What is Alzheimer's disease? - Chapter 19

What does Alzheimer's disease look like?

What is the prevalence?

Alzheimer's disease is the most common type of dementia. Progressive memory disorders are the most distinctive symptoms of this neurodegenerative disorder. The memory impairments gradually increase as the illness slowly creeps in. The diagnosis of dementia due to Alzheimer's disease is made if two or more cognitive domains are affected. Global cognitive deterioration is involved in a later stage of the disease. Neuropsychiatric symptoms such as depression, apathy, and anxiety also occur frequently. After the onset of the disease, a patient lives on average about seven to eight years. Prevalence will increase in the coming years due to two factors, collectively referred to as 'double aging': there are more elderly people who are getting older and older (the average life expectancy is increasing). As you get older, there is a high chance of developing Alzheimer's. Both the prevalence and the incidence double with every five years of life increase (0.8% in the 65-69 category; 28.5% in the 90+ category). However, dementia can also develop at an early age (before the age of sixty-five).

What are the risk factors?

The main risk factor is higher age. The second risk factor is being a woman. The third risk factor is related to genetic predisposition, although the non-familial (sporadic) form is more common.

What does Alzheimer's disease look like clinically?

The diagnosis of Alzheimer's disease is made “per exclusionem”: if all other causes of cognitive decline are excluded, this diagnosis remains. A more inclusive approach is discussed later. First, the severity of the symptoms is determined (syndrome diagnosis); is dementia present or not? If this is found to be the case, the next question concerns the type of dementia that is present (etiological diagnosis). The NIA-AA criteria make a distinction between a low, medium or high probability to underlying Alzheimer pathology. A definite diagnosis can be made post-mortem when the neuropathological characteristics of Alzheimer's disease have been demonstrated during an autopsy or when a genetic mutation is present. In the DSM-5, a distinction is made between extensive neurocognitive disorder (dementia) and minor neurocognitive disorder (mild cognitive impairment).

What is a mild cognitive impairment?

Sometimes the development of dementia is preceded by 'mild cognitive impairment' (MCI). In the case of 'amnestic MCI' there are disorders within episodic memory; in a 'non-amnestic MCI' the impairments are found in a different domain. If there are impairments in multiple domains, this is referred to as an 'MCI in various domains'. The risk of developing Alzheimer's disease seems to be highest in patients with the amnestic type of MCI. Dementia develops in 10-15% of patients with MCI within the first five years. However, many patients remain stable or even recover.

What is Alzheimer's neuropathology?

Plaques and tangles

Alzheimer's neuropathology covers senile plaques (accumulations of the amyloid beta-protein between brain cells) and neurofibrillary tangles (entanglements of the tau protein in brain cells). Both induce cell death and atrophy (shrinkage) of the brain.

Amyloid cascade hypothesis

The amyloid-cascade hypothesis (AC hypothesis) is the best known hypothesis about the pathogenesis of Alzheimer. This hypothesis assumes that the first step in the development of Alzheimer's disease is the abnormal cleavage of the APP. This creates an imbalance between the production and breakdown of amyloid beta protein, as a result of which this protein starts to aggregate and form plaques. At a later stage the tangles of the tau protein are added: the tau proteins correlate strongly with the severity of dementia. There is no medicine yet.

Vascular hypothesis

Many Alzheimer's patients have mixed pathology: they have the neuropathological characteristics of Alzheimer's but also have cerebrovascular damage. Younger patients more often have the pure form of Alzheimer's disease. The vascular hypothesis states that vascular damage contributes to Alzheimer's disease, and is an addition to the AC hypothesis.

What is the neuropsychological picture of Alzheimer's disease?

How is the disease diagnosed?

A clinical interview with someone who knows the person with suspected dementia well is very important in diagnosing Alzheimer's disease. The first impression of cognitive functioning is made using the MMSE (Mini-Mental State Examination). 

What are the neuropsychological symptoms?

The best known symptom is having memory problems. The gradual increase in memory impairments is caused by the atrophy of the medial temporal lobe (which also includes the hippocampus). The pattern in which a patient goes from cognitive decline in two domains to a general cognitive decline varies per person. During the initial phase there often is an anterograde episodic memory disorder. Retrograde memory impairment develops in a later stage. Impairments in sense of orientation and language are also common in the initial stage of the illness. Shortages in executive functioning (attention and cognitive flexibility) occur when the disease develops, and get worse as the disease progresses and the tasks become more complex. Apraxia and visual-perceptual (both visual-spatial perception and visual shape and object recognition) disorders can also occur.

What types of dementia are there?

With Alzheimer's disease, memory problems are most prominent; this is less the case in dementia with Lewy bodies. Impairments in language are the core symptom of semantic dementia and primary progressive aphasia. Slowness and decreased mental flexibility are mainly associated with vascular dementia. The division between cortical dementia or subcortical dementia is no longer made because the symptoms do not adhere to such neuroanatomical substrates.

Can Alzheimer's disease be seen as a single entity?

Alzheimer's disease has a typical and atypical course. In the typical course memory impairments are the prominent feature; the atypical variant often reveals at an early age (around 55) and is characterized by language or visual-spatial disorders. Alzheimer's is more progressive in younger patients (van der Vlies and colleagues, 2009). 'Posterior cortical atrophy' (PCA) is the visual form of Alzheimer's (visual dysfunctions but memory and executive functions are intact).

Neuropsychiatric symptoms

Behavioral changes and changes in mental state are among the neuropsychiatric symptoms. These symptoms are very common in dementia patients, but often decrease in the long term due to reduced anosognosia.

What changes occur in the brain?

Diagnosis of Alzheimer's disease is completely dependent on clinical manifestations, but neuroimaging using either CT or MRI is often part of the diagnostic work-up. An atrophy of the medial temporal lobe (and therefore the hippocampus) is a feature consistent with Alzheimer's. The degree of atrophy is determined on the basis of Scheltens visual rating scale (this is a five-point scale, a score of 2 or more indicates atrophy). General atrophy occurs at a later stage. In young patients, atrophy is limited primarily in the parietal areas. Often there is also damage to the small vessels in the form of microbleeds, lacunar infarcts (small infarcts in the areas of the smaller blood vessels in the deeper tissues) and whit matter anomalies. EEGs have shown that Alzheimer's patients often have a diffusely delayed EEG: more slow waves and less fast waves. A specific PET scan has shown that the temporo-parietal areas are less active compared to healthy controls. A new type of PET is amyloid PET: for the first time it is possible to visualize the accumulation of amyloid beta in a living subject.

Treatment with cholinesterase inhibitors

Cholinesterase inhibitors are prescribed to reduce symptoms in mild to moderate Alzheimer's disease. The cholinesterase inhibitors ensure that acetylcholine is broken down less quickly and therefore stays in the synapse longer. If the disease stabilises for six months, the treatment has been successful. The effect is therefore small and there are annoying everyday side effects such as diarrhea and nausea.