Multiple system atrophy with amyloid-β-predominant Alzheimer’s disease neuropathologic change

Tomoya Kon; Shojiro Ichimata; Daniel G Di Luca; Ivan Martinez-Valbuena; Ain Kim; Koji Yoshida; Abdullah A Alruwaita; Galit Kleiner; Antonio P Strafella; Shelley L Forrest; Christine Sato; Ekaterina Rogaeva; Susan H Fox; Anthony E Lang; Gabor G Kovacs

doi:10.1093/braincomms/fcae141

. 2024 Apr 17;6(3):fcae141. doi: 10.1093/braincomms/fcae141

Multiple system atrophy with amyloid-β-predominant Alzheimer’s disease neuropathologic change

Tomoya Kon ^1,², Shojiro Ichimata ^3,⁴, Daniel G Di Luca ^5,⁶, Ivan Martinez-Valbuena ⁷, Ain Kim ⁸, Koji Yoshida ^9,¹⁰, Abdullah A Alruwaita ^11,¹², Galit Kleiner ^13,¹⁴, Antonio P Strafella ^15,¹⁶, Shelley L Forrest ^17,^18,¹⁹, Christine Sato ²⁰, Ekaterina Rogaeva ²¹, Susan H Fox ²², Anthony E Lang ^23,^24,²⁵, Gabor G Kovacs ^26,^27,^28,^29,^30,^31,^✉

¹ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

² Department of Neurology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan

³ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

⁴ Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan

⁵ Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada

⁶ Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA

⁷ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

⁸ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

⁹ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

¹⁰ Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan

¹¹ Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada

¹² Neurology Department, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia

¹³ Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada

¹⁴ Movement Disorders and Spasticity Management Clinic, Pamela and Paul Austin Centre for Neurology and Behavioral Support, Baycrest Centre for Geriatric Care, Toronto, ON M6A 2E1, Canada

¹⁵ Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada

¹⁶ Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada

¹⁷ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

¹⁸ Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, ON M5T 0S8, Canada

¹⁹ Faculty of Medicine, Health and Human Sciences, Dementia Research Centre, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia

²⁰ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

²¹ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

²² Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada

²³ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

²⁴ Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada

²⁵ Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada

²⁶ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada

²⁷ Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada

²⁸ Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada

²⁹ Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, ON M5T 0S8, Canada

³⁰ Faculty of Medicine, Health and Human Sciences, Dementia Research Centre, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia

³¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada

^✉

Correspondence to: Gabor G. Kovacs, MD, PhD Tanz Centre for Research in Neurodegenerative Disease University of Toronto, 60 Leonard Ave, Toronto, ON M5T 0S8, Canada E-mail: gabor.kovacs@utoronto.ca

PMCID: PMC11073746 PMID: 38712319

Abstract

Multiple system atrophy is a neurodegenerative disease with α-synuclein pathology predominating in the striatonigral and olivopontocerebellar systems. Mixed pathologies are considered to be of low frequency and mostly comprise primary age-related tauopathy or low levels of Alzheimer’s disease-related neuropathologic change. Therefore, the concomitant presence of different misfolded proteins in the same brain region is less likely in multiple system atrophy. During the neuropathological evaluation of 21 consecutive multiple system atrophy cases, we identified four cases exhibiting an unusual discrepancy between high Thal amyloid-β phase and low transentorhinal Braak neurofibrillary tangle stage. We mapped α-synuclein pathology, measured the size and number of glial cytoplasmic inclusions and compared the amyloid-β peptides between multiple system atrophy and Alzheimer’s disease. In addition, we performed α-synuclein seeding assay from the affected putamen samples. We performed genetic testing for APOE, MAPT, PSEN1, PSEN2 and APP. We refer to the four multiple system atrophy cases with discrepancy between amyloid-β and tau pathology as ‘amyloid-β-predominant Alzheimer’s disease neuropathologic change-multiple system atrophy’ to distinguish these from multiple system atrophy with primary age-related tauopathy or multiple system atrophy with typical Alzheimer’s disease neuropathologic change. As most multiple system atrophy cases with mixed pathologies reported in the literature, these cases did not show a peculiar clinical or MRI profile. Three amyloid-β-predominant Alzheimer’s disease neuropathologic change-multiple system atrophy cases were available for genetic testing, and all carried the APOE ɛ4 allele. The extent and severity of neuronal loss and α-synuclein pathology were not different compared with typical multiple system atrophy cases. Analysis of amyloid-β peptides revealed more premature amyloid-β plaques in amyloid-β-predominant Alzheimer’s disease neuropathologic change-multiple system atrophy compared with Alzheimer’s disease. α-Synuclein seeding amplification assay showed differences in the kinetics in two cases. This study highlights a rare mixed pathology variant of multiple system atrophy in which there is an anatomical meeting point of amyloid-β and α-synuclein, i.e. the striatum or cerebellum. Since biomarkers are entering clinical practice, these cases will be recognized, and the clinicians have to be informed that the prognosis is not necessarily different than in pure multiple system atrophy cases but that the effect of potential α-synuclein-based therapies might be influenced by the co-presence of amyloid-β in regions where α-synuclein also aggregates. We propose that mixed pathologies should be interpreted not only based on differences in the clinical phenotype but also on whether protein depositions regionally overlap, potentially leading to a different response to α-synuclein-targeted therapies.

