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Brain asymmetry may offer a new window into Alzheimer’s disease (AD) progression before and after symptoms emerge.

Researchers recently evaluated cortical thickness asymmetry in autosomal dominant AD using MRI data from the Clinic Barcelona cohort and a larger confirmatory cohort from the Dominantly Inherited Alzheimer Network. The cortical asymmetry index distinguished mutation carriers from healthy controls, including asymptomatic carriers in the Barcelona cohort and symptomatic carriers in both cohorts. Higher asymmetry was associated with closer proximity to expected symptom onset, lower MMSE scores, and higher neurofilament light levels in plasma or cerebrospinal fluid. Longitudinally, asymmetry increased in symptomatic mutation carriers, suggesting cortical asymmetry may reflect evolving neurodegeneration across the inherited AD continuum.

These findings indicate that cortical asymmetry may help detect and monitor disease-related neuroanatomical changes in inherited AD.

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https://academic.oup.com/braincomms/article/8/1/fcaf488/8384451?login=false

Air pollution is increasingly recognized as a brain health risk, and this recent Danish registry study links long-term exposure to a higher risk of Lewy body dementia.

Researchers identified 3,024 people with dementia with Lewy bodies (DLB) and 3,808 with Parkinson's disease-related dementia (PDD) diagnosed from 2001 to 2021, matching each case with 10 controls. Ten-year average exposure to PM2.5 and nitrogen dioxide was assessed before diagnosis. After adjusting for demographic, socioeconomic, medical, psychiatric, and area-level factors, higher PM2.5 exposure was associated with markedly greater risk of both DLB and PDD, with a stronger association for DLB. Nitrogen dioxide exposure also showed increased risk, again more pronounced for DLB.

These findings suggest ambient air pollution may contribute to later risk of Lewy body dementia and strengthen the rationale for studying environmental drivers of neurodegeneration.

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https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2849005

TDP-43 diseases remain difficult to diagnose clinically because symptoms can overlap significantly across dementia subtypes; however, new data have helped to advance a biomarker-based path forward.

Researchers developed a digital seed amplification assay that partitions individual TDP-43 aggregates into nanoliter compartments, enabling highly sensitive quantification of seeds in CSF. In 40 CSF samples from people with genetic or sporadic FTLD-TDP and healthy controls, TDP-43 seed concentrations were significantly higher in FTLD-TDP. Higher aggregate levels also correlated with greater clinical severity, suggesting the assay may capture biologically meaningful disease burden. This level of precision could help distinguish TDP-43–driven disease from clinically similar dementia syndromes. By measuring single aggregates with low detection limits, this platform could support more accurate diagnosis, patient stratification, and future monitoring in FTLD-TDP and other TDP-43 proteinopathies.

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https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71272

Early synaptic changes may offer a window into how Alzheimer’s disease (AD) begins before major neuronal loss.

In a recent study, primary cortical neurons exposed to low levels of amyloid-beta (AB) oligomers showed increased synapse density, particularly at single synaptic boutons and multi-innervated spines. This pattern mirrors the synaptic increases observed during MCI, a transitional stage before AD dementia. Although overall new protein production did not change, proteomic analysis revealed selective disruptions in newly synthesized proteins linked to synaptic signaling, cytoskeletal control, mitochondrial function, autophagy, and the ubiquitin-proteasome system.

Early amyloid exposure may reshape synapses and proteostasis in ways that could be therapeutically targeted.

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https://www.nature.com/articles/s41398-026-03905-x

A blood-based tau signal may help identify Alzheimer’s disease risk before amyloid PET scans turn positive.

Among cognitively unimpaired older adults, researchers found that higher baseline plasma % phosphorylated tau 217 (%pTau217) was associated with faster accumulation of amyloid-β and tau on PET imaging over time. These brain changes were also linked to greater downstream cognitive decline. Importantly, even among participants who were amyloid PET-negative at baseline, elevated %pTau217 predicted future increases in both amyloid and tau signals. This suggests that plasma %pTau217 may detect early biological momentum toward Alzheimer’s pathology before conventional imaging thresholds are reached. By contrast, very low %pTau217 levels were associated with limited accumulation of AD-related pathology and a lower risk of cognitive decline.

