Vogel JW, Young AL, Oxtoby NP, Smith R, Ossenkoppele R, Strandberg OT, La Joie R, Aksman LM, Grothe MJ, Iturria-Medina Y, Alzheimer’s Disease Neuroimaging Initiative, Pontecorvo MJ, Devous MD, Rabinovici GD, Alexander DC, Lyoo CH, Evans AC, Hansson O. Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med. 2021 May;27(5):871-881. Epub 2021 Apr 29 PubMed.

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  1. To lump or to split? While Alzheimer’s disease is typically considered a late-onset, slowly progressive, amnestic syndrome, clinicians have long recognized substantial clinical heterogeneity. While in large part this may relate to the co-occurrence of other pathologies, including vascular disease, TDP43, and Lewy bodies (Boyle et al., 2018), even relatively “pure” AD may present with distinct phenotypes, including posterior cortical atrophy (the visual variant of AD), logopenic aphasia (early speech impairment), and rare cases of dysexecutive/behavioral AD and corticobasal syndrome AD (Graff-Radford et al., 2021). These variants, often overrepresented in young-onset cases, are associated with differential patterns of atrophy and tau deposition, and possibly also with different epidemiological, molecular, and genetic underpinnings (Graff-Radford et al., 2021). 

    Emerging evidence from pathological (Murray et al., 2011) and neuropsychology studies have shown, however, that while these clinical phenotypes may be extremes, even within so-called “typical AD” there is substantial heterogeneity. The advent of powerful computing techniques such as Subtype and Stage Inference (SuStaIn), has further advanced the ability to tease out subtypes in a data-driven manner. SuSTaIn was initially applied to MRI and neuropsychology data, parsing typical AD cases into three different subtypes (Young et al., 2018). 

    In this latest paper, Vogel and colleagues apply this powerful technique to a number of cohorts with tau PET data, providing evidence for the existence of four different subtypes—limbic, medial-temporal sparing, posterior, and lateral temporal variants—each with allied clinical and cognitive profiles, different longitudinal outcomes, and different predicted epicenters of tau deposition and spread (Vogel et al., Nature Medicine, in press). For those interested in atypical AD, the fact that the latter two subtypes appear to overlap with PCA and LPA, respectively, is of particular interest; but these intriguing findings have wide-ranging implications for the field of AD research more generally.

    From a purely clinical standpoint they question the existence of “typical AD,” reinforce the need for careful clinical phenotyping, and suggest that subtyping may in due course allow for more individualized approaches to patient care and prognostication. From a basic science and clinical translational perspective, they demonstrate that simple one-size-fits-all staging models cannot capture the complexity of AD, suggesting instead a more complex scheme combining age, disease duration, and spatiotemporal tau distribution; defining and studying subtypes in this way may provide novel insights into pathological mechanisms including selective vulnerability and mechanisms of spread. For diagnostic frameworks, they reinforce the (known) limitations of categorizing individuals simply on the basis of presence/absence of AD pathologies—even before accounting for co-pathologies. And for clinical trialists the fact that different subtypes may have different clinical presentations, rates of progression, patterns of spread, and perhaps subtly differences in pathophysiology may lead to more bespoke clinical studies targeting not just different stages but different subgroups of AD.

    References:

    Boyle PA, Yu L, Wilson RS, Leurgans SE, Schneider JA, Bennett DA. Person-specific contribution of neuropathologies to cognitive loss in old age. Ann Neurol. 2018 Jan;83(1):74-83. Epub 2018 Jan 14 PubMed.

    Graff-Radford J, Yong KX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, Rabinovici GD, Schott JM, Jones DT, Murray ME. New insights into atypical Alzheimer's disease in the era of biomarkers. Lancet Neurol. 2021 Mar;20(3):222-234. PubMed.

    Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. PubMed.

    Young AL, Marinescu RV, Oxtoby NP, Bocchetta M, Yong K, Firth NC, Cash DM, Thomas DL, Dick KM, Cardoso J, van Swieten J, Borroni B, Galimberti D, Masellis M, Tartaglia MC, Rowe JB, Graff C, Tagliavini F, Frisoni GB, Laforce R Jr, Finger E, de Mendonça A, Sorbi S, Warren JD, Crutch S, Fox NC, Ourselin S, Schott JM, Rohrer JD, Alexander DC, Genetic FTD Initiative (GENFI), Alzheimer’s Disease Neuroimaging Initiative (ADNI). Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference. Nat Commun. 2018 Oct 15;9(1):4273. PubMed.

