Donepezil, rivastigmine, galantamine and memantine for ...

Description of underlying health
problem
Dementia is a generic term describing chronic or
progressive dysfunction of cortical and subcortical
function that results in complex cognitive decline.
These cognitive changes are commonly
accompanied by disturbances of mood, behaviour
and personality. 2 AD is the most common cause of
dementia. Other causes of dementia include
vascular dementia (VAD), dementia with Lewy
bodies (DLB) and frontotemporal or frontal lobe
dementia (FLD). 3–5
Dementia in AD is a primary degenerative
cerebral disease of unknown aetiology with
characteristic neuropathological and
neurochemical features. The disorder is usually
insidious in onset and it is difficult to set a clear
threshold on the continuum between normality
and dementia, but this is often defined when
cognitive impairment is sufficient to interfere with
normal social functioning. AD develops slowly but
steadily over a period of several years.
Progression of AD is characterised by a worsening
of cognition (thinking, conceiving, reasoning and
memory), functional ability (e.g. activities of daily
living) and behaviour and mood. Changes in one
or more of these domains and their effects on the
patient and their carers’ well-being provide the
basis for diagnosis, assessing severity and
progression of the syndrome.
Early onset AD
AD is primarily a disease affecting the elderly.
Although largely the same disease, early-onset AD
(EOAD) is AD with an onset before age 65 years.
It is a rare cause of the disease and these people
often have a family history of the disease.
Mutations in three genes have been identified in
those with a strong family history of the disease
[amyloid precursor protein (APP), presenilin-1 and
presenilin-2].
Mixed dementia
Despite a differentiation between VAD and AD,
current evidence suggests there is some degree of
overlap between the two disorders; a proportion of
patients with dementia display both vascular and
Chapter 2
Background
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Health Technology Assessment 2006; Vol. 10: No. 1
AD-type lesions. 6 This is often described as mixed
dementia or atypical dementia.
Risk factors
AD is thought to be caused by many interacting
factors. So far only age, family history and the E4
allele of the APOE gene have been confirmed as
risk factors for the disease. Other potential risk
factors are hypertension, vascular pathology, head
injury and herpes simplex infection. 2
Diagnosis
AD is the most common cause of dementia and its
characteristic insidious onset with slow
deterioration makes diagnosis difficult. In the
majority of cases the diagnosis is one of exclusion;
AD is diagnosed once other causes of dementia
have been excluded. AD is diagnosed on the basis
of a review of a full medical history corroborated
by a close relative or carer, physical examination,
blood investigations and mental state examination,
including cognitive assessment. Definitive
diagnosis of AD requires demonstration of
pathological features in brain tissue such as
degeneration of specific nerve cells and the
presence of neuritic plaques and neurofibrillary
tangles. This is usually made only on post-mortem
examination. Several different diagnostic criteria
for AD have been developed. The most generally
accepted clinical diagnostic criteria are those of
the National Institute of Neurological and
Communicative Disorders and Stroke and the
Alzheimer’s Disease and Related Disorders
Association (NINCDS-ADRDA) 7 (McKhann
criteria), the Diagnostic and Statistical Manual of
Mental Disorders (DSM), currently version IV
(DSM-IV), and the International Classification of
Diseases (ICD-10) (see Appendix 1).
The NINCDS-ADRDA provides clinical guidance
for ‘possible’, ‘probable’ and ‘definite’ diagnosis of
AD. A diagnosis of possible AD is made when no
other disease appears to be primarily responsible
for the dementia or when the onset of symptoms
is not typical of AD. A diagnosis of probable AD
requires a patient to have dementia and a history
and pattern of symptoms consistent with those
generally seen in AD. Definite AD is diagnosed
when evidence is shown through brain biopsy or at
autopsy. The sensitivity and specificity of the
3