These findings strengthen the role of blood biomarkers in earlier risk stratification, monitoring, and prevention-focused clinical research.

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https://www.nature.com/articles/s41467-026-71269-3

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Tau and α-synuclein (αSyn) can assemble into dynamic condensates that influence both normal neuronal function and neurodegenerative disease.

A recent study showed that tubulin is a key regulator of these Tau:αSyn assemblies. When tubulin is present, it enters condensates, supports microtubule polymerization, and helps prevent harmful oligomer formation. Without tubulin, tau-driven condensation shifts toward a pathological state, accelerating the formation of Tau:αSyn heterodimers and amyloid fibrils. Researchers also identified distinct structural signatures that distinguish tubulin-rich, microtubule-supportive condensates from tubulin-absent, disease-linked condensates. In neuronal models, microtubule loss promoted toxic oligomer formation and neurite degeneration, whereas inducible tau condensation helped stabilize microtubules, suggesting that the balance among tubulin, tau, and αSyn may determine whether condensates protect neuronal structure or fuel protein aggregation.

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https://www.nature.com/articles/s41467-026-69618-3

New multi-omic evidence suggests that ARIA, a major safety challenge in anti-amyloid Alzheimer’s therapies, may reflect a coordinated peripheral immune response rather than being solely a brain-imaging event.

By comparing blood from ARIA-positive patients with controls, researchers found expansion and clonal enrichment of CD8+ effector memory and terminally differentiated T cell populations. These cells exhibited transcriptional programs linked to cytotoxic activity, vascular trafficking, and short-lived effector function, along with metabolic shifts toward glycolysis. Modeling also indicated stronger monocyte-to-T cell communication via antigen presentation, adhesion, and chemokine pathways. Integration with cerebrovascular data suggested that ARIA-associated CD8+ TEMRA cells may be primed to interact with blood vessels. Although larger studies are needed, this immune signature could guide the development of future biomarkers for ARIA risk prediction.

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https://www.nature.com/articles/s41467-026-68921-3

New findings challenge the notion that microglia and macrophages only protect the brain from amyloid buildup in Alzheimer’s disease (AD).

Using human macrophage and stem cell-derived microglia models, researchers found that these immune cells can actively produce extracellular Aβ42 fibrils, a plaque-associated amyloid species linked to neurodegeneration. The cell-generated fibrils exhibited stronger seeding activity than synthetic fibrils and also promoted tau aggregation, linking immune-cell behavior to two major AD pathologies. Loss of TREM2, a key genetic risk factor for AD, intensified fibril formation, suggesting that inherited susceptibility may shape early amyloid spread through altered innate immune function. Transcriptomic data further revealed inflammatory programs resembling disease-associated microglial states. These results highlight a dual role for microglia: clearing harmful proteins while potentially facilitating amyloid assembly under certain conditions.

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https://www.pnas.org/doi/10.1073/pnas.2516774123

New single-cell and spatial profiling help to clarify why TDP-43 pathology affects specific neurons in ALS and ALS-FTD.

By analyzing post-mortem motor cortex tissue from ALS, ALS-FTD, and control donors, researchers found that cytoplasmic TDP-43 pathology was concentrated primarily in excitatory cortical neurons rather than being widespread across all brain cell types. The most affected groups included defined intratelencephalic and extratelencephalic neuron populations across cortical layers, including L2-L3, L3-L5, L5, and L6 subtypes. Multi-omic RNA and chromatin accessibility data also showed that TDP-43-related transcriptional disruptions, including cryptic exon inclusion, varied across cell types and engaged distinct gene networks.

These findings suggest that neuronal vulnerability in ALS is highly selective and that future therapies may need to target TDP-43 dysfunction in the precise cortical neuron populations most at risk.

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https://www.nature.com/articles/s41467-026-69944-6