Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease

Sirkis, Daniel W.; Bonham, Luke W.; Johnson, Taylor P.; Joie, Renaud La; Yokoyama, Jennifer S.

doi:10.1038/s41380-022-01531-9

Cited by 67 publications

(67 citation statements)

References 246 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, examination of brain structure and function via neuroimaging is a powerful method for the determination of neurodegenerative disease etiology. The use of positron emission tomography (PET) imaging, in particular, with radiotracers that bind to aggregated forms of tau has facilitated the in vivo detection of tau neuropathology in individuals with AD (reviewed in [19,100,101]). However, tau-PET tracers do not bind strongly to most forms of FTLD-tau pathology and may exhibit off-target binding in individuals with FTLD-TDP pathology [100,101].…”

Section: Discussionmentioning

confidence: 99%

“…However, tau-PET tracers do not bind strongly to most forms of FTLD-tau pathology and may exhibit off-target binding in individuals with FTLD-TDP pathology [100,101]. Alternatively, the use of CSF- and blood-based protein biomarkers holds great promise for AD [19,20,102] and FTD [21,103], although in the case of FTD, we still cannot discriminate between underlying FTLD-tau and -TDP pathology. Important limitations apply to several of these methods.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Single-cell RNA-seq reveals alterations in peripheralCX3CR1and nonclassical monocytes in familial tauopathy

Sirkis

Makarious

Johnson

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Emerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system. Methods: To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau. Results: Analysis of ~181,000 individual PBMC transcriptomes from MAPT pathogenic variant carriers (n = 8) and healthy non-carrier controls (n = 8) demonstrated striking differential expression in monocytes and natural killer (NK) cells. We observed a marked reduction in the expression of CX3CR1 - the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models - in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia. We confirmed differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using droplet digital PCR as an orthogonal technique for quantitative validation. Conclusions: Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-seq reveals alterations in peripheralCX3CR1and nonclassical monocytes in familial tauopathy

Sirkis

Makarious

Johnson

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…On the other hand, AD research has yet to progress towards analysis methods that make interindividual differences the focus rather than a source of error. Finding ways to dissect the heterogeneity of clinical and neuropathological profiles has become one of the central priorities in this field 13 .…”

Section: Introductionmentioning

confidence: 99%

Examining real-world Alzheimer’s disease heterogeneity using neuroanatomical normative modelling

Loreto

Verdi

Kia

et al. 2022

Preprint

View full text Add to dashboard Cite

Alzheimer′s disease (AD) has been traditionally associated with episodic memory impairment and medial temporal lobe atrophy. However, recent literature has highlighted the existence of atypical forms of AD, presenting with different cognitive and radiological profiles. Failure to appreciate the heterogeneity of AD in the past has led to misdiagnoses, diagnostic delays, clinical trial failures and risks limiting our understanding of the disease. AD research requires the incorporation of new analytic methods that are as free as possible from the intragroup homogeneity assumption underlying case-control approaches according to which patients belonging to the same group are comparable to each other. Neuroanatomical normative modelling is a promising technique allowing for modelling the variation in neuroimaging profiles and then assessing individual deviations from the respective distribution. Here, neuroanatomical normative modelling was applied for the first time to a real-worldclinical cohortof Alzheimer′s disease patients (n=86) who had a positive amyloid PET scan and a T1-weighted MR performed as part of their diagnostic workup. The model indexed normal cortical thickness distributions using a separate healthy reference dataset (n= 33,072), employing hierarchical Bayesian regression to predict cortical thickness per region using age and sex. Transfer learning was used to recalibrate the normative model on avalidation cohort(n=20) of scanner-matched cognitively normal individuals. Brain heterogeneity was quantified as z-scores at each of the 148 ROIs generated within each AD patient. Z-scores < -1.96 defined as outliers. Clinical features including disease severity, presenting phenotypes and comorbidities were collected from health records to explore their association with outlier profiles. Amyloid quantification was performed using an automated PET-only driven method to examine the association between amyloid burden and outliers. The total number of individual outliers (total outlier count) in biomarker-confirmed AD clinical patients ranged between 1 and 120 out of 148 (median 21.5). The superior temporal sulcus was the region with the highest count of outliers (60%) in AD patients. The mean proportion of outliers was higher in the temporal (31.5%) than in the extratemporal (19.1%) regions and up to 20% of patients had no temporal outliers. We found higher mean outlier count in patients with non-amnestic phenotypes, at more advanced disease stages and without depressive symptoms. Amyloid burden was negatively associated with outlier count. This study corroborates the heterogeneity of brain atrophy in AD and provides evidence that this approach can be used to explore anatomo-clinical correlations at an individual level.

