Early diagnosis of Alzheimer’s disease using biomarkers is becoming a clinical reality say experts

Delays in diagnosis of Alzheimer’s disease can mean lost opportunities for earlier medical and lifestyle intervention. However, promising new diagnostic technologies have the potential to detect Alzheimer’s disease, even before symptoms occur.

In ‘Detect Alzheimer’s disease early’, a podcast in the MindChangers series hosted on the recently launched ADBioHub, Prof Chris Rowe (Austin Health’s Director of Molecular Imaging Research in Melbourne and Director of the Australian Dementia Network) and Dr Qiao-Xin Li (Senior Manager of the National Dementia Diagnostics Laboratory at the Florey Institute in Melbourne) discussed how positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) biomarker testing are about to change the way we diagnose Alzheimer’s disease (AD) in the clinic.

The role of biomarker testing in the early diagnosis of Alzheimer’s disease

Prof Christopher Rowe introduced amyloid PET imaging into Australia in 2004 and his world-leading research team continue to explore the development and application of PET tracers for the study of AD.

Prof Rowe is currently developing new tests and biomarkers to support early intervention clinical trials in AD. He explained that, alongside measuring the cognitive hallmarks of AD, we can now support early risk assessment and diagnosis in three ways:

• PET imaging techniques
• Analysis of CSF
• Blood testing

While development of a blood biomarker assay for clinical use is still ongoing,¹ both PET imaging and CSF testing are already providing insights into the progression of AD from the preclinical phase to late-stage dementia.^2,3

Amyloid-β and tau protein deposition are core neuropathological features of AD and can be detected many years before symptoms appear. Amyloid PET is the least invasive approach, consisting of a 20-minute scan with a low dose of radiation. It is highly accurate in both detecting the presence of amyloid-β and tracking quantitative changes over time, explained Prof Rowe. However, it does come at a high financial cost.

Obtaining a CSF sample is less expensive than PET scanning and has the advantage of providing data on two biomarkers simultaneously (i.e. amyloid-β and tau).⁴ CSF analysis also carries low risk, but local anaesthetic and a lumbar puncture are required for sample collection making it less acceptable to some patients.⁵

To overcome these limitations of PET and CSF analysis, Dr Qiao-Xin Li, Senior Manager of the National Dementia Diagnostics Laboratory at the Florey Institute in Melbourne, will test promising new plasma-based methods in the near future. Her goal is to provide diagnostic tests that are accurate, affordable and accessible, and that could enable recruitment of at-risk patients who are at a very early stage in the disease process, into clinical trials for targeted amyloid therapies. She explained that plasma-based biomarker testing “will be a lot more accessible, to a wider population, that’s what we hope for.”

Is there a potential role of biomarkers beyond early diagnosis?

While both PET and CSF analysis are considered highly accurate in detecting the presence of amyloid-β, the dynamic range of PET measurements can also be used for tracking a patient’s amyloid-β load over time.⁵ Indeed, PET imaging allows for accurate quantification and localisation of amyloid-β, and this breadth of information can be used in multiple ways beyond the early diagnosis of AD. In the case of preclinical AD and mild cognitive impairment (MCI), these data could potentially be used to predict the rate of disease progression. As explained by Prof Rowe, “The amount of amyloid present does determine how quickly you progress to dementia”.

In addition to measuring quantities of amyloid-β, Prof Rowe also highlighted insights gained from mapping tau proteins in the brain. In contrast to amyloid-β imaging, tau imaging shows a strong regional association with clinical and anatomical heterogeneity in AD.⁶ For example, patients with the logopenic variant primary progressive aphasia present with language rather than memory concerns and show asymmetric left greater than right hemisphere tau accumulation.⁶ While there are currently no targeted therapies for specific AD subtypes, understanding the associated protein accumulation in different regions of the brain is highly relevant for developing and testing effective therapies.⁶

Are we ready for biomarkers to guide AD management in the clinic?

Accurate, earlier diagnosis of AD with biomarkers has the potential to create more opportunities for treatment intervention, with drug therapies and lifestyle changes. For example, a report published in The Lancet in 2020, ⁷ identified 12 modifiable risk factors for dementia, highlighting that treatment for hypertension has been shown to effectively prevent dementia.

The large, single-group, multisite longitudinal Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study⁸ (n=11,409) also showed that the use of amyloid-β PET was associated with changes in clinical management within 90 days in patients with MCI and dementia AD. In particular, the most frequent change in management involved the use of AD drugs.⁸ Furthermore, a negative amyloid-β result paired with MCI was also associated with treatment changes.⁸

Importantly, dementia can have many underlying causes which are often difficult to distinguish. For example, symptoms of frontotemporal dementia, hippocampal sclerosis or Limbic-predominant age-related TDP-43 encephalopathy (LATE) can be falsely diagnosed as AD in the absence of biomarker testing.⁹ Prof Rowe highlighted that clinical accuracy of AD diagnosis is only 70%, so wider use of biomarkers in diagnosis could help to improve the accuracy of diagnosis, thereby ensuring that patients receive appropriate treatment.

While further research is required to determine whether biomarkers are associated with improved clinical outcomes, results from the IDEAS study suggest their potential role in informing AD management and improving patient outcomes.⁸

“I think people want an answer, and they want it early, when they can still be involved in their future and future planning”, concluded Prof Rowe.

Learn more about how PET imaging and CSF biomarker testing are about to change the way we diagnose Alzheimer’s disease in the clinic in the ADBioHub Mind Changers podcast ‘Detect Alzheimer’s disease early’,

References:

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3. Alzheimer’s Association Report. Alzheimer’s Dement 2021;17:327–406.
4. Dubois Bet al. Lancet Neurol 2021;20:484-96.
5. Sperling R et al. Neuron 2014;84:608–22.
6. Ossenkoppele R et al. Brain 2016;139:1551–67.
7. Livingston G et al. Lancet2020;396:413–46.
8. Rabinovici GD et al. JAMA 2019;321:1286­­–94.
9. Hyman BT et al. Alzheimer’s Dement 2012;8:1–13.