Dementia is the clinically observable result of the cumulative burden of multiple pathological insults in the brain. Most elderly patients with dementia have multiple pathological changes underlying their dementia; however, the most common pathological substrate is AD.1,2
The clinical disease stages of AD have been divided into three phases. First is a pre-symptomatic phase in which individuals are cognitively normal but some have AD pathological changes. To some extent, labelling these individuals as having pre-symptomatic AD is a hypothesis rather than a statement of fact, because some of these individuals will die without ever expressing clinical symptoms.3–5
The hypothetical assumption is that an asymptomatic individual with pathological changes that are indicative of AD would ultimately have become symptomatic if he or she lived long enough. Second is a prodromal phase of AD, commonly referred to as mild cognitive impairment (MCI),6
which is characterised by the onset of the earliest cognitive symptoms (typically deficits in episodic memory) that do not meet the criteria for dementia. The severity of cognitive impairment in the MCI phase of AD varies from the earliest appearance of memory dysfunction to more widespread dysfunction in other cognitive domains. The final phase in the evolution of AD is dementia, defined as impairments in multiple domains that are severe enough to produce loss of function.
Recent recommendations have suggested redefining research criteria for AD by labelling individuals with memory impairment plus accompanying biomarker evidence of AD as having early AD.7
These investigators propose eliminating the distinction between pre-dementia (ie, MCI) and dementia, but this is not uniformly accepted because the label “dementia” serves a practical role in clinical practice. A clinical diagnosis of dementia is a clear indication to both the patient and family that the patient has a disorder that precludes independent living and has a decidedly worse prognosis than do milder forms of cognitive impairment, and implies that he or she is on an inevitable course toward complete loss of independence.
The concept of using biomarkers for early diagnostic purposes has a long history, with many studies showing that AD biomarkers can be used to predict conversion from MCI to AD. These prediction studies show that individuals destined to develop AD can be identified earlier in the disease course by use of the MCI designation with the addition of imaging and CSF biomarkers to enhance diagnostic specificity.8–13
However, at present, the clinical diagnosis of AD requires the presence of dementia.14
A widely accepted assumption is that AD begins with abnormal processing of amyloid precursor protein (APP), which then leads to excess production or reduced clearance of β-amyloid (Aβ) in the cortex.15
All known forms of autosomal-dominant AD involve genes that either encode APP itself, or encode protease subunits (PS1 and PS2) that are involved in the cleavage of Aβ from APP to generate amyloidogenic Aβ peptides. By unknown mechanisms, but possibly as a result of the toxic effects of Aβ oligomers,16
one or more forms of Aβ leads to a cascade characterised by abnormal tau aggregation, synaptic dysfunction, cell death, and brain shrinkage.17
The abnormal protein deposits that characterise AD pathologically are well known: Aβ plaques and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau. Neurodegeneration is as important as these hallmark pathological lesions of AD, and manifests as atrophy, neuron loss, and gliosis, which are routinely noted in research post-mortem examinations. Although the loss of synapses also is highly significant for the clinical manifestations of AD, this is difficult to assess without the use of labour-intensive morphometric methods, so it is not routinely measured in most AD research centres. Neurodegeneration and NFT deposition are both neuronal processes and occur in roughly the same topographic distribution. Aβ plaques are extracellular and occur in a different, but to some degree overlapping, topographic distribution from NFT and neurodegenerative pathological changes.
Clinical symptoms are more closely related to NFTs than to plaque formation.18,19
However, the most direct pathological substrate of clinical symptoms is neurodegeneration, and most specifically synapse loss.20
Recent autopsy data have confirmed that gross cerebral atrophy (indicating the loss of synapses and neurons), and not Aβ or NFT burden, is the most proximate pathological substrate of cognitive impairment in AD.5
Panel: Imaging and CSF biomarker categories in Alzheimer’s disease
Brain Aβ-plaque deposition Neurodegeneration
- CSF tau
- Structural MRI