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  • 1
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    Online Resource
    Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease
    American Medical Association (AMA) ; 2023
    In:  JAMA Neurology Vol. 80, No. 12 ( 2023-12-01), p. 1353-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 80, No. 12 ( 2023-12-01), p. 1353-
    Abstract: Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t  = 3.2 [ P  = .001]; ADNI: t  = 2.7 [ P  = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t  = −3.1 [ P  = .002]; ADNI: t  = −5.6 [ P   & amp;lt; .001]; HABS: t  = −2.2 [ P  = .03]), greater in older individuals (DIAN: t  = 6.8 [ P   & amp;lt; .001]; ADNI: t  = 9.1 [ P   & amp;lt; .001]; HABS: t  = 5.4 [ P   & amp;lt; .001]), and not associated with systemic vascular risk (DIAN: t  = 0.7 [ P  = .40]; ADNI: t  = 0.6 [ P  = .50]; HABS: t  = 1.8 [ P  = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P   & amp;lt; .001). Conclusions and Relevance The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2023.3618
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 2
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    Towards cascading genetic risk in Alzheimer’s disease
    Oxford University Press (OUP) ; 2024
    In:  Brain Vol. 147, No. 8 ( 2024-08-01), p. 2680-2690
    Details
    In: Brain, Oxford University Press (OUP), Vol. 147, No. 8 ( 2024-08-01), p. 2680-2690
    Abstract: Alzheimer’s disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (−). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer’s disease. Here, we investigate whether genetic risk for Alzheimer’s disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer’s Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A−T− status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T− status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T− status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A−T− to A+T−, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70–4.89; P & lt; 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84–1.42; P = 0.53). Conversely, for the transition from A+T− to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05–2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27–2.36; P & lt; 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05–6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87–3.49; P = 0.12). The genetic risk for late-onset Alzheimer’s disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer’s disease, in addition to opening therapeutic windows for targeted interventions.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awae176
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
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  • 3
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    Spatial Extent of Amyloid-β Levels and Associations With Tau-PET and Cognition
    American Medical Association (AMA) ; 2022
    In:  JAMA Neurology Vol. 79, No. 10 ( 2022-10-01), p. 1025-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 79, No. 10 ( 2022-10-01), p. 1025-
    Abstract: Preventive trials of anti-amyloid agents might preferably recruit persons showing earliest biologically relevant β-amyloid (Aβ) binding on positron emission tomography (PET). Objective To investigate the timing at which Aβ-PET binding starts showing associations with other markers of Alzheimer disease. Design, Setting, and Participants This longitudinal multicentric cohort study included 3 independent cohorts: Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) (data collected from 2012-2020), Alzheimer Disease Neuroimaging Initiative (ADNI) (data collected from 2005-2019), and Harvard Aging Brain Study (HABS) (data collected from 2011-2019). In a 3-tiered categorization of Aβ-PET binding spatial extent, individuals were assigned as having widespread Aβ deposition if they showed positive signal throughout a designated set of brain regions prone to early Aβ accumulation. Those with binding in some but not all were categorized as having regional deposition, while those who failed to show any criterion Aβ signal were considered Aβ-negative. All participants who were cognitively unimpaired at their first Aβ PET scan. Main Outcomes and Measures Differences in cerebrospinal fluid (CSF), genetics, tau-PET burden, and cognitive decline. Results A total of 817 participants were included, including 129 from the PREVENT-AD cohort (mean [SD] age, 63.5 [4.7] years; 33 [26%] male; 126 [98%] White), 400 from ADNI (mean [SD] age, 73.6 [5.8] years; 190 [47%] male; 10 [5%] Hispanic, 338 [91%] White), and 288 from HABS (mean [SD] age, 73.7 [6.2] years; 117 [40%] male; 234 [81%] White). Compared with Aβ-negative persons, those with regional Aβ binding showed proportionately more APOE ε4 carriers (18 [64%] vs 22 [27%] in PREVENT-AD and 34 [31%] vs 38 [19%] in ADNI), reduced CSF Aβ1-42 levels ( F  = 24 and 71), and greater longitudinal Aβ-PET accumulation (significant β = 0.019 to 0.056). Participants with widespread amyloid binding further exhibited notable cognitive decline (significant β = −0.014 to −0.08), greater CSF phosphorylated tau 181 ( F  = 5 and 27), and tau-PET binding (all F   & amp;gt; 7.55). Using each cohort’s specified dichotomous threshold for Aβ positivity or a visual read classification, most participants (56% to 100%, depending on classification method and cohort) with regional Aβ would have been classified Aβ-negative. Conclusions and Relevance Regional Aβ binding appears to be biologically relevant and participants at this stage remain relatively free from CSF phosphorylated tau 181 , tau-PET binding, and related cognitive decline, making them ideal targets for anti-amyloid agents. Most of these individuals would be classified as negative based on classical thresholds of Aβ positivity.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2022.2442
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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  • 4
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    Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Neurology Vol. 79, No. 9 ( 2012-08-28), p. 878-882
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 79, No. 9 ( 2012-08-28), p. 878-882