Keywords: alpha-synuclein, Alzheimer’s disease, amyloid-β, multiple system atrophy, tau

Kon et al. report multiple system atrophy cases with a discrepancy between high Thal amyloid-β phase and low Braak tangle stage lacking specific clinical features but showing anatomic meeting points for amyloid-β and α-synuclein. They propose that mixed pathologies should be interpreted also based on regional overlap of proteins.

Graphical Abstract

Introduction

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by various combinations of parkinsonism, cerebellar ataxia and autonomic dysfunction.^1,2 Pathologically, MSA is associated with predominant neuronal loss in the striatonigral and/or olivopontocerebellar systems, accompanied by the presence of characteristic α-synuclein (α-syn)-immunoreactive (ir) glial cytoplasmic inclusions (GCIs) distributed throughout the central nervous system.^1,2

Mixed pathologies are frequently observed in neurodegenerative diseases, which contribute to clinical symptoms.^3-6 Among these, Alzheimer’s disease-related neuropathologic change (ADNC) is the most frequent, characterized by the concomitant presence of neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques both following a characteristic hierarchical sequence.^7-9 In typical ADNC, the six stages of NFT and the five phases of Aβ pathologies increase in parallel. Cases with mild to moderate NFT pathology (Braak NFT Stages I–IV) and an absence of or minimal Aβ plaques (Thal Phases 0–2) are referred to as primary age-related tauopathy (PART).¹⁰ On the contrary, extensive Aβ pathology involving subcortical regions, the brainstem and cerebellum (i.e. Thal Phase 4 or 5) with tau pathology restricted to the transentorhinal/entorhinal regions (i.e. Braak Stage I or II) is a rare phenomenon: in a recent large international cohort, it represented 41 out of 2334 (1.7%).¹¹ Although mixed pathologies are usually mild, they can be observed in MSA patients^5,6,12-17 and typically comprise PART or low-level ADNC.

In this study, we describe four cases of MSA with a notable mixed pathology, revealing a remarkable discrepancy of widespread, high Thal phase and severe Aβ but minimal, low Braak stage tau pathology. We raise awareness of this variant, particularly since it provides the opportunity for the interaction of Aβ and α-syn in MSA-strategic anatomical regions, carrying the potential to influence the response to α-syn-targeted therapies. This supports the notion that cases with mixed proteinopathies might relate to distinct ‘strain-like’ features compared with those accumulating only one protein.^5,6,17

Materials and methods

Case materials

We included 21 consecutive MSA and 124 consecutive non-MSA cases from the University Health Network Neurodegenerative Brain Collection, University of Toronto (Toronto, Canada) between 1982 and 2023. For the non-MSA cases, we included cases where the apolipoprotein E (APOE) genotype was available (for details, see Supplementary Table 1). Clinical details were obtained from a retrospective review of clinical records. All brains were obtained post-mortem through appropriate consenting procedures with Local Ethical Committee approval. This study received approval from the University Health Network Research Ethics Board (Nr. 20-5258) and the University of Toronto (Nr. 39459), adhering to the ethical standards established in the 1964 Declaration of Helsinki, updated in 2008.

Neuropathologic assessment

Routine histological examination and immunohistochemistry were performed on 4-μm formalin-fixed paraffin-embedded tissue sections, targeting different Aβ epitopes,^18,19 including pan-Aβ (6F/3D), Aβ₄₀, Aβ₄₂, Aβ₄₃, pyroglutamate Aβ at the third glutamic acid (Aβ_Np3E), phosphorylated-Aβ at the eighth serine (Aβ_pSer8), anti-phosphorylated-tau, anti-α-syn and anti-phosphorylated TDP-43 antibodies. Supplementary Table 2 summarizes the antibodies and immunostaining pre-treatments used in this study. Immunostaining was conducted using the Dako Autostainer Link 48 and EnVision FLEX+ Visualization System, following the manufacturer’s instructions. All sections were subsequently counterstained with haematoxylin.

