DLB is the second most common neurodegenerative dementia after Alzheimer’s disease, but it is often much harder to identify confidently. Patients may experience fluctuating cognition, visual hallucinations, Parkinson-like movement problems and rapid-eye-movement sleep behavior disorder, in which they physically act out dreams. The disorder is driven primarily by the accumulation of abnormal alpha-synuclein, the protein associated with Lewy bodies, yet many patients also have Alzheimer’s-related amyloid and tau pathology. Autopsy studies suggest that Alzheimer’s co-pathology is present in as many as three-quarters of people with DLB. This biological mixture can blur the boundary between diseases, producing symptoms and biomarkers that do not fit neatly into a single diagnostic category.

The new study focused on two genetic influences that may help shape this biological diversity. GBA1 provides instructions for an enzyme involved in lysosomal function, the cellular recycling system that breaks down waste materials. Certain GBA1 variants impair this process and are associated with the accumulation and spread of alpha-synuclein in Parkinson’s disease and DLB. The mutations are particularly common among Ashkenazi Jewish populations, the group examined in this study. APOE ε4, by contrast, is the best-established common genetic risk factor for Alzheimer’s disease. It is linked to amyloid deposition, tau pathology and more aggressive cognitive decline, and is also frequent among people with DLB. Three participants carried both genetic risk factors, allowing the researchers to examine how they might contribute to overlapping but different metabolic signatures.

To see the brain’s energy patterns, the team used [18F]fluorodeoxyglucose positron-emission tomography, or FDG-PET. The radioactive glucose analogue is taken up by metabolically active brain cells, enabling PET to reveal regions in which glucose use is reduced. Rather than relying only on visual inspection, the researchers analyzed the scans in several complementary ways. They measured activity in anatomically defined brain regions, calculated the “cingulate island sign,” compared each scan with established Alzheimer’s-, Parkinson’s- and DLB-related metabolic networks, and applied a machine-learning model trained to distinguish healthy aging from Alzheimer’s disease, Parkinson’s disease and DLB. The study included 18 healthy controls and 17 first-degree relatives of patients, with scans collected between August 2019 and December 2023.

The clearest effect of APOE ε4 appeared in the cingulate island sign, a characteristic feature of DLB imaging. In typical DLB, the occipital cortex at the back of the brain shows reduced glucose metabolism, while the posterior cingulate cortex is relatively preserved compared with nearby regions such as the precuneus and cuneus. This “island” of preserved activity can help distinguish DLB from Alzheimer’s disease, where posterior cingulate metabolism is often more broadly impaired. In the study, DLB patients without APOE ε4 had a substantially stronger cingulate island sign than carriers: the median standardized score was 1.35 compared with 0.23. The difference remained statistically significant after accounting for age and disease duration, suggesting that APOE ε4 may selectively weaken one of the metabolic clues clinicians use to recognize DLB.

That weakened signal could have important consequences for diagnosis. If APOE ε4 increases Alzheimer’s-related amyloid and tau pathology in a person who also has Lewy body disease, the posterior cingulate cortex may become more metabolically vulnerable. The resulting PET scan could lose the distinctive contrast between a relatively preserved posterior cingulate and a metabolically reduced occipital cortex. In practical terms, an APOE ε4 carrier with DLB might produce a scan that appears more Alzheimer-like, particularly in the early stages when abnormalities are subtle. The study did not directly measure amyloid or tau in these participants, so the proposed mechanism remains an interpretation rather than a proven causal chain. Still, it fits earlier work connecting tau accumulation in the posterior cingulate with cognitive impairment and loss of the cingulate island sign in Lewy body disorders.

GBA1 status influenced the scans in a different way. The 14 GBA1 carriers, who represented 32.6 percent of the DLB group, tended to show a more consistent, Parkinson’s- and DLB-like whole-brain metabolic pattern. Non-carriers displayed greater variability and significantly higher expression of an Alzheimer’s disease-related metabolic pattern. Their median Alzheimer’s-related pattern score was 3.9, compared with 2.7 among carriers, a difference that remained significant in the study’s analysis. The non-carrier group also showed more variation in several disease-related networks, suggesting that their DLB diagnosis encompassed a wider range of underlying biological processes. The researchers caution that these were not separate metabolic categories; instead, the patients occupied positions along a continuous spectrum extending from typical DLB and Parkinson’s disease toward Alzheimer’s-like metabolism.

