Shared Molecular Fingerprint of Alzheimer’s and Lewy Body Dementia Revealed in Human Brain Maps

Alzheimer’s disease and dementia with Lewy bodies are the two most common causes of degenerative dementia, yet clinicians have long treated them as largely distinct entities, one defined by amyloid plaques and tau tangles, the other by aggregates of alpha-synuclein called Lewy bodies. A new study published in GeroScience has now drawn the most detailed molecular maps of both conditions across the human brain, and the picture that emerges is striking: beneath the different protein deposits, the two dementias share a common molecular core, a signature the researchers link to neurodegenerative aging itself. By sequencing the whole transcriptome of five brain regions from post-mortem tissue of carefully characterized donors, an Italian team has revealed both profound differences in how the two diseases reshape gene expression and a surprising set of overlapping molecular processes that could point toward new therapeutic targets.

The research was made possible by a uniquely rich resource. The donors were participants in InveCe.Ab, a population-based longitudinal study running in the town of Abbiategrasso since 2010, in which elderly volunteers underwent repeated neuromotor and neurocognitive assessments covering global cognition as well as memory, attention, executive functions, language and visuospatial abilities. When donors died, their brains were harvested within twenty-four hours and processed according to the Abbiategrasso Brain Bank protocol, which requires a complete histological characterization of all the main proteinopathies and vascular scoring before a neuropathological diagnosis is made. From this cohort, the researchers selected six subjects with a neuropathological diagnosis of Alzheimer’s disease, six with dementia with Lewy bodies, and three non-demented controls. This design matters because most post-mortem studies rely on diagnoses made from clinical records alone; here, the pathology was verified tissue by tissue.

The team dissected five brain regions from each subject: the hippocampus, the temporal cortex, the parietal cortex, the cingulate gyrus and the substantia nigra. These areas were chosen to capture the spatial heterogeneity of both diseases. RNA was extracted from cryopreserved tissue and libraries were prepared for RNA sequencing on an Illumina platform, with the resulting reads aligned to the human reference genome and quantified using the STAR/RSEM pipeline. Differentially expressed genes were identified with DESeq2, using a log2 fold-change threshold of at least one and a false discovery rate of 0.1 or less, a cutoff the authors justify for complex, heterogeneous primary brain tissue where a stricter threshold would generate excessive false negatives. Quantitative PCR served as a technical validation of the sequencing results.

The first major finding is a difference in scale. Alzheimer’s disease scrambles gene expression far more extensively than Lewy body dementia. In the Alzheimer’s brains, the temporal cortex alone yielded 1,571 differentially expressed genes, followed by the cingulate gyrus with 1,210, the hippocampus with 206, the parietal cortex with 109 and the substantia nigra with just 60. The Lewy body brains told an almost inverted story: the heaviest deregulation appeared in the substantia nigra with 138 differentially expressed genes, followed by the parietal cortex with 96, the hippocampus with 24, the cingulate gyrus with 13 and the temporal cortex with a mere 7. In both diseases the vast majority of affected transcripts were protein-coding messenger RNAs rather than long non-coding RNAs. The authors interpret this as evidence that Alzheimer’s pathogenesis is more complex and heterogeneous, whereas Lewy body disease follows a more stereotyped topography, a conclusion consistent with the neuropathological literature.

The biological character of the deregulated genes also followed a region-specific logic. In the Alzheimer’s brains, the hippocampus and temporal cortex showed transcriptomic changes dominated by synaptic function: enrichment analysis flagged synaptic transmission, ion channel activity, and the regulation of glutamatergic and GABAergic synapses, with many genes involved in voltage-gated potassium and sodium- and calcium-activated potassium channels strongly downregulated. By contrast, the cingulate gyrus and substantia nigra of the same brains were characterized by disruptions of proteostasis, the cellular machinery of protein folding and chaperone activity. In the Lewy body brains, the deregulated genes concentrated in the substantia nigra and parietal cortex pointed instead to a triad of failing processes: loss of proteostasis, an inadequate response to oxidative stress, and inflammation. The parietal cortex results also implicated the glial environment, a clue the authors consider potentially pivotal, since a parietal region affected later in the disease may mirror an early glial impairment in the substantia nigra that then snowballs into oxidative damage and protein mismanagement.