ADNC was assessed following the National Institute on Aging-Alzheimer’s Association guidelines.⁹ Additionally, the types of cerebral amyloid angiopathy (CAA),²⁰ Lewy,²¹ TDP-43²² and vascular pathologies^21,22 including arteriolosclerosis, infarcts and haemorrhages were evaluated.

In addition to the staging system described above, we semi-quantitatively graded the severity of neuronal loss, α-syn-ir neuronal cytoplasmic inclusions (NCIs) and GCIs and Aβ plaques using a 5-point scoring system as follows: Score 0, absence of pathology; Score 1, minimal; Score 2, mild; Score 3, moderate; and Score 4, severe.^23,24 Neuronal loss and vascular lesions were assessed on haematoxylin and eosin (H&E) staining. The severity of CAA was scored under a 10× objective lens as follows: Score 0, no CAA; Score 1, occasional blood vessels with CAA (<20%); Score 2, a moderate number (20–60%) of blood vessels with CAA; and Score 3, many (>60%) blood vessels with CAA.^23,25

Morphometry of α-syn-ir GCIs

The morphological variables (i.e. the size, number and area density of all α-syn pathology) in the putamen and cerebellum were quantified following previously established protocols²⁶ in four cases of Aβ-predominant ADNC-MSA (MSA 1–4) and 12 cases of non-Aβ-predominant ADNC-MSA (MSA 6, 8–12 and 15–20). The details of the method are provided in the Supplementary method. In brief, sections of the basal ganglia and cerebellum, immunostained with disease-associated α-syn (5G4), were scanned at 40× magnification using the TissueScope LE120 (Huron, Saint Jacobs, Canada). The putamen and cerebellar white matter were manually outlined and dissected using Adobe Photoshop software. To measure the size of GCIs, a minimum–maximum threshold was established to exclude non-GCI immunoreactivity and overlapping GCIs. Using this threshold on the dissected subregion image, the size of each GCI (in square pixels, px²) was quantified using the ‘analyse particles’ tool in ImageJ, after converting the images into binary. The number of GCIs was quantified using the ‘analyse particles’ tool on the image of the dissected subregion with the applied threshold, and the total ‘count’ was recorded. Subsequently, the total GCI ‘count’ was divided by the total area of tissue to calculate GCIs/mm². The density of all types of α-syn pathology was determined using the ‘analyse particles’ tool in ImageJ. The individual morphological variables were pooled and categorized into Aβ-predominant or non-Aβ-predominant groups.

Double-labelled immunofluorescent staining

Double-labelled immunostaining was conducted on the basal ganglia sections obtained from four cases exhibiting Aβ-predominant ADNC-MSA (MSA 1–4). The primary antibody cocktail targeting Aβ (6F3D) and phosphorylated-α-syn (EP1536Y) was incubated overnight, followed by staining with secondary antibodies labelled with Alexa Fluor 488 and 555, as detailed in Supplementary Table 2. To mitigate autofluorescence, 1% Sudan Black B was introduced. The prepared sections were then mounted using ProLong Gold antifade reagent containing 4′,6-diamidino-2-phenylindole. Image acquisition was executed with a Nikon C2Si+ confocal microscope equipped with a 40× objective lens, and the images were captured using NIS-Elements AR software.

α-syn seeding amplification assay

α-syn seeding amplification assay was performed to investigate the seeding capacity of the misfolded α-syn present in the putamen. This assay was conducted in three cases of Aβ-predominant ADNC-MSA (MSA 1–3), one case of intermediate form Aβ-predominant ADNC-MSA (MSA 5) and four cases of non-Aβ-predominant ADNC-MSA (MSA 12, 14, 19 and 20), as previously reported.^27,28

Genetic analysis

The genotypes for APOE and microtubule-associated protein tau (MAPT) and the presence of pathogenic mutations in amyloid precursor protein (APP) and the presenilin genes (PSEN1 and PSEN2) were examined as previously described.²⁹

ADNC density plot

Both A (Thal Aβ phases) and B (Braak NFT stages) scores in ADNC were plotted for all APOE genotype available MSA and non-MSA cases (n = 143), and a regression line and 95% confidence intervals were generated using JMP 14.3 software (JMP Statistical Discovery LLC, Cary, NC, USA). The plotted density distribution was represented as the quantile density contour.

