Distinct tau PET imaging patterns in typical and atypical Alzheimer’s disease
Abstract
This scientific commentary refers to ‘Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease’, by Ossenkoppele et al. (doi: 10.1093/brain/aww027 ). Specific protein inclusions define most neurodegenerative diseases at the pathological level. Alzheimer’s disease is characterized by abnormal extracellular amyloid-β deposits associated with intraneuronal tau aggregation in the cell body (neurofibrillary tangles), in the dendrites (neuropil threads) or in the axons of the senile plaque corona. In typical Alzheimer’s disease, the progression of cognitive deficits is consistent with the extension of tau pathology from the medial temporal regions (entorhinal cortex, parahippocampal gyrus and hippocampal formation) through the neocortical associative areas, resulting in early progressive impairment of episodic memory followed by aphasia, apraxia and agnosia. Aside from this common presentation, some patients with a diagnosis confirmed at post-mortem present with atypical clinical symptoms such as primary progressive aphasia, usually of the logopenic type, visuo-spatial deficits (posterior cortical atrophy), or predominant dysexecutive (frontal) syndrome ( Alladi et al. , 2007 ). In addition, age of onset influences the clinical presentation. In early onset Alzheimer’s disease, temporo-parietal cortical damage is predominant with relative sparing of episodic memory, whereas greater medial temporal lobe atrophy and severe amnesia have been observed in late onset Alzheimer’s disease ( Hamelin et al. , 2015 ). In this issue of Brain , Ossenkoppele et al. (2016) study the heterogeneity of tau deposition in patients with clinical variants of Alzheimer’s disease by using molecular PET imaging to examine the underlying biological mechanisms in vivo . Recent advances in Alzheimer’s disease biomarkers provide information about the pathophysiological process associated with the disease, and make it possible to go beyond the clinical diagnosis. Biomarkers are classified into two major categories: (i) biomarkers of amyloid-β accumulation, namely high tracer retention on amyloid PET imaging and low CSF amyloid-β; and (ii) biomarkers of neuronal degeneration or injury, namely increased CSF tau (both total and phosphorylated tau), decreased FDG uptake on PET, and atrophy on structural MRI ( Albert et al. , 2011 ) ( Fig. 1 ). In Alzheimer’s disease, biomarkers of neuronal injury are thought to reflect tau pathology or its consequences. Until now, the only component of the Alzheimer’s disease pathophysiological process that could be imaged by PET was fibrillar amyloid deposition. Recently, new PET ligands have been developed that can be used to identify and quantify the spatial and temporal pattern of tau pathology ( Villemagne et al. , 2015 ). Coupling amyloid and tau PET imaging provides a unique opportunity to assess both proteinopathies in the same patients. Alzheimer’s disease is associated with accumulation of two main misfolded proteins. Amyloid deposition precedes clinical symptoms by a decade or more. Its progression in the human brain (from neocortical regions to cerebellum) does not mirror the clinical progression of symptoms in Alzheimer’s disease. Amyloid pathology can be assessed by amyloid PET imaging and by measurement of amyloid peptide 1–42 in CSF (pathophysiological biomarkers, in red). Circumscribed tau accumulation has been described in young healthy subjects in subcortical regions. The progression of tau pathology is closely correlated with cognitive deficits. In typical Alzheimer’s disease, neurofibrillary degeneration is identified in areas critical for episodic memory, such as medial temporal regions. As the condition progresses, cognitive deficits occur in various domains (language, praxis, visuospatial), which is consistent with the extension of lesions into neocortical associative areas. In atypical Alzheimer’s disease, tau pathology preferentially occupies brain areas that are critical for the cognitive functions specifically affected in the distinct variants. Tau pathology can be assessed by tau PET imaging and by measurement of tau levels in CSF (pathophysiological biomarkers, in red), and indirectly by regional cortical hypometabolism using FDG-PET, regional cortical atrophy using structural MRI, and the pattern of cognitive impairment. Unresolved questions concerning the chronology of the pathophysiological events and the interactions between amyloid-β (Aβ) and tau pathologies are indicated with question marks. LOAD = late-onset Alzheimer’s disease; EOAD = early-onset Alzheimer’s disease; PPA = primary progressive aphasia; PCA = posterior cortical atrophy. Ossenkoppele et al. examined the regional pattern of tau deposits in various clinical presentations of Alzheimer’s disease using the novel PET tracer 18 F-AV1451. This tracer was found to bind selectively to tau lesions composed primarily of paired helical filaments, such as intra and extraneuronal tangles and dystr
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Recent work has provided insights into the heterogeneity of AD by characterizing different subtypes of tau deposition patterns, which can be relevant for individually adapted prognosis.
“Even though tau pathology often spreads in a distinct spatial pattern, recent work has provided insights into the heterogeneity of the disease by characterizing different subtypes of the tau deposition patterns, which can be of relevance for an individually adapted prognosis. 19 , 20”
From Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data (2025) · cites this paper as [20]
Variance in distribution and burden of tauopathy in AD is closely associated with clinical phenotype, cognitive deficit, and rate of cognitive decline.
“Variance in the distribution and burden of tauopathy in AD is closely associated with the clinical phenotype, 13 cognitive deficit, 14 and rate of cognitive decline. 15”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [13]
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“One of them is its limitation in reflecting the various and atypical spatial patterns of tau accumulation in PET [30, 31].”
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Image-level trajectory inference of tau pathology using variational autoencoder for Flortaucipir PETPreprint
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- Authors
- Sarazin, M., Lagarde, J., & Bottlaender, M.
- Affiliations
- Inserm (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-04-26
- Volume
- 139
- Issue
- 5
- Pages
- 1321-1324
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2343379702
- Cited by
- 20
- References
- 14
- Citations by year
- 2026: 1 · 2025: 4 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2018: 4 · 2017: 3 · 2016: 2
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- Alzheimer's disease, tau PET imaging, atypical Alzheimer's disease, primary progressive aphasia, posterior cortical atrophy, frontal lobe syndrome, neurofibrillary tangles, neuropil threads, amyloid-beta, CSF tau, FDG-PET, neurodegeneration biomarkers, clinical heterogeneity, age of onset, medial temporal lobe atrophy
- MeSH terms
- Alzheimer Disease, Brain, Humans, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography
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