    View all comments by Jonathan Schott

  2. In this very nice work Vogel, Hansson, and colleagues found that in a large number of individuals with underlying AD pathology, four general patterns of tau pathology were observed based on tau-PET scans. These patterns were linked closely to the four types of clinical/anatomic patterns of cognitive decline seen in people who develop AD—1) amnestic/limbic; 2) non-amnestic cortical; 3) posterior cortical atrophy; and 4) logopenic aphasia.

    Some previous pathological data, as well as more recently published clinical/tau PET data, have strongly suggested that these clinical patterns that are seen correlate well with the presence of tau pathology in specific areas of the brain that subserve the cognitive functions that decline. This large study strongly confirms and extends previous findings that these clinical patterns generally correspond well with tau accumulation in these different patterns, and it characterizes these patterns extremely well using advanced biostatistical techniques.

    The findings have important implications for trying to better understand what leads to these different patterns mechanistically. In addition, in clinical trials, if they can be identified via both clinical and biomarker criteria with tau imaging, it will be important to determine if the different subtypes respond differently to different treatments.

    View all comments by David Holtzman

  3. This is impressive work by Vogel and colleagues. It is very supportive of a line of investigation that we have been conducting that focuses on understanding individual variability in dementia using data-driven approaches coupled with detailed clinical phenotyping.

    Using independent component analysis (ICA) of tau-PET scans, we found five patterns of tau deposition (Jones et al., 2017). Only one of these patterns was "typical"; the others were atypical and associated with younger age-of-onset, just as Vogel reports. One of the most striking patterns was nearly identical to a brain network associated with executive functioning (i.e., working memory) that we previously found in a data-driven analysis of functional MRI in 892 cognitively normal subjects in the Mayo Clinic Study of Aging (Jones et al., 2012).

    After observing this network in functional MRI data, we began noticing this same pattern in FDG-PET scans of patients that we were seeing in our clinical practice. These individuals were younger than typical Alzheimer’s disease patients and had striking clinical features related to working memory dysfunction. They also did not have significant atrophy in the hippocampus. It became clear that these striking cases were a variation on a theme of predominate and early executive dysfunction as the defining clinical feature. We then defined the clinical construct of a progressive dysexecutive syndrome and collected our clinical experience with these cases in a recent manuscript (Townley et al., 2020). It should be emphasized that we focused only on individuals with biomarker evidence of AD, but other degenerative diseases can present with a progressive dysexecutive syndrome (Jones, 2020).

    These individuals with positive AD biomarkers that met our criteria for a progressive dysexecutive syndrome had the exact same characteristics as the "S2 variant" described by Vogel and colleagues. They had less hippocampal atrophy, younger age-of-onset, were less likely to be ApoE4-positive, and multimodal imaging showed greater involvement of parieto-frontal brain regions on MRI, FDG-PET, and tau-PET. We also had detailed postmortem autopsy studies that showed that these cases had pathologically defined hippocampal sparing AD (Murray et al., 2011). We have also observed these relationships using hierarchical clustering of tau-PET and clinical-characteristic-based subcategorization (Lowe et al., 2018).

    We also recently conducted a data-driven analysis of 492 patients on the AD spectrum, and have found that the imaging heterogeneity can be explained by a low-dimensional manifold we have termed the Global Functional State Space (Jones et al., 2020). The dysexecutive AD patients, or the "S2 variant," showed dysfunction in an extreme portion of the GFSS associated with executive functioning, further validating the clinical construct of dysexecutive AD.

    We also found that all degenerative dementia syndromes exist along a continuum, specifically indexed by the GFSS, and distinct phenotypes occupy the extremes of this landscape.

    References:

    Jones D, Lowe V, Graff-Radford J, Botha H, Wiepert D, Murphy MC, Murray M, Senjem M, Gunter J, Wiste H, Boeve B, Knopman D, Petersen R, Jack C. Patterns of neurodegeneration in dementia reflect a global functional state space. medRxiv November 12, 2020. medRxiv.

    Jones DT. Multiple aetiologies of the progressive dysexecutive syndrome and the importance of biomarkers. Brain Commun. 2020;2(2):fcaa127. Epub 2020 Nov 1 PubMed.

