One of the most common question I get asked when giving public talks is: “What is the difference between dementia and Alzheimer’s disease?”

So, let’s get this question out of the way first. Alzheimer’s disease is one type of dementia. More precisely Alzheimer’s disease is the most common form of dementia, accounting for ~60-70% of all people with dementia. Because Alzheimer’s disease is the most common form of dementia, people often equate dementia with Alzheimer’s disease. However, Alzheimer’s disease is only one type of dementia.

But how many types of dementia are there?

This seemingly innocent question is actually not that easy to answer. The reason why it is difficult to answer is that it depends on how we measure the types of dementia.

Dementia as a clinical syndrome

The most common way to measure or define different types of dementias is via their clinical syndromes. Clinical syndromes refer to the collection of symptoms people present with at their doctor. You might have heard of the phrase that dementia is ‘a collection of symptoms’, which describes exactly dementia as a syndrome.

For example, Alzheimer’s disease presents in most people with impaired memory for events (episodic memory) and temporal & spatial orientation. If a doctor notices these symptoms they are more likely to give those people a diagnosis of Alzheimer’s disease. In other words, doctors classify dementia by their clinical symptoms.

Based on these clinical symptoms we can define the following clinical types of dementia:

1. Alzheimer’s disease
2. Vascular dementia
3. Mixed dementia – A combination of Alzheimer’s disease and Vascular dementia
4. Dementia with Lewy Bodies
5. Frontotemporal dementia, including:
   • Behavioural variant frontotemporal dementia
   • Semantic variant primary progressive aphasia – formerly called Semantic Dementia
   • Nonfluent primary progressive aphasia
6. Motor Neurone Disease with Frontotemporal dementia
7. Posterior cortical atrophy
8. Logopenic variant primary progressive aphasia
9. Progressive supranuclear palsy
10. Corticobasal degeneration

So, all in all, there are around 12 clinical subtypes of dementia. I say deliberately ‘around’ as there are also other clinical subtypes of dementia, such as rare genetic forms or dementia which is secondary to other diseases. For example, many people with Parkinson’s disease develop dementia in the late, advanced stages of the disease – so-called Parkinson’s disease dementia.

Based on these rare genetic and ‘secondary dementias, let’s round-up and say that there are ~15 clinical subtypes of dementia but some will be exceedingly rare. Even of the above listed, you might not have heard of some or most of them. The reason is that Alzheimer’s disease, Vascular & Mixed dementia account for ~80-90% of dementias, making the other clinical dementia types very rare.

Seems all pretty straightforward, doesn’t it?

But here comes the twist.

Instead of categorising types of dementia by their clinical symptoms, we can also classify dementia by their underlying disease/pathology causing those symptoms.

What do I mean by that?

Dementia as a protein disease

We should remember that all dementias are caused by the accumulation and clumping together of proteins in the brain. (The exception is vascular dementia which is caused by ruptures or blockages of blood vessels in the brain.) If a lot of proteins accumulate and clump together, they become toxic to the neighbouring nerve cells and eventually the nerve cells die in that region of the brain.

Once we lose nerve cells in a particular region of the brain, the specific functions of that brain region become affected. It is this disruption of these specific functions in the brain areas which we notice as clinical symptoms in people with dementia. In essence, the accumulating proteins are actually the cause for the clinical symptoms in dementia.

For example, proteins in Alzheimer’s disease start accumulating in the hippocampus – a brain region important for our episodic memory and orientation. Once the nerve cells start dying in the hippocampus because of the toxic proteins, we develop memory and orientation symptoms, as the hippocampus cannot function anymore properly.

The key point to remember is that proteins are the cause of all dementias – except for vascular dementia. However, the types of proteins clumping together are often different between different dementias. This means we can also classify dementias by the types of proteins which are causing the dementias and not their clinical symptoms.

What are then the proteins causing dementia and how many are there?

The main proteins causing dementia are:

1. Amyloid
2. Tau – Includes different versions of tau.
3. TDP-43 (TAR DNA binding protein 43) – Includes different versions of TDP-43.
4. Alpha-synuclein

Instead of having ~15 clinical dementia types, there are only 4 main types of proteins causing all dementias.

How can this be?

The reason for this is that proteins can overlap between different clinical types of dementia. This means that a protein accumulating can cause different symptoms, it just depends where it is accumulating the brain as it affects the functions in that brain region.

The classic example for this is Alzheimer’s disease. Alzheimer’s disease is caused by the confluence of two proteins – Amyloid and Tau. For most people in Alzheimer’s disease Amyloid and Tau emerge together in the hippocampus, causing the typical memory and orientation problems. However, Amyloid and Tau can also emerge in other brain regions causing very different symptoms. For example, Amyloid and Tau can emerge in the more posterior brain regions (the parietal and occipital lobes of the brain) causing symptoms with vision – or as the clinicians would define it Posterior Cortical Atrophy.

The key point to understand is that where these proteins accumulate in the brain will make a significant difference to the symptoms people with those proteins will have. They might present for example with memory or vision problems but actually, it is the same proteins which are causing these quite different symptoms. In essence, Posterior Cortical Atrophy is therefore a ‘visual symptom form’ of Alzheimer’s disease.

Is your head spinning? Do not worry, even experts in the field get confused between the overlaps and differences clinical and protein types of dementia.

The key point to remember is that all dementias – except vascular dementia – are caused by four different proteins (Amyloid, Tau, TDP-43, Alpha-synuclein). However, where in the brain these proteins accumulate will determine the clinical symptoms of dementia.

Does it really matter to classify dementias via clinical symptoms or proteins?

It does, as it depends how we treat dementia .

If we want to treat the symptoms of the disease, as most clinicians and healthcare professionals currently do, then the clinical subtypes are clearly more important. It is less relevant which proteins are underlying the clinical subtypes as we are more interested in alleviating the symptoms of the people with dementia.

However, for scientists who develop new treatments for dementia, the clinical types of dementia are less relevant, as they want to treat the underlying proteins causing these symptoms. Most scientific treatment approaches are to slow down or stop the proteins accumulating for the different dementias, so it is more important to know which proteins are accumulating in people with the disease than their clinical symptoms.

Classifying dementia via clinical symptoms or proteins is, therefore, ‘different sides of the same coin’ – though admittedly 15 clinical sides versus 4 proteins sides. Both classifications are valid approaches but with very different purposes.

The future

We can see that historically there has been and still is a stronger emphasis on the clinical types of dementia. However, the ground is shifting as classifying or diagnosing dementia by the underlying proteins will become more relevant in the near future.

The main reasons are that currently blood tests are developed which can measure the underlying proteins in people at risk of dementia or with early symptoms. Further, virtually all new medication development for dementia targets the accumulating proteins of the difference dementias.

This raises the question as to whether in the future we will need the clinical classification of dementia at all if we can diagnose and treat dementia via the proteins. Clearly, this is a deliberately controversial question but knowing that there are key differences as to how we classify dementia should make clear that clinical and scientific approaches towards dementia can be very different.

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