Future studies should prospectively acquire disease-specific severity measures and incorporate them as covariates in imaging analyses

The gap

Evidence profile

Sourced from the future-work section and future work of the source papers, classified as general, spanning 3 journals. Those papers have been cited 1 times in total.

Supporting evidence — 3 representative gaps

• Associations Between Nonspecific Blood-Derived Inflammatory Indices and MRI-Derived Frontal Network Degeneration in Progressive Supranuclear Palsy (2026) · Neurology International · doi

  Future studies should prospectively acquire disease-specific severity measures and incorporate them as covariates in imaging analyses. Comparison with AD would address a different clinical and neuroanatomical context, whereas inclusion of pathologically or biomarker-supported CBD would be particularly informative for determining whether the observed immune structural associations are specific to PSP or represent a feature shared across 4-repeat tauopathies. Future studies incorporating PSP, PD, and matched healthy controls would provide a more comprehensive framework for assessing disease specificity.

  generalfuture-work section
  Keywords: future studies prospectively acquire disease-specific severity measures incorporate
• Alzheimer’s Disease: From Pathogenesis to Emerging Therapeutic Targets (2026) · Journal of Clinical Medicine · cited 1× · doi

  The observation that TREM2 and PSEN1 variants predispose individuals specifically to AD rather than to other tauopathies, and that APOE isoforms and variants strongly influence the risk of AD, suggests that these genetic factors primarily affect the production, clearance, or accumulation of Aβ rather than tau itself. As described in the Thal Phases of Aβ deposition begins in the neocortex and subsequently spreads through subcortical regions, eventually reaching the brainstem and cerebellum [102]. Together with the rela- tively stereotyped pattern of tau propagation described by the Braak staging system, this reproducible spatial progression of pathology contributes to the clinical and pathological definition of AD as a distinct entity. However, the mechanisms underlying the highly stereotyped Aβ accumulation patterns remain unclear. Moreover, although tau pathology is influenced by Aβ in AD, it remains difficult to fully explain why tau accumulation appears to progress in a direction opposite to that of amyloid plaque deposition, spreading from the brainstem and limbic regions to the neocortex. Another unresolved issue is why, in contrast to many other tauopathies that predominantly involve 4-repeat tau, both 3-repeat and 4-repeat tau accumulate in AD, and how Aβ influences this isoform-specific pathology. Although this mini-review is primarily concerned with AD, insights gained from comparisons with other tauopathies may be informative for understanding disease-specific mechanisms. Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND) is a congenital condition caused by hyperactivation of mTOR and is characterized by neuronal accumulation of both 3-repeat and 4-repeat tau in the absence of Aβ deposi- https://doi.org/10.3390/jcm15062357 J. Clin. Med. 2026, 15, 2357 11 of 17 tion [103,104]. Because mTORC1 activation suppresses v-ATPase function [98], this mech- anism partially overlaps with the pathways implicated in AD. However, TAND exhibits pathological features and lesion distributions that differ from those of AD. Notably, sev- eral clinical trials of rapamycin (sirolimus), an mTORC1 inhibitor used in the treatment of Tuberous Sclerosis Complex, are currently underway for AD (NCT04629495, NCT06022068). Niemann–Pick disease type C (NPC), caused by variants in NPC1 that lead to lysosomal cholesterol accumulation, shows neuropathological features more closely resembling AD, including the presence of amyloid plaques and neurofibrillary tangles [105]. PSEN1 has been shown to be involved not only in the glycosylation of the v-ATPase V0a1 subunit but also in the glycosylation of NPC1 [106]. A comparative consideration of TAND and NPC raises the possibility that lysosomal cholesterol accumulation may be a key determinant in the formation of amyloid plaques. In vitro studies have suggested that tau protein may undergo liquid–liquid phase separation and form liquid droplets before fibrillar aggregation. However, it remains uncertain whether such liquid droplets form in degenerating neurons in vivo, whether pretangles represent a phase-separated state, and whether these processes are related to GVBs. Clarifying these questions may provide important insights into the early stages of tau aggregation. Despite these circumstances, recent in vitro studies have reported several molecular chaperones that co-condense within tau-containing liquid droplets and appear to suppress or delay tau fibril formation. These findings raise the possibility that if fibrillization can be slowed, the progression of tau pathology might be mitigated to some extent, even in the presence of impaired lysosomal function [107,108].

  generalfuture workevidence 5/5
  Keywords: accumulation repeat liquid pathology variants tauopathies amyloid tand lysosomal droplets whether psen rather primarily described
• Modeling Alzheimer’s disease with brain organoids: mechanisms, applications, and future directions (2026) · Frontiers in Cell and Developmental Biology · doi

  duplicates the human brain environment that cannot be matched by 2D cell cultures (Prasannan et al., 2022; Whitehouse et al., 2025). Human fibroblast-derived 3D-cultured generated brain organoids show strong tau pathology and Aβ aggregation, and APOE ε4-expressing organoids have much higher quantities of Aβ42 protein than their 2D counterparts (Kim et al., 2024). The formation of a brain-like structure in 3D occurs when Matrigel contains its ECM components laminin and collagen, supporting neuronal development and synaptic formation and resulting in improved pathological representation (Massimi et al., 2020; Prasannan et al., 2022). AD-related symptoms are enhanced by 3D architecture because 3D organoids develop Aβ plaque formation and tau hyperphosphorylation at faster rates than control samples. Furthermore, thioflavin T-positive aggregates and phosphorylated tau (p-Tau) deposits exist together with neuronal markers in the same areas of the tissue (Kim et al., 2024; Korde and Humpel, 2024). The physical limits of 3D environments allow the investigation of Aβ plaque behavior by analyzing the geometric shape and the relationships with brain tissue and the spatial arrangement. APP/ PS1 transgenic mouse cerebellum using synchrotron X-ray phase contrast tomography demonstrates that Aβ plaques in 3D organoids develop into elongated shapes that follow the same patterns as human AD brain tissue (Massimi et al., 2020). The structural simplicity of 2D cultures prevents the modeling of plaque-tissue interactions because they do not possess the required spatial organization. Three-dimensional organoids enable the study of plaque formation and the cause of neuritic dystrophy and synaptic degeneration through pre- and post-synaptic marker co- localization and the progressive reduction of synaptic puncta density (Guido et al., 2023; Kim et al., 2024). The 3D system elucidates Aβ aggregation together with cellular stress responses, including oxidative stress and mitochondrial dysfunction, at higher complexity than 2D cultures because 3D cultures need more power to function while their physical boundaries exist (Park et al., 2023; Whitehouse et al., 2025). The 3D organoid system offers new solutions because it allows the use of patient-specific genetic data and enables the study of in different cell types to addresses key restrictions found conventional 2D cell culture models. Aβ accumulation and caspase-induced cell death is shown in 3D brain spheroids derived from iPSCs of AD patients, enabling the conduct of large-scale drug tests for neuroprotective compounds, including curcumin and nordihydroguaiaretic acid (Park et al., 2023). The tri- culture system, consisting of

  generalfuture workevidence 5/5
  Keywords: brain organoids cell cultures formation synaptic plaque tissue human system prasannan whitehouse derived aggregation higher

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