    Jones DT, Graff-Radford J, Lowe VJ, Wiste HJ, Gunter JL, Senjem ML, Botha H, Kantarci K, Boeve BF, Knopman DS, Petersen RC, Jack CR Jr. Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum. Cortex. 2017 Dec;97:143-159. Epub 2017 Oct 3 PubMed.

    Jones DT, Vemuri P, Murphy MC, Gunter JL, Senjem ML, Machulda MM, Przybelski SA, Gregg BE, Kantarci K, Knopman DS, Boeve BF, Petersen RC, Jack CR. Non-stationarity in the "resting brain's" modular architecture. PLoS One. 2012;7(6):e39731. PubMed.

    Lowe VJ, Wiste HJ, Senjem ML, Weigand SD, Therneau TM, Boeve BF, Josephs KA, Fang P, Pandey MK, Murray ME, Kantarci K, Jones DT, Vemuri P, Graff-Radford J, Schwarz CG, Machulda MM, Mielke MM, Roberts RO, Knopman DS, Petersen RC, Jack CR Jr. Widespread brain tau and its association with ageing, Braak stage and Alzheimer's dementia. Brain. 2018 Jan 1;141(1):271-287. PubMed.

    Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. PubMed.

    Townley RA, Graff-Radford J, Mantyh WG, Botha H, Polsinelli AJ, Przybelski SA, Machulda MM, Makhlouf AT, Senjem ML, Murray ME, Reichard RR, Savica R, Boeve BF, Drubach DA, Josephs KA, Knopman DS, Lowe VJ, Jack CR Jr, Petersen RC, Jones DT. Progressive dysexecutive syndrome due to Alzheimer's disease: a description of 55 cases and comparison to other phenotypes. Brain Commun. 2020;2(1):fcaa068. Epub 2020 May 27 PubMed.

    View all comments by David Jones

  4. This study capitalized on cross-sectional tau PET and related data from an extremely large number of research participants in preclinical, MCI, and dementia stages. It used a machine learning algorithm to characterize four spatial patterns of tau-tangle burden and explore the extent to which these patterns are related to the pattern and severity of cognitive characteristics, the presence or absence of the APOE4 allele, and demographic characteristics including sex. The authors suggest implications for clinical course and subsequent tau-tangle deposition. The study supports the suggestion from smaller tau PET studies that the pattern of tau-tangle deposition is more heterogeneous and individually variable than suggested by neuropsychological studies and Braak stage.

    The study raises a number of intriguing questions that could be put to the test or confirmed in future studies. For instance, what accounts for the different patterns of tau-tangle deposition? To what extent does it impact a person’s phenotype? What is its relationship to CSF or plasma p-tau or other biomarker measurements, to age at biomarker and clinical onset or clinical course? How does it fit with pathophysiological progression, or differential response to disease-modifying treatments now in development? To what extent are these patterns related to APOE variants, other genetic and non-genetic risk and protective factors? What implications do the findings have for the size and design of clinical trials, participant enrichment or stratification, the analysis of tau PET images, and their role as a trial endpoint?

    I congratulate the authors for their innovative and thoughtful efforts and this important contribution to the field, and I look forward to seeing ways in which the field can capitalize on the findings to further advance the fight against AD.

    View all comments by Eric M. Reiman

  5. The fact that Alzheimer’s disease (AD) is heterogeneous and that the Braak staging of neurofibrillary tauopathy can be violated has been known for nearly 30 years through work on posterior cortical atrophy and primary progressive aphasia (PPA) (Mesulam, 1982; Mesulam and Weintraub, 1992; Gefen et al., 2012; Rogalski et al., 2016; Hof et al., 1993; Hof et al., 1997; Jagust et al., 1990).

    In approximately 40 percent of cases the progressive and relatively isolated language impairment of PPA is associated with AD neuropathology. When compared to the typical amnestic form of AD (DAT-AD), the form of AD that causes PPA (PPA-AD) is characterized by asymmetric cortical atrophy of the language-dominant (usually left) hemisphere, leftward predominance of neurofibrillary tangles (NFT), no association with ApoE4 as a risk factor, lesser frequency of limbic TDP-43, and closer linkage to familial dyslexia (Mesulam et al., 2021). In some cases, the language cortices have more NFT than limbic areas but in others it is the ratio of cortical-to-limbic NFT that is increased even when the medial temporal NFT density is at Braak stages 5-6. Only few PPA-AD cases are “hippocampal sparing” (Murray et al., 2011) postmortem, but most do have leftward asymmetry of NFT density (Gefen et al., 2012; Mesulam et al., 2021). What is remarkable is the preservation of memory in PPA-AD even when the postmortem shows typical NFT densities at Braak stages 5-6 (Mesulam et al., 2021).

