofilament light and cognitive/neuroimaging assessments. Each biomarker is detected in its own way and together help healthcare professionals (HCP) provide a patient with a clinical AD diagnosis whilst also providing context on how far along a patient is.

Cerebral spinal fluid (CSF) based biomarkers, which utilise the fluid that surrounds the central nervous system, are one of the most commonly used approaches. Over the last few years, these assays have become significantly more reliable and accurate allowing for detection of patients at earlier stages of disease. However, CSF collection requires a spinal tap or lumbar puncture, a process that involves a needle being inserted into the spinal cord. This is a painful process and requires a trained professional and time which limits the accessibility of such tests. Due to this, the development of more accessible biomarkers has been a significant focus for the field. One such advance has been the development of blood-derived biomarkers (BBBM), which include serum- and plasma-based biomarkers. BBBMs, similar to CSF, can measure Aβ_40/42 and tau but are more accessible without the need for a specialist with spinal tap training. Such advances in diagnostic accessibility and reliability are contributing to the earlier diagnosis and earlier treatment of patients with less advanced pathologies. However, this approach has yet to be given regulatory approval and are largely restricted to clinical trials. This may change though, with Eli Lilly, as part of its development of donanemab, having developed a BBBM targeting tau which it is continuing to be developed, now in collaboration with Roche, and may see commercial us in the future.

What’s next for AD drug development? 

Whilst Leqembi and donanemab are receiving the most limelight, there are several other promising drug developments expected over the course of the next year including data from Alector’s AL002, Eli Lilly’s remternetug, Anavex’s blarcameine and Cassava’s simufilam clinical trials as well as many more. There is also growing consensus that combination therapies with existing drugs for AD will start being developed, with therapeutic efficacy further enhanced by doing so. These could manifest in several ways including combining Aβ (Leqembi/donanemab) and TREM2 targeting drugs (AL002) or Aβ and tau (E2814) targeting combination therapies.  

Increased funding and greater public awareness of AD impact on people’s lives will also continue to influence future innovation in these areas. The potential financial benefits are also certainly an incentive for drug developers with the Alzheimer’s market estimated to be $4.2 billion in 2022 and expected to grow to $15.6 billion by 2030. The financial burden on payers and governments has led to the recognition by regulatory bodies of an unmet need and is also contributing to advancements in AD therapeutics. With the number of people with dementia in England and Wales expected to almost double to 1.7 million by 2040, the race is truly on to find safe, effective treatments, and early diagnosis through the development of BBBM will be critical to making this a reality.