Some individual genes stood out. In the substantia nigra of Alzheimer’s subjects, the most heavily downregulated genes were HBA2 and HBB, which encode the alpha and beta chains of hemoglobin, hinting at vascular involvement. In the Lewy body brains, the shared functional enrichment between parietal cortex and substantia nigra converged on a single gene, HIF3A, which encodes the alpha subunit of Hypoxia-Inducible Factor 3 and is normally upregulated in response to low oxygen in the brain. Its upregulation and methylation have previously been associated with circadian rhythm disruption in Alzheimer’s disease; this study now links HIF3A to Lewy body disease as well, connecting hypoxia signaling, vascular function and neurodegeneration in a single thread.

When the researchers overlapped the gene lists from the two diseases region by region, a common molecular architecture surfaced. Every one of the five regions showed shared deregulation between the pathologies, with the parietal cortex showing the most overlap at 20 shared differentially expressed genes, followed by the substantia nigra with 17, the hippocampus with 6, and the temporal and cingulate cortices with 3 each. Several of these shared genes appeared in both diseases with the same direction of change. IGF2, which encodes insulin-like growth factor 2, a promoter of memory enhancement and neurogenesis in the adult brain, was upregulated in the hippocampus and temporal cortex of both groups, suggesting a compensatory, neuroprotective response. DNAJB1, a member of the heat shock protein family central to proteostasis, was downregulated in both diseases in the temporal cortex and cingulate gyrus, pointing to a shared collapse of protein quality control. In the hippocampus, the upregulated shared genes included CXCR4, a chemokine receptor signaling an exacerbated inflammatory state, and PTRF, a factor associated with caveolae and rRNA transcription. In the substantia nigra, the shared genes enriched for nitric oxide and carbon dioxide transport in relation to the vascular environment, alongside protein folding, reinforcing the idea that vascular and cell-to-cell communication pathways are compromised in both conditions.

The authors place these findings within the framework of the hallmarks of aging. Loss of proteostasis, chronic inflammation, impaired intercellular communication and mitochondrial and vascular dysfunction are all recognized drivers of aging, and each appeared in the shared molecular signature of the two dementias. From this perspective, the differentially expressed genes act as proxies of a nonphysiological aging trajectory that tips the brain from healthy aging into neurodegeneration. The brain attempts to cope, mounting compensatory responses such as IGF2 upregulation, but the balance ultimately fails. Because the shared signature spans the entire brain rather than a single lesion site, the researchers propose that neurodegenerative aging may be characterized by a whole-brain contest between pathological and compensatory mechanisms, with each disease emerging when that balance breaks down in a particular way.

The study has honest limitations, which the authors lay out in detail. The cohort is small, particularly the three controls, so all results should be read as preliminary. Post-mortem interval, agonal state, end-of-life conditions and dementia itself can all degrade RNA quality, and comorbidities such as diabetes, hypertension and limbic-predominant age-related TDP-43 encephalopathy may have influenced the expression profiles. Bulk RNA sequencing also cannot distinguish altered regulation within individual cell types from shifts in cellular composition, so the team could not attribute the signatures to specific cell populations, although comparisons with single-cell studies suggest oligodendrocytes and GABAergic inhibitory neurons are likely contributors. Even so, the work fills a gap, since single-cell atlases typically cover only one brain region. The therapeutic implication is perhaps the boldest claim: rather than continuing to chase immunological removal of amyloid or synuclein deposits after they have formed, the authors argue that understanding the molecular processes that occur before pathological lesions are deposited could enable personalized, preventive interventions aimed at restoring proteostasis and glial health, targeting the primary hallmarks of aging that appear to light the fuse for both diseases.

Subject of Research: Comparative whole-transcriptome mapping of molecular changes shared by Alzheimer's disease and dementia with Lewy bodies across five human brain regions

Article Title: A pattern to rule them all: tracing a human brain map of molecular aspects shared by Alzheimer’s disease and dementia with Lewy bodies

Article References: A pattern to rule them all: tracing a human brain map of molecular aspects shared by Alzheimer’s disease and dementia with Lewy bodies. (n.d.). https://doi.org/10.1007/s11357-026-02581-5

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02581-5

Keywords: Alzheimer's disease, dementia with Lewy bodies, transcriptomics, neurodegeneration, aging, proteostasis, substantia nigra, hippocampus, inflammation, RNA sequencing, alpha-synuclein, personalized therapy