    The jaw-dropping 2,324 tau PET scans analyzed by Vogel et al. and the sophisticated SuStaIn analyses provide high-tech confirmation of heterogeneity in AD. The beauty of this approach is its potential ability to map tauopathy and therefore NFT distribution early in the course of the disease. However, while this obviates the problems of retrospective clinicopathologic inferences based on postmortem analyses, imaging modalities lack the precision of quantitative microscopy. It is also important to keep in mind that NFTs have complicated lifecycles. They emerge as intracellular paired helical filaments (PHFs), destroy the neurons within which they form, and remain as extracellular tombstones of lost neurons. Does the tau PET ligand penetrate the cell and identify nascent NFT at the PHF stage, or does it bind only the tombstones? A better understanding of the cellular correlates of PET ligands will enhance the value of information obtained through these spectacular modalities of molecular imaging.       

    References:

    Mesulam MM. Slowly progressive aphasia without generalized dementia. Ann Neurol. 1982 Jun;11(6):592-8. PubMed.

    Mesulam MM, Weintraub S, F. Boller et al., Editors. Primary progressive aphasia: Sharpening the focus on a clinical syndrome, in Heterogeneity of Alzheimer's Disease. Springer-Verlag: Berlin. 1992

    Gefen T, Gasho K, Rademaker A, Lalehzari M, Weintraub S, Rogalski E, Wieneke C, Bigio E, Geula C, Mesulam MM. Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia. Brain. 2012 May;135(Pt 5):1554-65. PubMed.

    Rogalski E, Sridhar J, Rader B, Martersteck A, Chen K, Cobia D, Thompson CK, Weintraub S, Bigio EH, Mesulam MM. Aphasic variant of Alzheimer disease: Clinical, anatomic, and genetic features. Neurology. 2016 Sep 27;87(13):1337-43. Epub 2016 Aug 26 PubMed.

    Hof PR, Archin N, Osmand AP, Dougherty JH, Wells C, Bouras C, Morrison JH. Posterior cortical atrophy in Alzheimer's disease: analysis of a new case and re-evaluation of a historical report. Acta Neuropathol. 1993;86(3):215-23. PubMed.

    Hof PR, Vogt BA, Bouras C, Morrison JH. Atypical form of Alzheimer's disease with prominent posterior cortical atrophy: a review of lesion distribution and circuit disconnection in cortical visual pathways. Vision Res. 1997 Dec;37(24):3609-25. PubMed.

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    Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. PubMed.

    Mesulam MM, Coventry C, Kuang A, Bigio EH, Mao Q, Flanagan ME, Gefen T, Sridhar J, Geula C, Zhang H, Weintraub S, Rogalski EJ. Memory Resilience in Alzheimer Disease With Primary Progressive Aphasia. Neurology. 2021 Feb 9;96(6):e916-e925. Epub 2021 Jan 13 PubMed.

    View all comments by Marsel Mesulam

  6. Vogel et al. found four patterns of tau pathology based on tau PET scan in a large number of people. This pattern is similar to the one we proposed recently, suggesting four major subtypes of AD:

    (1) Typical AD: frequency about 55 percent, balanced tau NFT counts in hippocampus and association cortex; multidomain amnestic syndrome; low final MMSE scores; high Aβ load in occipital cortex, less in middle temporal and parietal cortex; high burden of WMHs; frequent CAA; frequent APOE4 genotype, and increased Lewy and TDP-43 co-pathologies.

    (2) Hippocampal-sparing AD: relative frequency 17 percent; tau NFT counts preliminary in neocortex; higher rate of cortical atrophy; young onset/death; male sex; nonamnestic syndrome; faster disease progression; most aggressive form; high cognitive reserve; APOE4 neg., low burden of WMHs; marked Aβ PET binding in frontal & parietal cortex; less frequent Lewy & TDP-43 co-pathologies.

