Citations

Abstract Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non‐amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large‐scale clinical trials, which typically focus on late‐onset, sporadic amnestic‐predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid‐targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early‐onset amnestic and non‐amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome‐specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.

Abstract The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

AbstractINTRODUCTIONDelay in diagnosis of posterior cortical atrophy (PCA) syndrome is common, and the lack of familiarity with assessment tools for identifying visual cortical dysfunction is a contributing factor. We propose recommendations for the approach to the evaluation of PCA clinical features during the office visit, the neuropsychological evaluation, and the research setting. A recommended screening battery for eye clinics is also proposed.METHODSRecommendations were developed using results from a web‐based survey of members of Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Atypical Alzheimer's Disease Professional Interest Area (PIA), literature review, and consensus by the PCA assessment working party of the Atypical Alzheimer's Disease PIA.RESULTSSurvey results revealed robust agreement for assessment tool preferences for PCA features, and many respondents indicated that they reserve assessment tools for use only when PCA is suspected. For some PCA features, curated tools were preferred over validated battery tools, particularly for the office visit. Consensus recommendations superseded survey preferences for two core cognitive features within the 2017 PCA diagnostic criteria.DISCUSSIONThese consensus recommendations provide an evaluation framework for PCA clinical features and can facilitate timely and accurate recognition and diagnosis of PCA. Broader use of these tools should be sought, and development and validation of novel PCA clinical outcome assessments are needed to improve our understanding of atypical AD and other dementias and support the inclusion of those with PCA in treatment trials.

Abstract Introduction A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Methods Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web‐based quantitative survey regarding symptom frequency and the conceptualization of PCA. Results A three‐level classification framework for PCA is described comprising both syndrome‐ and disease‐level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico‐radiological syndrome. Classification level 2 (PCA‐pure, PCA‐plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA‐AD], Lewy body disease [PCA‐LBD], corticobasal degeneration [PCA‐CBD], prion disease [PCA‐prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome‐level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. Discussion There was strong agreement regarding the definition of the core clinico‐radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single‐center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.

AbstractIntroductionThe genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.MethodsWe genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome‐wide association study.ResultsWe confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome‐wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).DiscussionWe provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.