Lewy body disease is a neurodegenerative disorder characterized by intra-neuronal accumulation of α-synuclein, encompassing Parkinson’s disease and dementia with Lewy bodies. Parkinson’s disease presents with motor symptoms such as bradykinesia and cognitive impairment. Dementia with Lewy bodies, the second most common form of dementia after Alzheimer’s disease, is characterized by cognitive impairment with visual hallucinations and Parkinsonism. Recent attention has focused on prodromal symptoms of Lewy body disease, such as autonomic dysfunction (e.g., constipation), olfactory dysfunction, and REM sleep behavior disorder, which appear 10-20 years before the onset of motor or cognitive symptoms.
Our previous research identified that 5.7% of healthy individuals over 50 years old have two or more prodromal symptoms, defining them as high-risk subjects for developing Lewy body disease (Hattori et al. J Neurol 267(5):1516-1526, 2020). High-risk individuals had mild cognitive decline and hyposmia compared with low-risk individuals with no prodromal symptoms. Approximately one-third of the high-risk individuals had deficits in DaT-SPECT or cardiac MIBG scintigraphy, and the prevalence of abnormalities on DaT-SPECT was 4 times higher in the high-risk individuals than that in the low-risk individuals (Hattori et al. NPJ Parkinsons Dis 9:1-9, 2023) (Figure 1).
While α-synuclein pathology is known to contribute to dementia in Parkinson’s disease and dementia with Lewy bodies, previous post-mortem studies have shown that over 70% of patients with dementia with Lewy bodies and 50% of patients with Parkinson’s disease dementia also have comorbid Alzheimer’s disease pathology. Given the recent approval of antibody treatments for Alzheimer’s disease, understanding the comorbid Alzheimer’s pathology in Lewy body disease is crucial as it may serve as a potential treatment target. This study aimed to elucidate the comorbid Alzheimer’s disease pathology in the pre- and post-onset stages of Lewy body disease by measuring plasma biomarkers for Alzheimer’s disease (amyloid-β and phosphorylated tau 181) and neurodegeneration (neurofilament light chain) in 84 patients with Parkinson’s disease, 16 patients with dementia with Lewy bodies, 82 high-risk individuals, and 37 low-risk individuals without prodromal symptoms.
The study found that patients with Parkinson’s disease with cognitive impairment and patients with dementia with Lewy bodies had elevated levels of Alzheimer’s disease-related biomarkers (Aβ composite and p-tau181) compared to low-risk individuals. However, high-risk individuals did not show an increase in these biomarkers. The neurodegeneration marker neurofilament light chain (NfL) was elevated in patients with Parkinson’s disease and dementia with Lewy bodies and high-risk individuals compared to low-risk individuals (Figure 2).
Classifying the progression of Alzheimer’s pathology based on the presence (+) or absence (-) of amyloid-β (A), tau (T), and neurodegeneration (N) revealed that Parkinson’s disease and dementia with Lewy bodies patients had a higher proportion of A+T+(N)+, indicating comorbid Alzheimer’s pathology. In contrast, high-risk individuals showed a higher proportion of A-T-(N)+, suggesting neurodegeneration without Alzheimer’s pathology (Table 1).
In patients with Parkinson’s disease, Aβ composite levels were associated with cognitive function, while p-tau181 levels were associated with motor and non-motor symptoms. NfL levels were associated with cognitive function, motor symptoms, and non-motor symptoms. These findings suggested that Alzheimer’s disease-related changes affect both cognitive and motor functions. High-risk individuals showed no correlation between these biomarkers and clinical symptoms, but those with higher NfL levels had a higher rate of abnormal cardiac MIBG scintigraphy images. These results suggest that comorbid Alzheimer’s disease pathology in Parkinson’s disease and dementia with Lewy bodies begins to appear after the disease onset rather than during the prodromal phase. Additionally, the elevation of NfL in high-risk individuals, despite the absence of increased Alzheimer’s disease-related biomarkers, suggests that NfL may potentially detect α-synuclein-induced neurodegeneration in the prodromal phase.
In summary, this study suggests that Alzheimer’s disease-related changes in Lewy body disease begin to appear after the disease onset rather than in the prodromal phase. With the recent introduction of anti-amyloid-β antibody treatments for early-stage Alzheimer’s disease patients, comorbid Alzheimer’s pathology in Lewy body disease may become a future treatment target. Our research group is currently conducting longitudinal evaluations of high-risk individuals for Lewy body disease. We aim to elucidate further when comorbid Alzheimer’s pathology appears in Lewy body disease and how it affects neurological prognosis by longitudinally following and evaluating both Lewy body disease patients and high-risk individuals.