Literature review

We conducted a literature review of Aβ-predominant ADNC-MSA cases using PubMed on 1 November 2023. The search terms included ‘multiple system atrophy’ AND ‘autopsy’; ‘multiple system atrophy’, AND ‘pathology’; ‘multiple system atrophy’ AND ‘Alzheimer’; ‘multiple system atrophy’ AND ‘Alzheimer’s disease’, ‘multiple system atrophy’ AND ‘amyloid’; ‘multiple system atrophy’ AND ‘Aβ’. The inclusion criteria to define Aβ-predominant ANDC-MSA encompassed cases featuring individuals with a Thal phase of 4 or higher and a Braak NFT stage of II or lower, corresponding to National Institute on Aging-Alzheimer’s Association ADNC ABC scores A3B1 and A3B0.

Statistical analysis

Categorical variables were analysed using Fisher’s exact test, while continuous variables were analysed using the Mann–Whitney U test. Propensity score matching was used to compare the frequency of Aβ-predominant ADNC cases and APOE ɛ4 carriers between MSA and non-MSA cases. Statistical analyses were conducted using SPSS Statistics (version 23, IBM, Chicago, IL, USA) and JMP 14.3 (JMP Statistical Discovery LLC, Cary, NC, USA). Significance levels were set at P < 0.05 utilizing a two-tailed approach.

Results

Summary of the demographic and clinical features of the cohort

Table 1 summarizes the clinical, genetic and pathological features of MSA cases, which consisted of 21 consecutive MSA patients, with 15 of them being female. Detailed clinical, genetic, radiological and pathological features were also summarized in Supplementary Table 3. All patients were confirmed to have MSA through autopsy. Among them, four cases (19%; MSA 1–4) exhibited a Thal phase of 5, and one case (MSA 5) was Thal Phase 3, with corresponding Braak stages ranging from 1 to 2. The remaining cases had Thal Phases 0–2 with Braak Stages 0–II. The four cases with Thal Phase 5 had peculiar characteristics as described below; we defined them as ‘Aβ-predominant ADNC-MSA’ and one case of Thal Phase 3 as ‘intermediate form of Aβ-predominant ADNC-MSA’, to distinguish from the 16 cases lacking this feature (non-Aβ MSA). Among the latter MSA cases, one patient (MSA 6) was pure MSA without any other mixed pathologies, while the remaining 15 cases displayed mixed pathology compatible with PART.¹⁰ All patients received a diagnosis of clinically established or probable MSA,¹ except for one patient in the non-Aβ-predominant ADNC-MSA (MSA 7), diagnosed with clinically established Parkinson’s disease.³⁰ There were no statistically significant differences in age at onset, age at death, disease duration, clinical MSA subtypes (MSA-P or MSA-C) or the presence of cognitive impairment, Parkinsonism, cerebellar signs, autonomic failure or levodopa responsiveness between Aβ and non-Aβ-predominant MSA cases. The frequency of the APOE ɛ4 allele was not significantly different between Aβ-predominant ADNC-MSA and non-Aβ MSA cases (3 out of 3 cases versus 5 out of 15 cases, P = 0.07). There was no significant difference in the prevalence of carriers with MAPT H1/H1 or H2/H2 haplotypes between Aβ-predominant and non-Aβ-predominant patients. None of the Aβ-predominant cases had mutations in APP, PSEN1 or PSEN2. Radiologically, the frequency of typical MSA findings,¹ encompassing atrophy in the putamen, brainstem (including the ‘hot-cross-bun sign’) and cerebellum, did not differ between Aβ-predominant ADNC-MSA and non-Aβ MSA cases. Pathologically, Aβ-predominant ADNC-MSA cases displayed a higher incidence of CAA compared with non-Aβ MSA cases (4 out of 4 cases versus 2 out of 16 cases, P = 0.003).

Table 1.