The machine-learning analysis reinforced that interpretation. The model, known as generalized matrix learning vector quantization, was trained using an independent cohort from the University Medical Center Groningen and then used to project the Tel Aviv participants into a multidimensional space based on glucose uptake in 48 brain regions. GBA1 carriers clustered more tightly around the model’s DLB prototype and showed a modest tendency to lie closer to the Parkinson’s disease prototype. Non-carriers were more dispersed, with some positioned toward the Alzheimer’s disease region and others deep within the DLB space, where they appeared to have a stronger overall metabolic expression of disease. The difference in within-group clustering was statistically significant. However, the model correctly classified only 60 percent of DLB patients overall, emphasizing that the approach currently describes biological similarity rather than providing a stand-alone diagnostic test.

The genetic effects also aligned with clinical findings, although the study was not large enough to establish individual-level predictions. Higher expression of Alzheimer’s-, Parkinson’s- and DLB-related metabolic patterns was associated with lower scores on the Mini-Mental State Examination and the Montreal Cognitive Assessment, indicating greater cognitive impairment. APOE ε4 carriers had lower average Mini-Mental State Examination scores than non-carriers, a difference that could itself have contributed to their reduced cingulate island sign. Motor severity, measured with the motor section of the Unified Parkinson’s Disease Rating Scale, correlated with disease duration but not with the PET network scores. Healthy controls and relatives were generally recognized as healthy by the machine-learning model, and the two healthy relatives who carried GBA1 mutations did not show a scan pattern suggesting elevated DLB risk.

The researchers stress that the findings need replication in larger and more diverse populations. The study involved only 43 DLB patients, and the sample was drawn from an Ashkenazi Jewish cohort in which GBA1 variants are unusually frequent. The small number of participants also prevented reliable comparisons between individual mutations, which can have different biological effects. The APOE ε4 carrier group had more cognitive impairment, making it difficult to separate genetic effects from disease severity. In addition, the machine-learning analysis included a limited overlap between participants used for scanner harmonization and those evaluated in the test cohort. No metabolic signature accurately identified a patient’s genetic status on an individual basis. Even so, the convergence of regional measurements, disease-network analysis and machine learning suggests that genetic background is not merely a risk factor operating before disease onset. It may continue to shape how DLB unfolds in the living brain.

The broader message is that DLB may be less like a single disease than a family of related biological trajectories. GBA1 mutations appear to favor a more homogeneous alpha-synuclein-associated pattern resembling Parkinson’s disease and classic DLB, while APOE ε4 may make a specific brain region, the posterior cingulate cortex, more susceptible to Alzheimer’s-like dysfunction. Combining genetic testing with advanced FDG-PET analysis could therefore help clinicians recognize patients whose scans fall outside the textbook pattern. It might also allow researchers to design more informative clinical trials by separating participants with relatively pure synuclein-driven disease from those with substantial Alzheimer’s co-pathology. For now, the results do not change clinical diagnosis or treatment, but they offer a compelling explanation for why the same label—dementia with Lewy bodies—can conceal markedly different metabolic stories inside the brain.

Subject of Research: Genetic influences on brain glucose-metabolism patterns in dementia with Lewy bodies

Article Title: Effect of genetic factors on [¹⁸F]FDG PET metabolic phenotypes in dementia with Lewy bodies

Article References: Lövdal S, Meles SK, Carli G, et al. “Effect of genetic factors on [¹⁸F]FDG PET metabolic phenotypes in dementia with Lewy bodies.” European Journal of Nuclear Medicine and Molecular Imaging (2026). Original research article

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08124-6

Keywords: dementia with Lewy bodies, GBA1 mutations, APOE ε4, FDG-PET, cingulate island sign, Alzheimer’s disease, Parkinson’s disease, brain glucose metabolism

Dementia with Lewy bodies is characterized by cognitive decline, fluctuating attention, visual hallucinations, and parkinsonian motor symptoms. One of its hallmark features is the pronounced sensitivity to antipsychotic drugs, often causing severe adverse reactions including worsened motor symptoms and increased mortality risk. Historically, clinical caution has predominantly revolved around traditional antipsychotics. However, this recent case strongly implicates gabapentinoids, a class of anticonvulsant and neuropathic pain medications, as potent triggers of psychosis in DLB, even at doses significantly lower than those previously associated with such effects.

The subject of the case was a woman in her late seventies diagnosed with mild dementia and subtle parkinsonism. For neuropathic pain management, she was prescribed mirogabalin at a modest dose of 15 mg daily. Shortly after treatment initiation, she began to experience vivid hallucinations accompanied by delusional misidentification—a well-documented psychotic manifestation linked with dementia with Lewy bodies. Remarkably, these symptoms emerged rapidly, underscoring an acute neuropsychiatric response to the drug rather than a gradual side effect.

Following discontinuation of mirogabalin, the patient’s psychotic symptoms substantially abated but did not fully resolve, suggesting residual neurochemical imbalances. Investigations including dopamine-transporter scintigraphy revealed bilateral striatal uptake reduction, consistent with dopaminergic deficit—a pathological hallmark of DLB. Subsequent administration of donepezil, an acetylcholinesterase inhibitor, facilitated further mitigation of her psychosis, highlighting the interplay between cholinergic pathways and psychotic symptomatology in this disorder.

