Alzheimer disease is a common neurodegenerative disease, responsible for 60-80% of all dementias, and imposing a significant burden on developed nations. It is the result of accumulation and deposition of cerebral amyloid-β (Aβ) and is the most common cerebral amyloid deposition disease.
Alzheimer disease is the most common cause of dementia, responsible for 60-80% of all dementias 2,7. The prevalence is strongly linked to age, with >1% of 60-64-year-old patients being diagnosed with the condition, compared to 20-40% of those over 85-90 years of age 2.
Risk factors include 2,7:
- advanced age
- female gender
- apolipoprotein E (ApoE) ε4 (epsilon 4) allele carrier status
- current smoking
- family history of dementia
- mutations of amyloid precursor protein
- Down syndrome
In addition to the genetic and environmental factors above, the age of presentation is also influenced by socioeconomic factors 2,4:
- formal education
- occupational status
- social network and family support
Individuals with premorbid higher function/supports are able to compensate for early disease changes to a greater degree and thus present later. Consequently, when well-supported patients eventually present, they tend to have more marked morphological changes on imaging 4.
Traditionally, Alzheimer disease has been clinically characterized predominantly by memory deficits, at least in initial stages. It has become increasingly evident that in addition to the typical presentation, a number of atypical clinical patterns exist, which are nonetheless pathologically Alzheimer disease.
Classical/typical Alzheimer disease
The typical patient with Alzheimer disease will present initially with antegrade episodic memory deficits 1,5. Over time (often years), the disease progresses, with eventual involvement of attentional and executive processes, semantic memory, praxis, and visuoperceptual abilities 1. Neuropsychiatric symptoms are also common and eventually affect almost all patients. These include apathy, depression, anxiety, aggression/agitation, and psychosis (delusions and hallucinations) 2.
Atypical/variant Alzheimer disease
These entities, often recognized clinically well before they were identified to be pathologically identical to Alzheimer disease, are characterized by slowly progressive focal cortical atrophy, with symptoms and signs matched to the affected area 1. Examples include:
- posterior cortical atrophy
- frontal variant of Alzheimer disease
- minority of cases with predominant semantic dementia
Clinical diagnosis is made by identifying a progressive decline in memory both with clinical examinations and neuropsychologic tests and has been historically based on the NINCDS-ADRA criteria, which divides patients according to the certainty of the diagnosis into 5:
- definite: clinical diagnosis and histologic confirmation
- probable: typical clinical syndrome without histologic confirmation
- 81% sensitive, 73% specific 5
- possible: atypical clinical features without histologic confirmation but no alternative diagnosis
Although using longitudinal clinical criteria is highly sensitive in diagnosing a dementia of any type (>90%), they are relatively inaccurate (<70%) in diagnosing Alzheimer disease specifically 3.
Importantly, the NINCDS-ADRA criteria only include imaging and laboratory examination or blood and CSF in excluding other causes.
The only definitive diagnostic test is brain biopsy which in practice is rarely obtained. As such, the combination of clinical features and neuroimaging are usually considered sufficient, although, especially with the recognition of variants, this approach undoubtedly misdiagnoses a significant number of cases.
A number of CSF biomarkers are being used which may further aid in diagnosis. These include beta-amyloid, total tau, and hyperphosphorylated tau 2.
Alzheimer disease is characterized by the accumulation within the brain of cerebral amyloid-β (Aβ or Abeta) forming neuritic plaques, neurofibrillary tangles and eventually progressive loss of neurons 2,7.
Cerebral amyloid-β particularly deposits in association areas of the neocortex, the posterior cingulate and precuneus, as well as the limbic cortex, although the reason for this distribution has not been elucidated 7.
The underlying reason for the accumulation of senile (neuritic) plaques and neurofibrillary tangles remains poorly understood, as does the reason for non-uniform distribution in the cortex.
Although CT is able to demonstrate the characteristic patterns of cortical atrophy, MRI is more sensitive to these changes and better able to exclude other causes of dementia (e.g. multi-infarct dementia) and as such is the favored modality. In addition to structural imaging, molecular imaging with PET is increasingly of value in the diagnosis of Alzheimer disease.
The primary role of MRI (and CT for that matter) in the diagnosis of Alzheimer disease is the assessment of volume change in characteristic locations which can yield a diagnostic accuracy of up to 87% 3. Unfortunately, such volume loss is not apparent early in the course of the disease 7.
The diagnosis should be made on the basis of two features:
- mesial temporal lobe atrophy (particularly the hippocampus, entorhinal cortex and perirhinal cortex) 10
- temporoparietal cortical atrophy
Mesial temporal lobe atrophy can be assessed directly or indirectly. Direct assessment is of hippocampal or parahippocampal volume loss while indirect assessment relies on an enlargement of the parahippocampal fissures. The former is more sensitive and specific but ideally, requires actual volumetric calculations rather than 'eyeballing' the scan 3. These measures have been combined in the medial temporal atrophy score which has been shown to be predictive of progression from mild cognitive impairment (MCI) to dementia 5,6.