Summary of the clinical, genetic and pathological findings of the MSA cohort

	Clinical findings				Genetics		Pathological findings
Case	Sex	Age at death	Disease duration, years	Clinical diagnosis	ApoE	MAPT	ADNC	CAA type*
MSA 1	F	64	6	MSA-P	3/4	H1/H1	A3B1C2 (T5, BrII)	Type 1
MSA 2	F	61	3	MSA-C	4/4	H1/H1	A3B1C2 (T5, BrI)	Type 1
MSA 3	F	74	6	MSA-P	3/4	H1/H1	A3B1C2 (T5, BrII)	Type 1
MSA 4	F	69	6	MSA-P	n.a.	n.a.	A3B1C2 (T5, BrI–II)	Type 1
MSA 5	M	69	12	MSA-C	3/3	H1/H2	A2B1C1 (T3, BrI)	Type 2
MSA 6	F	46	6	MSA-P	3/4	H1/H1	A0B0C0 (T0, Br0)	-
MSA 7	F	46	6	PD	3/3	H1/H1	A0B1C0 (T0, BrI)	-
MSA 8	F	76	6	MSA-P	3/4	H2/H2	A0B1C0 (T0, BrII)	-
MSA 9	M	64	4	MSA	3/3	H1/H1	A0B1C0 (T0, BrII)	-
MSA 10	M	62	10	MSA-C	3/3	H1/H1	A0B1C0 (T0, BrII)	-
MSA 11	M	62	15	MSA-C	3/3	H1/H1	A0B1C0 (T0, BrII)	-
MSA 12	F	61	4	MSA-P	3/3	H1/H1	A0B1C0 (T0, BrI)	-
MSA 13	M	68	5	MSA-P	3/3	H1/H1	A0B1C0 (T0, BrII)	-
MSA 14	F	76	4	MSA-P	3/3	H1/H1	A0B1C0 (T0, BrI)	-
MSA 15	M	73	7	MSA	3/3	H1/H2	A1B1C0 (T1, BrI)	-
MSA 16	F	69	4	MSA-P	3/3	H1/H1	A1B1C0 (T2, BrII)	-
MSA 17	F	68	6	MSA	3/4	H1/H1	A1B1C0 (T1, BrII)	Type 1
MSA 18	F	71	7	MSA-P	2/4	H1/H1	A1B1C1 (T2, BrII)	-
MSA 19	F	64	5	MSA-P	3/3	H1/H1	A1B1C0 (T1, BrI)	-
MSA 20	F	66	8	MSA-P	2/4	H1/H1	A1B1C0 (T1, BrI)	Type 2
MSA 21	F	66	7	MSA-C	n.a.	n.a.	A1B1C1 (T1, BrI)	-

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Cases 1–4 represent Aβ-predominant ADNC-MSA cases.

ADNC, Alzheimer’s disease neuropathologic change; APOE, apolipoprotein E: Br, Braak NFT stage; CAA, cerebral amyloid angiopathy; n.a, not available; T, Thal Aβ phase.

*P < 0.05, MSA 1–4 versus MSA 5–21 by Fisher’s exact test.

Pathological findings of MSA with divergent Aβ phase and NFT stage

We identified four cases that fulfilled the criteria for ADNC A3B1, which we refer to Aβ-predominant ADNC-MSA cases. Figure 1 and Table 2 present the pathological features of the four Aβ-predominant MSA cases. All cases exhibited neuronal loss, α-syn-ir NCIs and GCIs in both the striatonigral and olivopontocerebellar systems. These findings were consistent with typical MSA pathology. Only one case (MSA 1) showed a few α-syn-ir NCIs in the hippocampus. Regarding Aβ pathology, diffuse plaques were abundant in the temporal cortex and striatum in all four cases, in the frontal cortex in three out of four cases and in the occipital cortex in two out of four cases. Less amount of cored plaques was observed in the cerebral cortices in all four cases. A defining characteristic of these cases was that tau pathology was minimal in all four. CAA pathology was present with capillary CAA being prominent in all four cases in the cerebral cortices and cerebellum, particularly in the occipital cortex. All four cases showed relatively uniform pathology, with many diffuse plaques in the cerebral cortices and basal ganglia, and prominent capillary CAA in the cerebral cortices with the most severe in the occipital cortex in three carries of APOE ɛ4 allele (MSA 4 was unavailable for genetic testing). Vascular pathologies, except for CAA, as well as Lewy-type and TDP-43 pathologies, were absent in all Aβ-predominant ADNC-MSA cases (Table 2). Given that the occurrence of mixed pathology involving Lewy-type, TDP-43 and vascular pathologies in MSA is only 5–8% in a large cohort¹⁷ and our Aβ-predominant ADNC-MSA cases did not contain any of these pathologies, we concentrated on the assessment of ADNC pathology in the subsequent analyses.

**Representative images of Aβ-predominant Alzheimer’s disease neuropathological changes MSA.** Absence of phosphorylated tau immunoreactivity in the temporal cortex, contrasting with widespread and severe Aβ pathologies throughout the brain. The substantia nigra was not available in MSA 4. Bars represent 100 μm. Cbll, cerebellum; Hippo, hippocampus; Occ, occipital cortex; pTau, phosphorylated tau; SN, substantia nigra; Str, striatum; Temp, temporal cortex.

Table 2.