The clinical course took another unexpected turn when pregabalin, another gabapentinoid, was introduced at an equally low dose of 25 mg daily to manage a resurgence of neuropathic pain. Almost mirroring the prior episode, the patient’s psychosis rapidly re-emerged, reinforcing the suspected causative relationship between gabapentinoid exposure and neuropsychiatric exacerbations in DLB. Discontinuation once again led to symptom resolution, cementing the causal link.

Traditionally, pregabalin-associated psychosis has been documented predominantly at substantially higher doses, ranging from 300 to 450 mg daily, and predominantly in populations without underlying neurodegenerative disease. This report’s novel finding that psychotic episodes can be instigated at minuscule dosages in DLB patients underscores a unique hypersensitivity profile for gabapentinoids within this group. The pathophysiological basis may involve an exaggerated modulation of glutamatergic and GABAergic neurotransmission, already disrupted in Lewy body dementia.

Neuropharmacologically, gabapentinoids act primarily by binding to the α2δ subunit of voltage-gated calcium channels, reducing excitatory neurotransmitter release. While neuroprotective in some contexts, in DLB, where neuronal circuits are already compromised, this modulation may inadvertently destabilize the delicate neurotransmitter balance. This disruption may precipitate hallucinations, delusions, and other psychotic phenomena that mirror or exacerbate the natural symptom profile of the disease.

The clinical implications of these observations cannot be overstated. Gabapentinoids are frequently employed in neuropathic pain management due to their relatively favorable side effect profiles and minimal abuse potential. However, this case signals the urgent need for healthcare providers to exercise heightened vigilance when prescribing these medications to patients with Lewy body dementia, regardless of dose. Regular monitoring for emergence or worsening of psychiatric symptoms should be rigorous and perhaps necessitate alternative pain management strategies.

Furthermore, this case invites a broader reconsideration of pharmacotherapy paradigms in neurodegeneration-associated psychosis. The neuronal vulnerabilities in DLB may extend beyond dopaminergic hypersensitivity to include a profound susceptibility to agents influencing multiple neurotransmitter systems. Consequently, the development of targeted guidelines and protocols for gabapentinoid use in dementia populations is warranted to prevent inadvertent harm.

From a research standpoint, this report opens avenues for mechanistic studies into the molecular underpinnings of gabapentinoid-induced psychosis in neurodegenerative states. Delineating the specific receptor-level interactions, calcium channel subtypes involved, and downstream signaling cascades may reveal new therapeutic targets that either mitigate adverse effects or exploit these pathways beneficially. Additionally, longitudinal cohort studies to ascertain prevalence and risk factors for gabapentinoid sensitivity in DLB could refine clinical risk stratification.

Moreover, the pharmacodynamic interactions between gabapentinoids and cholinesterase inhibitors like donepezil, which appeared to alleviate psychosis in this patient, merit rigorous examination. Enhancing cholinergic transmission may represent a compensatory mechanism counteracting gabapentinoid-induced disruptions. These findings hint at possible combination therapies or dosage adjustments tailored specifically for vulnerable dementia subsets.

In conclusion, this remarkable case throws a spotlight on an underrecognized yet critical dimension of dementia with Lewy bodies management. Low-dose gabapentinoids, long considered safe in general populations, may invoke acute and severe psychosis in those with Lewy body pathology. The neuropsychiatric safety profiles of these common medications require urgent reevaluation in the context of neurodegeneration. Clinicians and researchers alike must grapple with these findings to optimize patient outcomes and avoid precipitating profound neuropsychiatric crises under the guise of symptom palliation.

As the global burden of dementia rises inevitably, such nuanced insights into drug-disease interactions will become increasingly pivotal. This case serves both as a cautionary tale and a catalyst for deeper inquiry into pharmacovigilance in complex neurological disorders. The evolving landscape of neurodegenerative treatment demands that therapeutic innovations be balanced with meticulous attention to the unique susceptibilities of affected individuals.

Subject of Research: Psychosis induced by low-dose gabapentinoids in a patient with dementia with Lewy bodies.

Article Title: A case of dementia with Lewy bodies with psychosis induced by low-dose gabapentinoids.

Article References:
Kanemoto, H., Akiyama, T., Taomoto, D. et al. A case of dementia with Lewy bodies with psychosis induced by low-dose gabapentinoids. BMC Psychiatry 25, 491 (2025). https://doi.org/10.1186/s12888-025-06937-7

Image Credits: AI Generated

DOI: https://doi.org/10.1186/s12888-025-06937-7