    (3) Limbic-predominant AD: relative frequency 21 percent; tau NFT counts predominantly in hippocampus; more severe atrophy in the medial temporal lobe; older age at onset/death; female sex; amnestic syndrome; slow disease progression; greater Aβ PET binding in frontal and parietal cortex; higher burden if WMHs; overloaded cognitive reserve; frequent APOE4 and MAPT H1H1 genotypes; hippocampal sclerosis; frequent TDP-43 co-pathology; less CAA, but more hypertensive angiopathy.

    (4) Minimal atrophy AD: relative frequency 17 percent; no or minimal gray matter atrophy; intermediate age at onset; less intensive cortical tau pathology, but Aβ present; reduced metabolism in parietal cortex; low educational level/cognitive reserve; slow rate of progression; CAA may be present, but increased small vessel disease.

    It is suggested that type 4 progresses to type 2 and further to type 1, as can type 3 progress to type 1, but type 2 can directly progress to type 1.

    These four types appear not to be identical but in many respects similar to those described by Vogel et al. In addition, we should emphasize that only about 40-42 percent of all brains with AD pathology are "pure" AD types, while all the others are complicated by other co-pathologies.

    References:

    Jellinger KA. Pathobiological Subtypes of Alzheimer Disease. Dement Geriatr Cogn Disord. 2020;49(4):321-333. Epub 2021 Jan 11 PubMed.

    Jellinger KA. Neuropathological assessment of the Alzheimer spectrum. J Neural Transm (Vienna). 2020 Sep;127(9):1229-1256. Epub 2020 Aug 1 PubMed.

    View all comments by Kurt A. Jellinger

  7. We would like to congratulate Vogel and colleagues for their interesting article, which confirms, in a large tau PET dataset, the existence of four AD subtypes that are well known from neuropathological and MRI studies, as well as from clinical praxis.

    In our systematic review from 2020, we foresaw that subtyping on tau PET would deliver important data to understand in-life trajectories of AD subtypes discovered at autopsy (Ferreira et al., 2020). During the last three years, several studies have discussed the topic, including one from our own lab, and now the study from Vogel and colleagues (Whitwell et al., 2018; Charil et al., 2019; Jeon et al., 2019; Ossenkopelle et al., 2020; Mohanty et al., 2020). A common thread in all these studies is the existence of between-subject variability in tau PET binding that can roughly be encapsulated into subtypes of prominent cortical tau, prominent medial-temporal tau, and typical AD.

    In our view, the great contribution from Vogel and colleagues is the expansion of the topic in several directions. Firstly, they applied a data-driven method called SuStaIn. In this regard, it is important to enrich the current literature to assess the convergence between different subtyping methods, whether they are data-driven (Whitwell et al., 2018; Jeon et al., 2019; Vogel et al., 2021) or hypothesis-driven (Charil et al., 2019; Ossenkopelle et al., 2020; Mohanty et al., 2020), since the agreement between subtyping methods is currently low (Mohanty et al., 2020). Secondly, the authors assessed the largest cohort to date in a study of this kind, including 443 tau-PET-positive individuals, and a validation using an independent cohort of 469 individuals with a second tau tracer. Thirdly, the SuStaIn method seems to be the closest we can get today to understand the trajectories of tau spreading.

    Should we now forget typical Alzheimer’s? In our view, the study by Vogel and colleagues does not suggest so. The authors nicely show between-subject variability in tau PET binding within a cohort where typical AD is the most common pattern of tau distribution. In our opinion, except for the MTL-sparing AD subtype (prevalence, 17 percent), all other subtypes in the study represent variations within typical AD. We agree that full-blown typical AD does not seem to emerge in earlier SuStaIn stages. This may be due to the large proportion of cognitively unimpaired subjects in their cohort. Nonetheless, all four subtypes do converge into typical AD at advanced SuStaIn stages.

    A remaining question is, what are the underlying mechanisms for the trajectories of these subtypes? Vogel et al. get us closer to an answer, but the mystery cannot be solved using a cross-sectional method such as SuStaIn. To date, only one method for longitudinal clustering has been developed, indicating that many subjects converge into typical AD at advanced disease stages (Poulakis et al., 2021, in print). Longitudinal clustering approaches overcome the assumption that subjects remain in the same subtype when the disease advances, which is unrealistic but is supported by SuStaIn (Yang et al., 2021, in press).