Pathological features of MSA cases with Aβ-predominant ADNC

	MSA 1	MSA 2	MSA 3	MSA 4
Lewy pathology	None	None	None	None
TDP-43 pathology	None	None	None	None
MSA pathology
Putamen
Neuronal loss	4	0	4	4
α-Synuclein-positive NCI/GCI	4/4	1/2	4/4	4/4
Substantia nigra
Neuronal loss	3	2	3	n.a.
α-Synuclein-positive NCI/GCI	3/4	2/2	2/3	n.a.
Pontine base
Neuronal loss	2	4	1	n.a.
α-Synuclein-positive NCI	3/4	3/4	2/3	n.a.
Inferior olivary nuclei
Neuronal loss	2	4	0	n.a.
α-Synuclein-positive NCI	2/1	3/1	1/1	n.a.
Cerebellum
Neuronal loss (Purkinje cells)	2	3	2	2
α-Synuclein-positive NCI/GCI	0/4	0/4	0/3	0/2
Hippocampus
Neuronal loss	0	0	0	0
α-Synuclein-positive NCI/GCI	2/2	0/1	0/1	0/1
Aβ pathology (6F3D)
Frontal cortex
Diffuse plaque/cored plaque	4/2	4/2	4/2	2/1
CAA capillary/non-capillary	3/0	3/0	4/3	3/3
Temporal cortex
Diffuse plaque/cored plaque	4/2	4/2	4/2	4/2
CAA capillary/non-capillary	3/0	3/0	3/0	3/0
Occipital cortex
Diffuse plaque/cored plaque	1/1	4/1	3/2	1/0
CAA capillary/non-capillary	3/4	4/4	4/4	4/4
Hippocampus
Diffuse plaque/cored plaque	3/0	3/0	3/0	1/0
CAA capillary/non-capillary	2/3	1/0	2/0	0/0
Striatum
Diffuse plaque/cored plaque	4/0	4/0	4/1	4/0
CAA capillary/non-capillary	0/0	0/0	1/0	2/0
Midbrain
Diffuse plaque/cored plaque	2/0	1/0	1/0	n.a.
CAA capillary/non-capillary	1/0	0/0	0/0	n.a.
Cerebellum
Diffuse plaque/cored plaque	3/0	2/0	3/0	1/0
CAA capillary/non-capillary	3/1	3/3	3/2	3/1

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Aβ, amyloid-beta; CAA, cerebral amyloid angiopathy; GCI, glial cytoplasmic inclusion; NCI, neuronal cytoplasmic inclusion; NFT, neurofibrillary tangle.

Next, we compared the Aβ pathology in Aβ-predominant ADNC-MSA with Alzheimer’s disease cases without α-syn, TDP-43 or vascular pathologies, using antibodies for various Aβ peptides in the temporal cortex and striatum (summarized in Supplementary Fig. 1 and Table 3). Aβ-predominant ADNC-MSA cases had lower Braak NFT and CERAD stages compared with Alzheimer’s disease cases with similar Thal Aβ-phase (P < 0.001 and P < 0.01, respectively). In the temporal cortex and striatum, Aβ-predominant ADNC-MSA cases exhibited fewer cored plaques with pan-Aβ (6F/3D), Aβ₄₀, Aβ₄₂, Aβ₄₃ and Aβ_Np3E than Alzheimer’s disease cases (P < 0.05). Furthermore, Aβ-predominant ADNC-MSA cases showed fewer Aβ₄₀- and Aβ₄₃-ir diffuse plaques in the striatum than Alzheimer’s disease cases (P < 0.05 and P < 0.01, respectively).

Table 3.

Aβ-peptide molecular signatures between MSA cases with Aβ-predominant ADNC and Alzheimer’s disease cases