show abstract

“…Indeed, besides the typical, amnestic-predominant variant [2], less prevalent/incident AD phenotypes exist, i.e., posterior cortical atrophy (PCA) [3], logopenic variant of primary progressive aphasia (lvPPA) [4], and a behavioural variant of AD (bvAD) [5] – primarily characterized by visual-perceptual and spatial deficits, language impairment within the phonological and lexical-semantic components, and cognitive/behavioural, dysexecutive features, respectively. While the differential diagnosis among AD variants mostly relies on clinical and radiological features [1], little is known on the capability of AD-related cerebrospinal fluid (CSF) biomarkers – i.e., amyloid β 42 (Aβ 42 ) and β 40 (Aβ 40 ), total tau, and phosphorylated tau (P-tau 181 ) [1] – in discriminating atypical from typical AD phenotypes [6]. This study aimed at testing whether each of these individual biomarkers contributes to the identification of atypical phenotypes among a retrospective cohort of probable AD patients diagnosed by means of Aβ 42/40 ratio.…”

Section: Introductionmentioning

confidence: 99%

CSF Aβ40 and P-Tau181 Might Differentiate Atypical from Typical AD Phenotypes: Preliminary Evidence

et al. 2022

View full text Add to dashboard Cite

Objectives: This study aimed at testing whether CSF levels of amyloid β42 (Aβ42), Aβ40, total tau, and phosphorylated tau (P-tau181) individually contribute to the identification of atypical phenotypes among a retrospective cohort of probable Alzheimer’s disease (AD) patients diagnosed by means of the ratio between Aβ42 and Aβ40 (Aβ42/40). Methods: The retrospective study cohort comprised 50 probable AD patients diagnosed by means of the ratio between Aβ42 and Aβ40 (Aβ42/40) and for whom total tau and P-tau181 values were also available. Patients were clinically classified as typical, amnestic-predominant AD (N = 39; 16 males; mean age: 73.4 ± 7.6 years; mean disease duration: 27.4 ± 24.7 months), or atypical phenotypes (N = 11; 6 males; mean age: 70.2 ± 6.5 years; mean disease duration: 35.5 ± 24.9 months) – i.e., posterior cortical atrophy (N = 4), logopenic-variant primary progressive aphasia (N = 4), and behavioural variant AD (N = 3). A logistic regression allowed predicting the occurrence of atypical versus typical phenotypes based on age, sex, and Aβ42, Aβ40, total tau, and P-tau181 levels. Results: Atypical and typical AD patients were comparable for Aβ42/40 values. Only Aβ40 and P-tau181 levels positively (p = 0.015) and negatively (p = 0.019) predicted the occurrence of atypical AD phenotypes, respectively. Classification precision was of 86%, yielding excellent specificity (94.9%) but poor sensitivity (54.5%). Conclusions: The present study delivers promising, albeit preliminary, evidence on the utility of Aβ40 and P-tau181 CSF biomarkers in differentiating atypical from typical Aβ42/40-confirmed AD phenotypes, prompting further research and confirmation on larger cohorts.

show abstract

Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease

Cited by 67 publications

References 246 publications

Single-cell RNA-seq reveals alterations in peripheralCX3CR1and nonclassical monocytes in familial tauopathy

Single-cell RNA-seq reveals alterations in peripheralCX3CR1and nonclassical monocytes in familial tauopathy

Examining real-world Alzheimer’s disease heterogeneity using neuroanatomical normative modelling

CSF Aβ40 and P-Tau181 Might Differentiate Atypical from Typical AD Phenotypes: Preliminary Evidence

Contact Info

Product

Resources

About