Technologies for imaging the pathophysiology of Alzheimer disease (AD) now permit studies of the relationships between the two major proteins deposited in this disease — amyloid-β (Aβ) and tau — and their effects on measures of neurodegeneration and cognition in humans. Deposition of Aβ in the medial parietal cortex appears to be the first stage in the development of AD, although tau aggregates in the medial temporal lobe (MTL) precede Aβ deposition in cognitively healthy older people. Whether aggregation of tau in the MTL is the first stage in AD or a fairly benign phenomenon that may be transformed and spread in the presence of Aβ is a major unresolved question. Despite a strong link between Aβ and tau, the relationship between Aβ and neurodegeneration is weak; rather, it is tau that is associated with brain atrophy and hypometabolism, which, in turn, are related to cognition. Although there is support for an interaction between Aβ and tau resulting in neurodegeneration that leads to dementia, the unknown nature of this interaction, the strikingly different patterns of brain Aβ and tau deposition and the appearance of neurodegeneration in the absence of Aβ and tau are challenges to this model that ultimately must be explained.
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Research described in this article was supported in part by US National Institutes of Health grants AG034570, AG045611 and AG019724. The author is indebted to R. La Joie, S. Landau, A. Maass and G. Rabinovici for their thoughtful comments.
Nature Reviews Neuroscience thanks K. Josephs, P. Matthews and M. Rossor for their contribution to the peer review of this work.
The author serves as a consultant to BioClinica, Novartis and Genentech.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Aβ plaques
Also termed neuritic or senile plaques, Aβ plaques are one of the pathological hallmarks of AD and are composed of aggregates of the Aβ protein that are found at postmortem examination of the brain.
- Neurofibrillary tangles
The other major pathological hallmark of AD, they are composed of aggregated forms of hyperphosphorylated tau protein as intraneuronal paired helical filaments.
- Mild cognitive impairment
(MCI). An intermediate stage between normal cognition and dementia; individuals with MCI usually experience amnesia and are at increased risk of developing AD.
- Amyloid cascade hypothesis
A dominant hypothesis in the AD research field proposing that Aβ generation is the inciting event that leads to subsequent downstream processes of tau deposition and neurodegeneration, eventuating in dementia.
- Default-mode network
(DMN). A canonical resting-state network of the brain that is active when individuals are not engaged in attending to or responding to external stimuli.
Brain regions (or nodes) that have many connections to other brain regions and serve as areas of convergence of information from multiple processing streams.
- Rich club
A group of brain regions (or nodes) that are highly connected to one another and that show a high degree of hub-like connectivity to many other brain regions.
- Braak neuropathological staging
A widely adopted method of classification of tau pathology based on cross-sectional autopsy data that proposes a progression of tau neurofibrillary pathology from the MTL (Braak stages I/II) through a limbic stage (III/IV) to a diffuse neocortical stage (V/VI).
- Apolipoprotein E
(APOE). A polymorphic gene with three alleles; the APOE ε4 allele is a risk factor for LOAD.
- Suspected non-Alzheimer pathophysiology
(SNAP). A descriptive term for evidence of neurodegeneration in the absence of biomarker evidence of Aβ.
- Primary age-related tauopathy
(PART). An autopsy finding reflecting neurofibrillary tau pathology in the absence of Aβ pathology; fairly common in older people and with an unknown relationship to AD.
- Cognitive reserve
A hypothetical construct proposing differences in individual susceptibility to account for why people with similar levels of disease pathology show different levels of cognitive ability.
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Jagust, W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat Rev Neurosci 19, 687–700 (2018). https://doi.org/10.1038/s41583-018-0067-3
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