	MSA 1	MSA 2	MSA 3	MSA 4	AD1	AD2	AD3	AD4	P-value
Thal Aβ phase	5	5	5	5	4	5	5	5	n.s.
Braak NFT stage	II	I	II	I–II	VI	VI	VI	VI	<0.001
CERAD	2	2	2	2	3	3	3	3	<0.01
Aβ immunoreactivity
Temporal cortex
Pan-Aβ (6F3D)
Diffuse plaque	4	4	4	4	4	4	4	4	n.s.
Cored plaque	2	2	2	2	4	3	3	3	<0.05
Aβ₄₀
Diffuse plaque	3	2	4	3	3	4	4	3	n.s.
Cored plaque	2	0	1	1	3	3	3	3	<0.05
Aβ₄₂
Diffuse plaque	4	4	4	4	4	4	4	4	n.s.
Cored plaque	2	2	2	2	4	4	3	3	<0.05
Aβ₄₃
Diffuse plaque	4	4	4	4	4	4	4	4	n.s.
Cored plaque	2	1	2	2	4	4	3	3	<0.05
Aβ_Np3E
Diffuse plaque	4	4	4	4	4	4	4	4	n.s.
Cored plaque	2	2	2	2	4	3	3	3	<0.05
Aβ_pSer8
Diffuse plaque	3	3	3	3	4	4	3	2	n.s.
Cored plaque	2	1	2	1	3	2	2	2	n.s.
Striatum
Pan-Aβ (6F3D)
Diffuse plaque	4	4	4	4	4	4	4	4	n.s.
Cored plaque	0	0	1	0	2	3	2	1	<0.05
Aβ₄₀
Diffuse plaque	0	0	1	0	2	3	3	2	<0.05
Cored plaque	0	0	0	0	2	3	2	0	<0.05
Aβ₄₂
Diffuse plaque	4	4	4	4	4	4	4	4	n.s.
Cored plaque	0	0	1	0	2	3	2	1	<0.05
Aβ₄₃
Diffuse plaque	3	3	3	3	4	4	4	4	<0.01
Cored plaque	0	0	0	0	2	3	2	0	<0.05
Aβ_Np3E
Diffuse plaque	4	4	4	4	4	3	4	4	n.s.
Cored plaque	0	0	0	0	2	3	2	1	<0.05
Aβ_pSer8
Diffuse plaque	3	2	3	1	3	3	4	1	n.s.
Cored plaque	0	0	1	0	2	3	0	0	n.s.

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Mann–Whitney U test is applied for statistics. The values highlighted in bold indicate statistical significance.

Aβ_Np3E, pyroglutamate Aβ at the third glutamic acid; Aβ_pSer8, phosphorylated-Aβ at the eighth serine; n.s., not significant.

Double-labelled immunofluorescent staining

Given the identification of both Aβ plaques and α-syn-ir GCIs in the striatum, further double-labelled immunofluorescent staining was performed. It is noteworthy that Aβ plaques, α-syn-ir GCIs and neurites did not co-localize in GCIs in Aβ-predominant ADNC-MSA; however, due to the diffuse fine granular deposition pattern of Aβ in the neuropil, a few α-syn dots in the neuropil did co-exist in the same locations (Supplementary Fig. 2).

Morphometry of α-syn-ir GCIs

The mean size of GCIs, the number of GCIs/mm² and the area density of all types of α-syn pathology in the putamen and cerebellum white matter were similar between Aβ-predominant ADNC-MSA cases and non-Aβ MSA cases (Fig. 2A and Supplementary Fig. 3; n = 4 versus n = 12).

α-syn seeding amplification assay

α-syn seeding amplification assay was performed in eight cases, including three Aβ-predominant ADNC-MSA (MSA 1–3), one intermediate form Aβ-predominant ADNC-MSA (MSA 5) and four non-Aβ-MSA cases (MSA 12, 14, 19 and 20). Among these, two cases exhibited distinctive seeding curves (Fig. 2B). Both cases had Aβ pathology in the putamen, with one being Aβ-predominant ADNC-MSA (MSA 1) and the other intermediate form Aβ-predominant ADNC-MSA case (MSA 5). In contrast, two other Aβ-predominant ADNC-MSA cases (MSA 2 and 3) and four cases lacking Aβ pathology in the putamen displayed comparable seeding kinetics (Fig. 2B).

Impact of APOE ɛ4 allele on Aβ-predominant ADNC pathology

To explore whether the discrepancy between extensive Aβ but minimal tau pathology is associated with the presence of APOE ɛ4 allele, we further examined Alzheimer’s disease neuropathologic change in 124 consecutive various non-MSA-type neurodegenerative diseases and 19 MSA cases for which APOE genotypes were available. Among these cases, 53 (42.7%) were APOE ɛ4 carriers. The frequency of APOE ɛ4 carriers did not differ between MSA and non-MSA cases (8/19 versus 53/124, P = 1). In the non-MSA cohort, only four cases (3.2%) that were all APOE ɛ4 carriers exhibited ADNC score A3B1 (see Supplemental Table 1). The frequency of Aβ-predominant ADNC cases was significantly higher in MSA than in non-MSA cases (3/19 versus 4/124, P < 0.05). However, when age and sex were matched using propensity scores, there were no statistical differences (P = 0.6). In Fig. 3A, ADNC A and B scores, the regression line and 95% confidence intervals are plotted in MSA and non-MSA cases with available APOE genotypes (n = 143), revealing a strong correlation between ADNC A and B scores (r = 0.71, P < 0.001), with ADNC A3B1 above the upper limit of the 95% confidence interval. Figure 3B and C shows ADNC A and B scores in all APOE ɛ4 carriers (n = 61) and all APOE ɛ4 non-carriers (n = 82), respectively, suggesting the presence of APOE ɛ4 increases the baseline of the A score. Figure 3D and E depicts ADNC A and B scores in MSA APOE ɛ4 carriers (n = 8) and non-MSA APOE ɛ4 carriers (n = 53), respectively, indicating that the regression line is steeper in MSA than in non-MSA cases, which is supporting the observation of the discrepancy between A and B scores in our MSA cohort.

