Braak stage 1

Braak stage is a measure of how many tangles there are in the brain, and where they are.

Braak stage 1 is the point at which tau protein starts to clump into tau tangles. There are no external symptoms at this stage, and might take another 30 or 40 years before there is noticeable dementia—but from this point, further decline is inevitable.

Nearly everyone will reach Braak stage 1 at some age between 40 and 90 years old. About 30% of 50 year olds have reached Braak stage 1, and about 50% of 62 year olds.

At Braak stage 1, the tau tangles have begun to form in the transitional entorhinal region. This is a "relay station" between the cortex and the hippocampus, which is critical for memory.

Braak stage 2

At Braak stage 2, tau tangles are causing cell death (yellow) in the transitional entorhinal region, a part of the brain that filters sensory input before passing it on to the memory. Tau protein is aggregating in the hippocampus (pink) which is crucial for memory, and in the cortex (blue) which is associated with conscious thought.

By Braak stage 2, tau tangles have accumulated further and have caused some neurons to burst apart and die. However, mental testing still shows minimal impairment. Tangles at this level or worse are found in the brains of about 60% of over-65s.

At this stage the tau tangles are much more extensive in the transitional entorhinal region (highlighted in yellow) and have begun to kill neurons here. This region is a "relay station" where sensory input is filtered before being stored in the memory. Meanwhile, in the brain's hippocampus (pink) and neo-cortex, tau protein is also beginning to aggregate but has not yet formed tangles.

Braak stage 3

By Braak stage 3 tau tangles and neuronal death have likely caused some memory impairment, but only about 10% of patients at this stage will be diagnosed as suffering from dementia. About 45% of 80 year olds have reached this stage.

Tau tangles build up inside brain cells, eventually causing them to explode and die.

At this stage, the tau tangles have begun to cause extensive neuronal death. The mechanism for neuronal death is that the tau tangles grow out of control. They fill up the neuron, causing its membrane to burst. Neuron death is irreversible.

The tau protein has formed extensive tangles in the transitional entorhinal region. In the hippocampus, tau protein has also aggregated and begun to form tangles. And in the neo-cortext, tau protein is beginning to aggregate.

Braak stage 4

Tau tangles have caused the death of many neurons in parts of the brain responsible for memory and spatial orientation, the hippocampus (pink) and the transitional entorhinal region (yellow). These tangles grow out of control inside neurons, eventually causing them to burst and die. Tangles are also starting to form in the neo-cortext (blue), a part of the brain associated with conscious thought and higher brain functions.

By Braak stage 4, even though the tau tangles still occupy only a small portion of the brain, they have caused significant memory and cognitive impairment. 70% of patients with this level of tangles in their brain will be diagnosed as suffering from dementia.

By this stage, the tau tangles have formed extensively in the transitional entorhinal region and the hippocampus where they have caused neuronal death, and they are starting to form in the neo-cortex. The neo-cortex is the largest part of the brain, and is involved in higher functions such as sensory perception, conscious thought and language.

Braak stage: 5

Tau tangles haveformed in many parts of the brain: the hippocampus (pink), the transitional entorhinal region (yellow) and the neo-cortext (blue). They have caused the death of many neurons in these regions, causing severe memory and cognitive impairment.

At Braak stage 5, the tau tangles have caused extensive neuronal death, giving rise to severe memory and cognitive impairment. About 80% of patients with this level of tangles will be diagnosed as suffering from moderate to severe dementia.

Tangles have formed extensively in the transitional entorhinal region, the hippocampus, and the neo-cortex.

Braak stage 6

Average Braak stage, by age

The horizontal axis shows age. The vertical axis shows what percentage of people of that age are expected to have which Braak stage. Tan: Braak stage 1 or higher Sage: Braak stage 2 or higher Red: Braak stage 3 or higher Grey: Braak stage 4 or higher

By Braak stage 6, tau tangles have formed extensively in the transitional entorhinal region, the hippocampus (which is critical for memory), and the neo-cortex.

The tau tangles have caused extensive neuronal death. All patients with this many tangles in their brain will be diagnosed as suffering from severe dementia. They will be completely unable to take care of themselves and will have trouble recognizing family members.

MMSE and Braak stage

MMSE, the Mini Mental State Exam, is a popular brief questionnaire that is used to assess cognitive impairment. If the cognitive impairment is caused by tangles, then it relates to Braak Stage as follows:

	Braak	MMSE	Symptoms
MCI	2–3	26–30	Mild memory loss / impairment Normal cognitive abilities MCI is frequently a precursor to AD, but does not lead to AD in all cases
Mild AD	3–4	20–26	Mild memory loss / impairment Slight decrease in cognitive function Mild behavioural changes (e.g. depression, anxiety)
Moderate AD	4–5	11–19	Progressive memory loss; increasingly disorganized and confused thinking Increasing behavioural symptoms, including agitation, paranoia etc. Need for assistance in daily activities
Severe AD	5–6	0–10	Severe memory loss and dementia Agitation, aggression, paranoia and delusions Loss of motor skills Patients often require hospitalization or long-term care