Clinical update: Alzheimer’s – A number of recent studies targeting the amyloid pathway in Alzheimer’s disease have proved negative, and there is now some doubt as to whether amyloid plays as central a role in the disease as had previously been thought. Experts have recently proposed that amyloid may be a necessary but not sufficient factor for neuro-degeneration to occur.
Alzheimer’s disease (AD) research to date has centred mainly on amyloid proteins as a trigger in the cascade that leads to neuronal cell death. Accumulations of amyloid plaques around the synapses and neurofibrillary tangles in the body of the neurons are two pathological hallmarks of AD. Classic theories – based on the early onset autosomal dominant forms of AD, which account for less than 2 per cent of all Alzheimer’s cases – are related to the processing of amyloid protein.
Amyloid precursor protein is a normal protein in the brain that is transported to the cell membrane and later broken down. What happens in AD is that there is cleaving of this protein at the wrong place. An extra-long form of Amyloid called A beta 42 results. Monomers cluster into oligomers and these cluster further into plaques, which are deposited around the synapses.
“Many disease-modifying therapies have been focused on either preventing the accumulation of amyloid or increasing its clearance,” said Dr Damien Gallagher of The Memory Clinic at St James’s Hospital, Dublin.
Secretase inhibitors have targeted the enzyme that is responsible for cleaving the abnormally long amyloid molecule and some therapies have aimed at stopping these from aggregating together to form neurotoxic oligomers and plaques.
Certain researchers believe that tau protein is the pre-eminent cause of AD, while others believe that abnormally phosphorylated tau occurs as a consequence of the amyloid protein. A vascular ‘camp’ has also gained support, which proposes that amyloid and tau proteins accumulate as a consequence of microvascular injury.
The vast majority of AD occurs in later life and may be accounted for by an interaction between complex genetic and environmental factors. With regard to environmental factors, recent population studies have reported that vascular risk factors in mid-life, such as hypertension, obesity and hypercholesterolemia are associated with an increased risk of developing AD in later life. It is already known that the clinical expression of AD is facilitated by co-morbid cerebrovascular disease. Thus the management of vascular risk factors is important.
There has also been data from population studies suggesting that individuals who are more socially and physically active and engage in more cognitive stimulating activities have a decreased risk of developing dementia and AD. These findings raise interesting possibilities for future strategies to possibly delay or prevent the onset of the disease, although it is unclear as yet whether these relationships may be considered causal, coincidental or are accounted for by external factors.
Short-term memory loss is the first classical hallmark of Alzheimer’s disease, reflecting the involvement of the medial temporal lobe, involved in the consolidation of memories. Alzheimer’s is an insidiously progressive disease and language problems (naming things, recalling the meaning of words and generating words) may become more prominent, as the disease involves the outer part of the temporal lobe – the temporal neo-cortex.
With frontal lobe involvement, patients may have increasing difficulties with planning and organising themselves, and there may be changes in personality, mood, motivation and social judgement. Difficulties with dressing, praxis and skilled motor tasks are also typically associated with parietal lobe involvement. Psychotic symptoms such as paranoia or hallucinations are ordinarily a feature of moderate to severe disease and may reflect pathology in frontal-subcortical circuits.
Instrumental activities of daily living such as managing finances and medication are impaired early on, while skills of basic self-care – such as washing, eating and dressing – are impaired in the later stages.
Medication such as cholinesterase inhibitors, when used appropriately, can enhance patient function, cognition and neuropsychiatric symptoms. Once AD has been diagnosed, cholinesterase inhibitors are the preferred pharmacological treatment. These include donepezil, rivastigmine and galantamine. The glutamate antagonist memantine is used when there is moderate to severe disease and may augment treatment with a cholinesterase inhibitor, usually when there is a Mini Mental State Examination (MMSE) score of 20 or less, although other factors are also considered.
In the Memory Clinic at St James’s Hospital, structured assessment tools quantify the specific pattern of cognitive deficits, functional impairments and features of the underlying disorder. Blood tests and neuroimaging can supplement detailed clinical and neuropsychological assessment and may be organised on an outpatient basis.
Where time is limited, clinical assessment should consist of both a patient and a collateral history, together with a brief cognitive screen. The MMSE may be completed in less than 10 minutes and also serves as a baseline for future visits.
Current research in the area of AD is aimed at finding new and more effective treatments that can disrupt the pathologic cascade of events leading to neuronal dysfunction and cell death. Such treatments are likely to be most effective if used in the earliest symptomatic stages of disease.
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