Making ready for early AD diagnosis

When disease-modifying therapy becomes available, screening for Alzheimer’s and its subsequent management will stretch healthcare resources on a massive scale. We need to be prepared. Even with the limited interventions now available, we should pursue the aim of widening opportunities for early diagnosis since there are clear benefits for people with the disease and their families.

There is a major mismatch between resources that are available to manage Alzheimer’s disease (AD) and those that may be needed, according to the recent EU RAND report which assessed preparedness in France, Germany, Italy, Spain, Sweden and the UK.1

The report makes a number of assumptions, and it has to be said that the first of them – the availability of a disease modifying therapy in 2020 – now looks less than likely. But the point of the exercise makes sense.

Are we prepared for the impact of early diagnosis?

Let us assume that – whenever such a therapy comes on stream – we will want 80% of potentially eligible people (essentially the 105 million who are aged 55 or over) to be screened. Let us say that half of the 14 million who are positive have further evaluation. Let us further assume that 90% of those who turn out to have mild cognitive impairment (MCI) have biomarker testing, and that half test positive; and that 80% of those people are suitable for treatment. That, according to the RAND calculations, means 2.3 million patients.

Resources to diagnose and treat AD must be more widely available if we are to maintain the ideal of universal healthcare

To meet that demand for screening and all the steps that follow, we have relatively few specialists. Even if we add up all the neurologists and geriatricians and old-age psychiatrists, there are still only 6.7 per hundred thousand population in France and 24 per hundred thousand in Germany. The other four countries lie between these figures.

Taking CSF biomarker testing as an example, it is clear that resources must be more widely available if we are to maintain our ideal of the universal availability of healthcare, José Luis Molinuevo, BarcelonaBeta Brain Research Center, Barcelona, Spain, told at an early diagnosis symposium at ADPD 2019.

Pursuing a practical, step-wise approach

In the current context, how should clinicians assess a patient with concerns about cognition?

We are eventually going to beat this disease, said Alireza Atri, Banner Sun Health Research Institute, Arizona, and Harvard Medical School, Boston, USA. The first step is accurate and timely diagnosis. And the starting point is listening carefully to patient history. It is important to assess prior functioning and the trajectory of change using what you hear from the patient and family members.

There is no biomarker for patient history: you assess past functioning and trajectory of change

Is there potential for something to be wrong? If there is, the next step is to assess in detail what is wrong. A cognitive assessment such as MoCA (Montreal Cognitive Assessment)  is a good tool, which may need to be followed by more formal neuropsychiatric assessment. And then comes the question of etiology. As we age, we accumulate pathologies.

Indifference and apathy are often early features of AD, said James Leverenz, Cleveland Clinic Lou Ruvo Center for Brain Health, Ohio, USA. But these are sometimes difficult to distinguish from depression.

At this stage, MRI is helpful since atrophy is evidence of a neurodegenerative disease; and focal hippocampal atrophy is the best-established structural imaging marker of AD.

Accurate and timely diagnosis is step one in care

Beyond MRI, there are the CSF markers, which were considered by Henrik Zetterberg, University of Gothenburg, Sweden, and University College London, UK. Total tau is increased in people with AD dementia, but also in other neurological conditions. Phosphorylated tau, a variant found in tangles, is increased in AD.  

While Aβ40 in isolation is not a reliable indicator of AD pathology, and CSF Aβ42 is decreased in AD – presumably because the protein is aggregated and deposited in the brain – the Aβ40/42 ratio is more informative than either marker alone.

Consider the wider clinical picture

In all of this, the wider clinical picture must play a part, the symposium speakers agreed. No marker should be considered in isolation. And, in moving along the path of investigation, the wishes of patients and families are paramount. Not all want to know in detail what is driving the problem.

And it is definitely not a case of “diagnose and Adios”, said Alireza Atri. Diagnosis is only the start of a new relationship based on a therapeutic alliance.

Pharmacological interventions can alleviate cognitive symptoms and improve function – even though this is only for a limited period of time. And non-pharmacological interventions such as encouraging cognitive and social engagement and exercise have small but significant effects. There is also benefit from early diagnosis in allowing patients and family to plan for the future. This includes provision for financial guidance, legal support, and patient safety.

Educational financial support for this symposium was provided by Biogen

  2. Blennow K, Zetterberg H. Biomarkers for Alzheimer's disease: current status and prospects for the future. J Intern Med. 2018 Dec;284(6):643-663. doi: 10.1111/joim.12816. Epub 2018 Aug 19.
  3. Dhiman K, Blennow K, Zetterberg H et al. Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer's disease pathogenesis. Cell Mol Life Sci. 2019 Feb 15. doi: 10.1007/s00018-019-03040-5. [Epub ahead of print]
  4. Bekris LM, Leverenz JB. The biomarker and therapeutic potential of miRNA in Alzheimer's disease. Neurodegener Dis Manag. 2015;5(1):61-74.
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