More common in the elderly but may occur in early adult life. Smoking seems protective (but of course owing to its association with vascular dementia is hardly a good thing !)
It is a complex polygenetic and environmental related neuropathology. The characterised molecular mechanisms have been summarised.
- Family Hx
- Head injury or other CNS insult
- Familial AD is autosomal dominant
- Down’s Syndrome
- Apolipoprotein E gene (associated with faster neurodegeneration in a range of neuropathologies)
- ε2 is under-represented in AD (but also has earlier mortality from ischaemic heart disease)
- ε4 is common
In common with all dementias, the main feature is neuronal cell loss, leading to the decline in cognitive functioning. The characteristic histopathological changes of diffuse and neuritic amyloid plaques and neurofibrillary tangles are not correlated fully with neuron loss which is believed to be owing to secondary inflammatory or other processes and thus cognitive function. Some familial cases associated with cerebral amyloid angiopathy and early onset with APP gene mutations.
The underlying mechanism may be a defect in transport of beta-amyloid away from the brain rather than an excess production of it, and receptors or transport protein infused into the sufferer might prevent progression.. The mechanisms that result in dementia are not straight forward and are definitely modulated by genetics and the environmental milieu. The postulated causal associations with β-amyloid, tau protein, neurotrophin depletion, inflammation, nerve damage, calcium regulation loss, cholesterol metabolism, axional-transport derangement, oxidative stress, insulin signalling and synaptic dysfunction amongst others will need to be proved by the success of therapeutic interventions that target these.
- Gradually increasing forgetfulness, behavioural changes, wandering, agitation, aggression
- Paranoia / persecutory delusions
- Cognitive decline - amnesia, aphasia, agnosia, apraxia
- Amnesia is an early change, with recent memories lost before remote memories. Initially problems are with acquisition or retrieval of memory, but remote memory is lost with disease progression.
- Nominal aphasia occurs earliest, with circumlocutions, repetitions & alternative wordings. Syntax becomes affected with paraphasia, receptive aphasia can develop. The final stages involve perseveration, echolalia, non-speech utterances
- Agnosia refers to the inability to name or recognise familiar objects. Prosopagnosia & autoprosopagnosia (mirror sign) may develop
- Apraxia occurs in the moderate stages of the illness. Difficulties with dressing & in kitchen may be noticed first but are preceded with difficulties with more complex tasks
- Other cognitive impairments include
Cognitive impairment is the main feature but in later disease primitive reflexes and mild parkinsonism or other neurodegenerative manifestations are possible.
None are specific although cerebral neuroimaging can be suggestive. Most should be done to exclude other pathologies. Focal atrophy on MRI of the inferior temporal region is suggestive. Neither serial cerebral MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid compound binding SPECT or PET, reduced CSF beta-amyloid nor increased CSF tau protein are useful in routine clinical practice presently.
None of the acetylcholinesterase inhibitors presently available works brilliantly. Memantine seems to be even less effective. The issue remains a controversial one between health economists, patients, their careers and physicians but in terms of clinical effectiveness we now know that the acetylcholinesterase inhibitors work in mild to severe dementia.
The acetylcholinesterase inhibitors and any sedative or drug with sediative side-effects may work. However many sedatives have significant potential side effects. Examples include:
- Paradoxical activation with Benzodiazepines
- There is a long history of problems with increase mortality with antipsychotics such as thoridazine now withdrawn, repeated more recently with the atypical antipsychotics where stroke and myocardial events are definitely increased with olanzapine and risperidone which do however act on behaviour better than placebo so are likely to be ineffective or harmful.
Out of desperation antipsychotics, and more recently in long term use atypical antipsychotics are often resorted to. These drugs may benefit the psychosis but net benefit in the long term is unclear despite widespread use.. Indeed we now know that compared to placebo in long term use, olanzapine , risperidone and quetiapine are likely to be ineffective or harmful.There is RCT evidence that quetiapine is better tolerated than haloperidol. Recent observational studies suggest that long term use of typical antipsychotics in this population may cause similar risks.
Although there is interesting work on agents to prevent evolution of the condition from mild cognitive impairment we know:
- Treating hypertension works best
- NSAIDs/COX 2 inhibitors - Harms outweigh benefits (indeed the relevant RCTs confirmed the risk of cardiovascular events)
- Statins - High dose may work but net benefit traded against harm and cost unknown
- Ginkgo - No net benefit.
- Drugs for Alzheimer's Disease, Therapeutics Letter
- Implications of AD2000 for the treatment of Alzheimer's disease, MeReC
- Galantamine (Reminyl) prolonged-release capsules for dementia in Alzheimer’s disease, National Prescribing Service, Australia
- Alzheimer's disease - donepezil, rivastigmine and galantamine, NICE
- For RCTs regarding Alzheimer's disease, click here.
- For systematic reviews regarding Alzheimer's disease, click here.
- Can curry cure Alzheimer's disease?
- ↑ http://npg.nature.com/nm/journal/vaop/ncurrent/full/nm1635.html Very new work, unevaluated.
- ↑ Carson S, McDonagh MS, Peterson K. A systematic review of the efficacy and safety of atypical antipsychotics in patients with psychological and behavioral symptoms of dementia. Journal of the American Geriatrics Society. 2006;54:354-61. (Direct link – subscription may be required.)
- ↑ Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003476. Review.
- ↑ Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2006;14:191-210. (Direct link – subscription may be required.)
- ↑ Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. The New England journal of medicine. 2006 Oct 12; 355(15):1525-38.(Link to article – subscription may be required.)
- ↑ Tariot PN, Schneider L, Katz IR, Mintzer JE, Street J, Copenhaver M, Williams-Hughes C. Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2006 Sep; 14(9):767-76.(Link to article – subscription may be required.)
- ↑ Trifirò G, Verhamme KM, Ziere G, Caputi AP, Ch Stricker BH, Sturkenboom MC. All-cause mortality associated with atypical and typical antipsychotics in demented outpatients. Pharmacoepidemiology and drug safety. 2007 May; 16(5):538-44.(Link to article – subscription may be required.)