    We find it important to underline the recent recommendation by the IWG group that AD diagnosis is restricted to subjects with both positive AD biomarkers and a specific AD phenotype (Dubois et al., 2021). The current findings should thus be put into that context.

    References:

    Charil A, Shcherbinin S, Southekal S, Devous MD, Mintun M, Murray ME, Miller BB, Schwarz AJ. Tau Subtypes of Alzheimer's Disease Determined in vivo Using Flortaucipir PET Imaging. J Alzheimers Dis. 2019;71(3):1037-1048. PubMed.

    Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, Bejanin A, Bombois S, Epelbaum S, Teichmann M, Habert MO, Nordberg A, Blennow K, Galasko D, Stern Y, Rowe CC, Salloway S, Schneider LS, Cummings JL, Feldman HH. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group. Lancet Neurol. 2021 Jun;20(6):484-496. Epub 2021 Apr 29 PubMed.

    Ferreira D, Nordberg A, Westman E. Biological subtypes of Alzheimer disease: A systematic review and meta-analysis. Neurology. 2020 Mar 10;94(10):436-448. Epub 2020 Feb 11 PubMed.

    Jeon S, Kang JM, Seo S, Jeong HJ, Funck T, Lee SY, Park KH, Lee YB, Yeon BK, Ido T, Okamura N, Evans AC, Na DL, Noh Y. Topographical Heterogeneity of Alzheimer's Disease Based on MR Imaging, Tau PET, and Amyloid PET. Front Aging Neurosci. 2019;11:211. Epub 2019 Aug 20 PubMed.

    Mohanty R, Mårtensson G, Poulakis K, Muehlboeck JS, Rodriguez-Vieitez E, Chiotis K, Grothe MJ, Nordberg A, Ferreira D, Westman E. Comparison of subtyping methods for neuroimaging studies in Alzheimer's disease: a call for harmonization. Brain Commun. 2020;2(2):fcaa192. Epub 2020 Nov 9 PubMed.

    Ossenkoppele R, Lyoo CH, Sudre CH, van Westen D, Cho H, Ryu YH, Choi JY, Smith R, Strandberg O, Palmqvist S, Westman E, Tsai R, Kramer J, Boxer AL, Gorno-Tempini ML, La Joie R, Miller BL, Rabinovici GD, Hansson O. Distinct tau PET patterns in atrophy-defined subtypes of Alzheimer's disease. Alzheimers Dement. 2020 Feb;16(2):335-344. Epub 2020 Jan 4 PubMed.

    Vogel JW, Young AL, Oxtoby NP, Smith R, Ossenkoppele R, Strandberg OT, La Joie R, Aksman LM, Grothe MJ, Iturria-Medina Y, Alzheimer’s Disease Neuroimaging Initiative, Pontecorvo MJ, Devous MD, Rabinovici GD, Alexander DC, Lyoo CH, Evans AC, Hansson O. Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med. 2021 May;27(5):871-881. Epub 2021 Apr 29 PubMed.

    Whitwell JL, Graff-Radford J, Tosakulwong N, Weigand SD, Machulda M, Senjem ML, Schwarz CG, Spychalla AJ, Jones DT, Drubach DA, Knopman DS, Boeve BF, Ertekin-Taner N, Petersen RC, Lowe VJ, Jack CR Jr, Josephs KA. [18 F]AV-1451 clustering of entorhinal and cortical uptake in Alzheimer's disease. Ann Neurol. 2018 Feb;83(2):248-257. Epub 2018 Feb 6 PubMed.

    View all comments by Eric Westman

  8. This is an impressive paper led by Jake Vogel and Oskar Hansson’s group, clearly demonstrating that the spatial patterns of tau pathology are more heterogeneous than commonly thought. In the to-date largest tau-PET sample of 1,612 individuals, they show four relatively common subtypes of tau pathology distribution (i.e., limbic-predominant, MTL sparing, posterior and lateral temporal), thereby questioning the concept of “typical” Alzheimer’s disease. Importantly, these subtypes are not only characterized by heterogeneous tau pathology distribution but also by different clinical characteristics, cognitive profiles, and progression rates, together supporting the view that the spatial distribution and spread of tau pathology is a key driver of clinical AD phenotypes.