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0b013e3182661d14
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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    detail.hit.zdb_id: 207147-2
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  • 5
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    Insulin-like growth factor binding protein-2 in at-risk adults and autopsy-confirmed Alzheimer brains
    Oxford University Press (OUP) ; 2024
    In:  Brain Vol. 147, No. 5 ( 2024-05-03), p. 1680-1695
    Details
    In: Brain, Oxford University Press (OUP), Vol. 147, No. 5 ( 2024-05-03), p. 1680-1695
    Abstract: Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 [CSF Aβ(+)/t-tau(+)]. In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad398
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
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    SSG: 12
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  • 6
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    Sex-specific modulation of amyloid-β on tau phosphorylation underlies faster tangle accumulation in females
    Oxford University Press (OUP) ; 2024
    In:  Brain Vol. 147, No. 4 ( 2024-04-04), p. 1497-1510
    Details
    In: Brain, Oxford University Press (OUP), Vol. 147, No. 4 ( 2024-04-04), p. 1497-1510
    Abstract: Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-β (Aβ) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that Aβ and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aβ plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated—specifically, whether the contribution of Aβ and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aβ-positive females presented higher CSF p-tau181 concentrations compared with Aβ-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aβ-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aβ and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aβ in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aβ plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad397
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
    detail.hit.zdb_id: 1474117-9
    detail.hit.zdb_id: 80072-7
    SSG: 12
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  • 7
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    Interpretable discriminant analysis for functional data supported on random nonlinear domains with an application to Alzheimer’s disease
    Oxford University Press (OUP) ; 2024
    In:  Journal of the Royal Statistical Society Series B: Statistical Methodology ( 2024-03-22)
    Details
    In: Journal of the Royal Statistical Society Series B: Statistical Methodology, Oxford University Press (OUP), ( 2024-03-22)
    Abstract: We introduce a novel framework for the classification of functional data supported on nonlinear, and possibly random, manifold domains. The motivating application is the identification of subjects with Alzheimer’s disease from their cortical surface geometry and associated cortical thickness map. The proposed model is based upon a reformulation of the classification problem as a regularized multivariate functional linear regression model. This allows us to adopt a direct approach to the estimation of the most discriminant direction while controlling for its complexity with appropriate differential regularization. Our approach does not require prior estimation of the covariance structure of the functional predictors, which is computationally prohibitive in our application setting. We provide a theoretical analysis of the out-of-sample prediction error of the proposed model and explore the finite sample performance in a simulation setting. We apply the proposed method to a pooled dataset from Alzheimer’s Disease Neuroimaging Initiative and Parkinson’s Progression Markers Initiative. Through this application, we identify discriminant directions that capture both cortical geometric and thickness predictive features of Alzheimer’s disease that are consistent with the existing neuroscience literature.
    Type of Medium: Online Resource
    ISSN: 1369-7412 , 1467-9868
    URL: Article
    DOI: 10.1093/jrsssb/qkae023
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
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  • 8
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    Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 2 ( 2023-01-10)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 2 ( 2023-01-10)
    Abstract: The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N  = 351) and Alzheimer’s disease (AD, N  = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2214634120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 9
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    Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 9 ( 2023-09-01), p. 3719-3734
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 9 ( 2023-09-01), p. 3719-3734
    Abstract: Mechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer’s disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = −0.062, P = 0.032), higher education level (Stβinteraction = −0.072, P = 0.011) and higher intracranial volume (Stβinteraction = −0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer’s disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad100
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    detail.hit.zdb_id: 80072-7
    SSG: 12
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  • 10
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    Staging tau pathology with tau PET in Alzheimer’s disease: a longitudinal study
    Springer Science and Business Media LLC ; 2021
    In:  Translational Psychiatry Vol. 11, No. 1 ( 2021-09-18)
    Details
    In: Translational Psychiatry, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-09-18)
    Abstract: A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18 F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18 F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.
    Type of Medium: Online Resource
    ISSN: 2158-3188
    URL: Article
    DOI: 10.1038/s41398-021-01602-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2609311-X
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