Additionally, and particularly relevant to posterior cortical atrophy or early-onset Alzheimer disease, is the presence of parietal atrophy. This is often best seen on the interhemispheric surface of the parietal lobe (see neurodegenerative MRI brain: an approach) by examining the posterior cingulate sulcal and parieto-occipital sulcal size and degree of atrophy of the precuneus and cortical surface of the parietal lobe. This has also been combined into a scoring system (see posterior atrophy score of parietal atrophy a.k.a. Koedam score).
Brain volume measurements, assessed with segmentation, demonstrate that patients with Alzheimer disease have accelerated rates of brain volume loss, typically around twice normal (1% vs ~0.5% per year) 7. This is even more marked in the hippocampi, with affected individuals exhibiting three times the volume loss per year (~4.5% vs ~1.5% per year) 7.
SPECT and PET are able to detect regional hypoperfusion/hypometabolism in a biparietal and bitemporal distribution.
F-18 fluorodeoxyglucose (FDG) PET typically shows bilateral temporoparietal, precuneus and posterior cingulate hypometabolism which is usually symmetric. Uptake may be asymmetric in the early stages. The anterior cingulate, visual cortex (provided the eyes were kept open during uptake time), basal ganglia, thalami, occipital lobes and cerebellum are usually spared. Classically, even late in the disease, the sensorimotor cortices are relatively spared 10. Frontal lobes may be involved in late stage 7.
C-11 Pittsburgh compound B, as well as newer compounds such as F-18 florbetapir (trade name Amyvid), F-18 flutemetamol (trade name Vizamyl), and F-18 florbetaben (trade name NeuraCeq), are PET tracers that bind preferentially to beta-amyloid fibrils and thus may be able to improve the specificity of antemortem diagnosis 8,9, although there is considerable overlap with normal controls 2,7.
With increased cerebral amyloid-β (Aβ) deposition, increased activity is demonstrated in the cortex 7. It is particularly useful in excluding Alzheimer disease as the cause of dementia, as a negative amyloid PET scan renders the diagnosis unlikely 7.
Newer PET agents that bind tau proteins in neurofibrillary tangles are being investigated (e.g. 18F-flortaucipir) which result in increased activity in the expected locations of deposition in Alzheimer disease (hippocampus, entorhinal cortex and temporal and parietal cortex) 7,10. These agents are, however, not specific to Alzheimer disease and will also deposit in other tauopathies (e.g. chronic traumatic encephalopathy and progressive supranuclear palsy) 10.
Treatment and prognosis
There is no cure for this disease; some drugs have been developed trying to improve symptoms or, at least, temporarily slow down their progression.
- cholinesterase inhibitors e.g. donepezil
- partial NMDA receptor antagonists
- medications for behavioral symptoms
- antiparkinsonian (movement symptoms)
- anticonvulsants/sedatives (behavioral)
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Related Radiopaedia articles
Neurodegenerative diseases are legion and their classification just as protean. A useful approach is to divide them according to underlying pathological process, although even using this schema, there is much overlap and thus resulting confusion.
neurodegenerative MRI brain (an approach)
- measurements and ratios
- midbrain to pons area ratio (for PSP)
- Magnetic Resonance Parkinsonism Index (MRPI) (for PSP)
- frontal horn width to intercaudate distance ratio (FH/CC) (for Huntington disease)
- intercaudate distance to inner table width ratio (CC/IT) (for Huntington disease)
- scoring systems
- measurements and ratios
- typical/classical Alzheimer disease
- variant (e.g. posterior cortical atrophy)
- chronic traumatic encephalopathy (CTE)
- corticobasal degeneration
- frontotemporal lobar degeneration (FTLD) (not all are tau)
- Pick disease
- progressive supranuclear palsy (PSP)
- Alzheimer disease
- cerebral amyloid angiopathy (CAA)
- transthyretine-associated cerebral amyloidosis
- neuronal intranuclear hyaline inclusion disease (NIHID)
- TDP-43 proteinopathies
- spinocerebellar ataxias
- Huntington disease
- hereditary spastic paraplegia
- clinically unclassifiable parkinsonism (CUP)
- Unverricht-Lundborg disease
prion diseases (not always included as neurodegenerative)
- Creutzfeldt-Jakob disease (sporadic, variant, familial, and iatrogenic)
- fatal familial insomnia
- Gerstmann-Straussler-Scheinker disease
- variably protease sensitive prionopathy