Approach
The clinical hallmarks of AD are cognitive deficits, identified either by the patient or by a family member or carer. Disease onset is insidious and there is gradual progression of symptoms.
The diagnosis of AD is made clinically. The average sensitivity for clinical diagnosis of probable AD is 81% and specificity is 70%, using post-mortem brain histopathology as the standard.[67]
Work-up for AD includes a complete history, physical examination, and cognitive screening. Neuropsychiatric testing may be necessary in some cases. Reversible causes of cerebral impairment should be excluded with initial laboratory testing and brain imaging.
In one prospective cohort study, the greatest risk factors for dementia were, in decreasing order of severity: age; the presence of one or more APOE e4 alleles; diabetes; mid-life smoking; less than secondary school education; black race; hypertension; and pre-hypertension.[41] Some of these are modifiable risk factors and should be investigated and targeted with appropriate interventions.
History from patient and carer
Accurate diagnosis requires a collateral history from an informant familiar with the patient’s daily function.
The presenting symptom is usually loss of recent memory first, and often difficulty with executive function and/or nominal dysphasia (difficulties in word finding and naming).
Patients also experience loss of episodic memory that is marked by, for example, loss of recall of the names of recent visitors, and may exhibit confabulation, confusion, and marked distortions of memory.
There is a loss of executive function with difficulty in reasoning, abstraction, and judgement. Performing tasks such as planning activities, organising events, and managing money becomes more challenging.
Cognitive deficits may include aphasia (language deficits), apraxia (inability to do tasks), and agnosia (inability to recognise using the senses).
Later in the disease progression, language difficulties are often marked by non-fluent speech, paraphrasing, and conveying information inappropriately.
The Alzheimer's Association has prepared a list of 10 common presenting features that may be helpful in forming a diagnosis. Alzheimer's Association: 10 early signs and symptoms of Alzheimer's Opens in new window
With progression of disease
Deficits in visuo-spatial function (seen as impaired performance in tasks such as clock-drawing, which is also an executive function task) and problems with driving become evident. Features such as prosopagnosia (not recognising familiar faces) and autoprosopagnosia (not recognising oneself in the mirror) tend to develop later in AD.
Progression of disease variably leads to changes in personality and affect. Behavioural abnormalities such as aggression, apathy, disinhibition, paranoia, delusions, hallucinations, and depression may become evident. Wandering, loss of spontaneous speech, incontinence, and the effects of institutionalisation tend to characterise the terminal stages of the illness. As cognitive function declines further, daily activities become so impaired that 24-hour assistance is required.
Cognitive testing
Commonly used tools include the Mini-Mental State Examination (MMSE) and the Blessed Dementia Scale. Several other tools are available for bedside screening (e.g., the Saint Louis University Mental Status examination, Mini-Cog). Saint Louis University School of Medicine: SLUMS Examination Opens in new window Alzheimer's Association: Mini-Cog(TM) Opens in new window The Montreal Cognitive Assessment (MoCA) test can be used to detect mild cognitive impairment.[68] Montreal Cognitive Assessment Opens in new window
Impaired recall, nominal dysphasia, disorientation (to time, place, and eventually person), constructional dyspraxia, and impaired executive functioning are common. The Geriatric Depression Scale should be used to screen for comorbid depression.[69] [ Geriatric Depression Scale Opens in new window ]
Physical examination
Physical examination is mostly unremarkable in the early stages. In advanced disease, patients may appear sloppily dressed, confused, apathetic, and/or disorientated, with a slow, shuffling gait and stooped posture. Findings such as focal neurological deficits, a stepwise course, skin and hair changes, or postural instability point to alternative diagnoses.
Terminal disease is marked by rigidity, and inability to walk and speak. The focus should shift to identifying complications such as infections, complications of dysphagia, risk of falls, and complications of immobility.
Laboratory investigations
Reversible causes of cerebral impairment should be excluded during initial laboratory testing.
Routine laboratory investigations include:
Full blood count
Basic metabolic panel including liver function tests and serum calcium
Thyroid-stimulating hormone
Vitamin B12
Urine drug screen (as appropriate)
Serological testing for syphilis (rapid plasma reagin/Venereal Disease Research Laboratory [VDRL]) in people at risk
HIV testing in people at risk.
Other investigations
Formal neuropsychological testing may be appropriate if there is diagnostic uncertainty. Genetic testing is offered in early onset dementia or when a strong family history is present.[70]
Cerebrospinal fluid (CSF) analysis should be considered when features suggest disorders such as HIV, Lyme disease, herpes infection, or prion disease.
CSF tau and ABeta pathology
A 2017 Cochrane review concluded that there is some uncertainty regarding the value of CSF biomarker measurement (total tau, phosphorylated tau [p‐tau], or p‐tau/ABeta ratio) for identifying which people with mild cognitive impairment will develop AD within a specified period.[71] However, a combination of low ABeta-1-42 and elevated tau or p-tau shows high diagnostic specificity in the context of cognitive changes.[72]
Consensus guidelines recommend using CSF biomarkers as an adjunct to clinical evaluation, for predicting functional decline or progression to AD among people with minor cognitive impairment.[73] Appropriate pre- and post-biomarker counselling is required.[73] CSF biomarker testing may be of some benefit in the differential diagnosis of AD and frontotemporal dementia, although imaging modalities can be used.[74]
Imaging studies
Structural imaging is recommended at least once during the work-up.[75][76]
Radiographical imaging with head computed tomography (CT) or magnetic resonance imaging (MRI) can exclude structural causes of dementia and may be used to assess hippocampal atrophy to support a diagnosis of AD.[77][78] MRI shows greater sensitivity than CT for identifying lesions.[79][80]
Brain Abeta protein deposition
Amyloid positron emission tomography (PET) has been used to detect in vivo Abeta protein deposition in patients with AD. Amyloid imaging with fluorine 18-labelled tracers (18F-florbetapir, 18F-florbetaben, and 18F-flutemetamol) can identify people with mild cognitive impairment who are at greater risk of developing AD.[81][82][83] Among patients with mild cognitive impairment or dementia of uncertain aetiology, the use of amyloid PET imaging has the potential to change clinical management.[84][85] Currently, amyloid PET imaging is primarily used in the research setting or in the evaluation of unusual presentations.
Neuronal degeneration and injury
Disproportionate atrophy on structural MRI in the medial, basal, and lateral temporal lobes, and medial parietal cortex, constitutes one of the clinical criteria for the diagnosis of AD.[86]
Fluorodeoxyglucose (FDG)-PET can distinguish patients with AD from people without AD, and shows characteristic reductions of regional glucose metabolic rates in patients with probable and definite AD.[87] FDG-PET is particularly useful in atypical presentations when imaging results are likely to impact patient care.[88][89]
SPECT and electroencephalogram
Single-photon emission computed tomography (SPECT) imaging is not universally available and is rarely required.[76] SPECT with Tc-99m hexamethylpropyleneamine oxime (HMPAO) shows bilateral temporoparietal hypoperfusion in patients with AD. These changes can occur early in the disease process and may help to distinguish AD from other forms of dementia.[90]
Electroencephalogram (EEG) is rarely a first-line test. Slowing of rhythm is more marked in Lewy body dementia than in AD.[91] EEG has characteristic features in Creutzfeld-Jacob disease and should be sought when temporal lobe signs, other seizure phenomena, or a clinical history suggestive of transient epileptic amnesia are present.
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