    The main finding of the paper matches well with previous postmortem and tau-PET studies, showing that tau pathology patterns can significantly deviate from the typical Braak-staging scheme, as described for early onset AD or rare, clinical AD variants, including logopenic primary progressive aphasia, posterior cortical atrophy, or dysexecutive AD (Murray et al., 2011; Ossenkoppele et al., 2016; Scholl et al., 2017; Sintini et al., 2019; Townley et al., 2020). Similarly, we and others have previously reported considerable heterogeneity in tau-PET patterns in the ADNI sample, with subtype-specific tau spreading patterns (Jones et al., 2017; Franzmeier et al., 2020). 

    While atypical tau distributions previously have been assumed to be relatively rare, the large sample used in the current study clearly illustrates that that tau subtypes are, in fact, relatively common, i.e., between 18-33 percent per subtype, and that rare clinical AD variants (e.g. PCA) may just represent “extreme” variants of these common tau subtypes. This view aligns well with the framework of AD as a spectrum disorder in which primary AD pathology can distribute along different neuronal networks and thus induce different types of cognitive symptoms and phenotypes (see also Jones et al., 2020). 

    The current findings are clinically important, because the heterogeneity in tau pathology may help clinical trials to determine patient-tailored clinical and neuroimaging endpoints, which may increase their sensitivity to detect treatment effects, as suggested by us previously (Franzmeier et al., 2020). The heuristic value of tau-PET subtyping for diagnostic and prognostic purposes will depend on the extent of within-subtype variability compared to between-subtype variability of tau pathology and cognitive profiles. The current work, however, means a big step toward individualized prediction of disease trajectories.

    Furthermore, the work will be important as a starting point for future studies to investigate the origin of different tau trajectories, including developmental predisposition (Rogalski et al., 2008; Miller et al., 2019), or regional vulnerability (Grothe et al., 2018) and their resulting AD phenotypes.

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    Schöll M, Ossenkoppele R, Strandberg O, Palmqvist S, Swedish BioFINDER study, Jögi J, Ohlsson T, Smith R, Hansson O. Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer's disease. Brain. 2017 Sep 1;140(9):2286-2294. PubMed.

    Sintini I, Martin PR, Graff-Radford J, Senjem ML, Schwarz CG, Machulda MM, Spychalla AJ, Drubach DA, Knopman DS, Petersen RC, Lowe VJ, Jack CR Jr, Josephs KA, Whitwell JL. Longitudinal tau-PET uptake and atrophy in atypical Alzheimer's disease. Neuroimage Clin. 2019;23:101823. Epub 2019 Apr 10 PubMed.

    Townley RA, Graff-Radford J, Mantyh WG, Botha H, Polsinelli AJ, Przybelski SA, Machulda MM, Makhlouf AT, Senjem ML, Murray ME, Reichard RR, Savica R, Boeve BF, Drubach DA, Josephs KA, Knopman DS, Lowe VJ, Jack CR Jr, Petersen RC, Jones DT. Progressive dysexecutive syndrome due to Alzheimer's disease: a description of 55 cases and comparison to other phenotypes. Brain Commun. 2020;2(1):fcaa068. Epub 2020 May 27 PubMed.

    View all comments by Michael Ewers

  9. In this important and well-powered tau PET study, Vogel, Hansson, and colleagues discovered four different patterns of tau deposition using machine learning. That individuals with these patterns had different cognitive profiles found in clinical practice supports the clinical relevance of their findings. These phenomenological findings support previous studies showing heterogeneity in the regions where tau deposition predominates in individuals, and raise important aspects to be addressed in subsequent studies, including those related to mechanisms of disease progression (e.g., what is leading to these different patterns of deposition (mechanically), and clinical trial designs. Trials using flortaucipir (FTP) PET uptake in regions of interest as a surrogate should take into account the different tau trajectories that individuals may follow, to try to minimize inter-individual variabilities in the regional rates of tau deposition. A modest rate of tau accumulation in a composite ROI could easily be confused with a therapeutic effect, if the individual's pattern of tau accumulation is not well captured by the chosen ROI).

