Which methods are used to diagnose the preclinical stage of Alzheimers disease?

Currently there is no single test that can accurately diagnose dementia.

A detailed medical history, memory and thinking tests (called neuropsychological or cognitive tests), laboratory tests and brain scans are typically used in the diagnosis process.

Current research into the diagnosis of Alzheimer's disease and other types of dementia aims to develop better methods for accurate and earlier diagnosis. Early diagnosis of dementia is currently important to allow time for planning and to maximise the potential for treatment.

In the future, identification of individuals in the preclinical phase of dementia, before symptoms of cognitive decline are evident, will be possible. So we will be able to predict who is going to develop dementia, rather than wait to diagnose dementia after it emerges. This could lead to lifestyle prevention strategies in order to delay dementia onset, and to earlier use of therapies that slow or halt the disease process.

Biomarker analysis

The search is on for "biomarkers" - biological markers which can indicate the presence of Alzheimer's disease, even before symptoms become evident.

Researchers have already identified several possible biomarkers for Alzheimer's disease in the cerebrospinal fluid (CSF), the liquid which surrounds the brain and spinal cord. Levels of beta-amyloid and tau (two proteins involved in the pathology of Alzheimer’s disease) in the CSF are already being used to aid diagnosis in some parts of the world.

Markers of inflammation and other brain changes associated with dementia can also be detected in the CSF and might be used alone or in combination with beta-amyloid levels to help clarify diagnosis.

Obtaining CSF requires a lumbar puncture, also known as a spinal tap, which involves inserting a needle into the spinal column. While this is a safe procedure, a simple blood test would be less invasive, so researchers are also investigating similarbiomarkers of dementia in the blood. Unfortunately, to date blood biomarkers have not proven to be as stable or accurate as those measured in the CSF, but research is continuing.

Neuroimaging: Visualising the brain

Neuroimaging describes a range of tools which are used to visualise the living brain, including computerised tomography (CT) scans, magnetic resonance imaging (MRI), single photon emission computerised tomography (SPECT) and positron emission tomography (PET).

Researchers are working on new ways of using neuroimaging tools to diagnose Alzheimer's disease and other types of dementia.

Positron Emission Tomography

In 2004, researchers successfully viewed beta-amyloid plaque deposits in the living human brain. The study used Pittsburgh Compound-B (PiB), a substance which binds to amyloid and can be visualised with PET scanning. The results demonstrated that people with Alzheimer's disease displayed more amyloid deposits in certain brain areas compared to people without the condition. More recent research has shown that PiB-PET can also detect the early brain changes of Alzheimer's disease before symptoms become apparent.

While PiB has proved quite effective, its widespread clinical use may be limited by the need for specialised equipment to produce PiB at the site of the PET scanner. Researchers are currently developing and testing other compounds that bind to beta-amyloid and may overcome the limitations of PiB.

Glucose metabolism in the brain is altered in dementia and these changes can be visualised using another form of PET imaging called FDG-PET. Different patterns of reduced glucose metabolism can be suggestive of different types of dementia and so FDG-PET is sometimes used as an aid to diagnosis. Recent research also suggests that FDG-PET can detect early brain changes before the emergence of dementia symptoms and predict progression to dementia. Research is continuing to further refine this procedure for dementia diagnosis.

Another type of PET scan uses compounds that bind to acetylcholine to detect brain changes due to Alzheimer’s disease. Acetylcholine is a neurotransmitter, or chemical messenger in the brain, that is involved in memory function. Detecting reduced acetylcholine activity in the memory areas of the brain may aid diagnosis of Alzheimer’s.

Magnetic Resonance Imaging

MRI is able to image the structure of the brain, which changes in dementia, to a very high resolution.

For example, a characteristic sign of Alzheimer’s disease is atrophy (shrinking) of a brain region called the hippocampus. This can easily be seen on an MRI scan and is currently used to aid diagnosis. International teams of researchers are working on standardising the scanning and analysis techniques used in MRI and establishing databases of scans of people with dementia.

It is hoped this research will eventually enable an individual’s scan taken anywhere in the world to be compared with those in the database to determine whether it is normal or suggests the presence of Alzheimer’s or another type of dementia.

New MRI methods are being used to image the white matter (nerve fibres) of the brain. The use of these in dementia research is in early stages, but may lead to the identification of characteristic patterns of white matter change that indicate different types of dementia and can be used in diagnosis.

One large Australian research study currently using PiB-PET and MRI is the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), a longitudinal study of ageing comprised of patients with Alzheimer's disease (AD), Mild Cognitive Impairment (MCI) and healthy volunteers. For more information visit the AIBL website.

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Page 2

From: Diagnosis of Early Alzheimer’s Disease: Clinical Practice in 2021

A - Presentation
• A 63-year-old Caucasian male patient (J.K) visited the memory clinic accompanied by his wife, having been referred by his PCP for evaluation of memory loss
• He presents with a history of an insidious onset of cognitive difficulties that have been progressive over the past 2 years. He considers his memory similar to his peers, and his deficits are not observable to people who know him casually
• At work, he has uncharacteristically confused orders and misplaced items, but has no difficulty keeping track of time, and his math, reading, and writing are intact. His wife says that people at work have started to notice him struggling to keep up and gently voiced their concerns to her
• The patient’s basic activities of daily living are intact, but more complex instrumental activities of daily living are showing erosion. He still drives, but no longer wants to drive to areas he is not familiar with
• He presents with no gait difficulty or balance problems. In terms of neuropsychiatric symptoms, his mood is more labile. He chokes up easily and is overall a little more down but attributes this to the fear and frustration over what is happening to him. He does have some mixed neuropsychiatric symptoms with intermittent depressive symptoms and anxiety as well as irritability
• Past medical history significant for hypertension, dyslipidemia, mild obesity, and glucose intolerance
• No history of neurotoxic exposure, head injuries with post-concussion syndrome, strokes, or seizures
• A positive family history of dementia with his father and paternal grandmother, where onset occurred in the late 60s
C - Assess/Differentiate
Blood tests:	All normal, except for serum glucose of 115 and HgbA1c of 6.5%
Neurologic examination:	Non-focal with faint bilateral palmomental reflex
Genotyping:	Homozygous for ApoE ε4; no autosomal dominant genes
Cognitive assessments:	MoCA score of 21/30
Structural imaging:	MRI showed mild small vessel disease and mild generalized atrophy Hippocampal volume and ratio were reduced by 25% based on volumetric software
D - Diagnose
CSF biomarkers:	Increased p-tau and t-tau Reduced Aβ42 Aβ42/40 ratio of 0.23
Diagnosis:	The most likely etiology is Alzheimer’s disease, especially in view of a positive family history with similar age of onset, ApoE ε4 status, and biomarker verification
E - Treat
• Advised patient to make lifestyle modifications, including controlling vascular risk factors and optimizing the management of other medical problems
• No treatment intervention required for neuropsychiatric symptoms at the time of diagnosis
• Provided information on local social worker to help support him and his family
• Encouraged regular follow-ups and monitoring
• Patient was referred for possible participation in a clinical trial

Abbreviations: Aβ, amyloid beta. ApoE, apolipoprotein E. HgbA1c, hemoglobin A1c. MoCA, Montreal Cognitive Assessment. MRI, magnetic resonance imaging. PCP, primary care physician. p-tau, phosphorylated tau. t-tau, total tau