Abstract and Introduction
Introduction
Alzheimer's disease (AD), the commonest cause of dementia, is estimated to affect over 400 000 people in the UK, with numbers around the world set to rise dramatically as the population ages. Distinguishing AD from other causes of cognitive impairment is important for numerous reasons, including provision of appropriate care and access to medications. As and when disease-modifying therapies become available, the priority for earlier and more accurate diagnosis will increase still further.
An important starting point is the definition of AD. This is not as straightforward as it might seem: concepts of AD have evolved rapidly over recent years, with new criteria proposed as recently as 2011 continuing to provoke debate. Ultimately, a diagnosis of AD requires pathological confirmation. However, even a pathological diagnosis comes with a degree of uncertainty and the pathological phenotype of AD is itself heterogeneous.
Diagnosis in life has until relatively recently depended on very broad clinical criteria dating back to the 1980s, mandating that an individual be 'demented', that is, have progressive impairment of memory and at least one other cognitive domain sufficient to impact on activities of daily living. The new criteria for diagnosis of AD have built on a large body of work demonstrating that biomarkers of AD—including MRI, cerebrospinal fluid (CSF) and positron emission tomography (PET)—may improve diagnostic sensitivity and specificity. The criteria also reflect a growing move to try to achieve earlier diagnosis. The new criteria propose that AD can be diagnosed with different degrees of certainty based on the extent of the cognitive deficits and presence/absence of biomarker abnormalities. These criteria were reviewed recently in this journal.
For the purposes of this article and with the aim of providing a practical guide to the differential diagnosis of AD, we will first consider the 'typical' clinical presentation of late-onset, sporadic, amnestic AD, before reviewing other conditions that can mimic these symptoms. Turning then to the chameleons, we will discuss some atypical or unusual clinical presentations that can be associated with histologically proven AD.
Clinical Features of 'Typical' AD
Although, as with any disease, no two individuals with AD are alike, several core features are sufficiently common to qualify as 'typical'. Affected individuals are usually elderly: the overall prevalence of dementia closely relates to that of AD, its commonest cause. The prevalence roughly doubles every 5 years, from ~1% in 65-year-olds to 69-year-olds to 30%+ in those aged 90 years or more. AD is typically sporadic, that is, the vast majority of patients do not have a family history consistent with autosomal-dominant inheritance. The cognitive deficits of AD are typically insidious rather than rapid in onset, with early problems relating to subtle changes in confidence and the emergence of problems with episodic memory, for example, forgetting appointments and telephone conversations. As the disease progresses, patients develop problems in other cognitive domains including anomia; problems with route finding and orientation; problems with arithmetic (eg, handling money) and spelling; and difficulties with multitasking and problem-solving. Whereas a degree of social withdrawal and depression are common, patients with mild–moderate AD typically have a preserved social façade, without major personality change. Early in the disease course the physical examination is typically normal, although later myoclonus is fairly common. The disease typically slowly and relentlessly progresses over several years, with concomitant impairments in activities of daily living requiring increasing assistance, until the patient eventually becomes dependent. Death occurs after a median of ~7 years, although with considerable variation between individuals. Currently, no investigations are required to reach a diagnosis of AD, although all patients should have blood testing and structural brain imaging as part of the diagnostic work-up. Brain imaging may be normal in the very early stages, but progressive atrophy, usually symmetrical and particularly involving medial temporal lobe structures, is typical. CSF examination is not routinely performed, but would be expected to be acellular and without oligoclonal bands. Where available, testing for CSF β-amyloid (Aβ)1–42 (low) and tau or phosphorylated tau (raised) supports a diagnosis of AD. Although not currently part of routine clinical practice, functional imaging using single photon emission computed tomography (SPECT) or glucose PET typically reveals temporo-parietal hypometabolism. Amyloid deposition can be imaged in vivo using PET combined with C PIB (Pittsburgh Compound B) or a number of relatively new F amyloid tracers, one of which (Florbetapir, or Amyvid) was recently licensed for clinical use in the USA.