    It should be noted that it is well known that different tau PET tracers show different patterns of deposition, due to differences in sensitivity to tangles and off-target binding. FTP has repeatedly shown patterns of tau accumulation not very compatible with Braak stages. On the other hand, other tracers may show patterns of accumulation more similar to the patterns proposed by Braak and colleagues. Since factors such as off-target binding cannot be excluded from the results, it would be desirable to replicate their findings using different techniques. The partial replication of their results using RO948 greatly supported their findings, but the fact that RO948 subtypes presented some differences from FTP subtypes emphasizes the importance of future studies designed to refine the “subtypes” proposed.

    This study is certainly a very important contribution to the field and paves the way for subsequent studies designed to replicate and refine these very important findings.

    View all comments by Tharick Pascoal

  10. The article by Vogel and colleagues indicates the existence of four spatiotemporal patterns in Alzheimer’s disease (AD), with a prevalence ranging between 18-33 percent each. The elegance of the SuStaIn approach applied here lies in the fact that these findings are entirely data-driven and not a priori defined by clinical diagnosis. Replication in an independent cohort, using a different PET ligand, reinforced the robustness of the study findings.

    Compared to the seminal neuropathological study on AD subtypes (Murray et al., 2011), this in vivo, data-driven classification confirms in principle the three subtypes described by Murray et al. and splits the “typical AD” group into a posterior variant as well as a lateral temporal variant of AD. These subtypes align well with the most common atypical clinical presentations of AD, i.e., posterior cortical atrophy and logopenic variant of primary progressive aphasia (LV PPA), respectively. In the clinic, the presence of positive amyloid biomarkers (PET or CSF) in atypical AD variants has long been the only indication to prescribe cholinergic medication for a given patient (Mesulam et al., 2019; Schaeverbeke et al., 2017). Thus, the findings of Vogel et al. will help to improve the clinical diagnosis of AD and its subtypes, and to establish more individualized treatment strategies.

    However, co-pathologies should not be forgotten. In addition to tau-based subclassifications, neuropathologists described other pathologies that co-exist in AD, specifically cerebral amyloid angiopathy (CAA), α-synuclein, and TDP-43 pathology (more recently described as LATE-NC) (Josephs et al., 2016; Thal et al., 2003; Toledo et al., 2016). Here, interactions of these co-pathologies with amyloid-β and/or tau pathology have been reported, including interactions with the prion protein (Gomes et al., 2019; Spires-Jones et al., 2017; Tomé et al., 2021). This suggests that these pathologies contribute to the clinical manifestation of dementia in the elderly and probably influence the tau-PET tracer binding pattern. Capillary CAA has previously been identified to indicate a distinct type of AD strongly associated with the presence of the APOE ε4 allele (Thal et al., 2010), which might correspond to the limbic type shown by Vogel et al., given that this subtype was also associated with APOE ε4. On top of that, by focusing on lesion morphology (Josephs et al., 2019) and TDP-43 phosphorylation patterns (Tomé et al., 2020), distinct TDP-43 neuropathological patterns have been identified in AD cases.

    Questions then arise as to whether and how these co-morbid pathologies, and their distributions, are associated with the four subtypes identified by Vogel and colleagues. Is a prediction possible for the underlying neuropathological picture when going beyond tau?

    And still, a caveat to all this needs to be taken into account: Tau PET detects only a small part of the tau pathology observed neuropathologically, which is usually restricted to Braak neurofibrillary tangle (NFT) stage V and VI cases (Soleimani-Meigooni et al., 2020). Therefore, the patterns reported by Vogel et al. are restricted to cases that may already be present with a (nearly) full-blown neuropathological picture of tau pathology related to the Braak NFT stage. However, the neuropathological subtypes defined by Murray et al. do not vary among Braak NFT stages. This indicates, in our opinion, that these AD subtypes do not challenge the neuropathological staging of tau pathology but add specific subtypes on top, which can be diagnosed mainly in an advanced stage of the underlying tau pathology. When focusing on prevention strategies that require a diagnosis of preclinical AD, the tau-PET based subtyping therefore may be of less help.

    Overall, this study may have an important impact on stratifying symptomatic AD patients for clinical trials in order to find the proper subgroup of patients eligible for a given treatment strategy. However, preclinical stages may be missed from these subtyping strategies. Future work will need to focus on the contribution of co-pathologies in these AD subtypes to allow a proper stratification in clinical trials.

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    View all comments by Jolien Schaeverbeke

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  1. Forget Typical Alzheimer's: AI Finds Four Types.

Mutations

  1. APOE C130R (ApoE4)