**National Institute on Aging-Alzheimer’s Association ADNC score plot.** ADNC A and B scores in all cases (A, n = 143), all *APOE* ɛ4 carriers (B, n = 61), all *APOE* ɛ4 non-carriers (C, n = 82), MSA *APOE* ɛ4 carriers (D, n = 8) and non-MSA *APOE* ɛ4 carriers (E, n = 53). The regression line (**A–E**) and the upper and lower 95% confidence intervals (A) are graphically represented.

Literature review

Our literature review identified three Aβ-predominant ADNC-MSA cases out of a total of 38 cases reported.^5,31,32 These cases are summarized in Table 4. The prevalence of Aβ variant MSA cases was found to be 3.8–9.1% in each cohort, with a total pooled prevalence of 7.9% (excluding a single case report). While this prevalence appears lower compared with our cohort, it did not show a statistically significant difference (P = 0.22). The median age at death was 68, and there was no statistical significance in comparison with our Aβ variant cases. Disease duration was reported for two patients (21 and 12 years), while one patient was not described. Cognitive status was only reported in two patients who showed no impairment, but their cognition was not formally evaluated. APOE genotype was reported for only one patient, which was as ɛ3/ɛ4.

Table 4.

Previously reported MSA cases with Aβ-predominant ADNC

Authors	Coughlin et al.³¹	Koga et al.³²	Robinson et al.⁵
Year	2022	2020	2018
Country	USA	USA	USA
Number of cases	1	1	1
ADNC	A3B1C1 (T5, BrII)	A3B1Cn.d. (T4, BrII)	A3B0-1Cn.d. (T4–5, Br 0–II)
Pathological MSA types	Mixed	Mixed (mixed pathology with LBD)	n.d.
Clinical MSA subtypes	MSA-P	MSA-C	n.d.
Age at death (years)	66	70	n.d.
Disease duration (years)	21	12	n.d.
Sex	F	M	n.d.
Percentages in the cohort	100% (1/1)	9.1% (1/11)	3.8% (1/26)
Cognitive impairment	n.d.	-	n.d.
Cognitive test	n.e.	n.e.	n.d.
Initial symptoms	Parkinsonism + autonomic	Gait ataxia	n.d.
Parkinsonism	+	+	n.d.
Cerebellar symptoms	−	+	n.d.
Autonomic failure	+	+	n.d.
L-DOPA efficacy	−	n.d.	n.d.
ApoE4 genotypes	n.d.	ɛ3ɛ4	n.d.
MRI findings	Hot cross ban +, marked atrophy in the pons and cerebellum	n.d.	n.d.

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ADNC, Alzheimer’s disease neuropathologic change; APOE, apolipoprotein E: Br, Braak NFT stage; LBD, Lewy body disease; n.d, not described; n.e., not examined; T, Thal Aβ phase.

Discussion

In this study, we present four cases of MSA with a discrepancy between a high Thal phase of Aβ deposition and a low Braak NFT stage. This discrepancy is unusual and unexpected even given the patients’ APOE genotype status and shorter disease duration than if they had pure Alzheimer’s disease without MSA. These cases showed only mild or no cognitive impairment, and the clinical and radiological features were not significantly different from cases without Aβ pathology.

ADNC is scored by staging schemes based on neuroanatomical hierarchy. Thal Aβ phase progresses from the neocortex through the hippocampus, basal ganglia/diencephalon, brainstem and cerebellum.⁸ Braak NFT staging begins in the entorhinal and limbic areas and progresses to neocortical regions.⁷ The prevalence of Alzheimer’s disease-related pathology increases with advancing age.^33,34 NFTs are found in over 80% of individuals in their 60s,^33,34 while Aβ plaques are observed in 30% of individuals in their 60s and 50–60% of individuals in their 80s.^33,34 Mixed pathologies are less frequent and typically mild in MSA patients.^{5,6,12-14,16,17} Based on these reports and our study, we consider four types of MSA based on ADNC-type mixed pathology: pure MSA, MSA with PART, MSA with typical ADNC where Braak NFT stages and Thal Aβ phases increase in parallel as reported in single case reports^35,36 and larger MSA cohorts,^5,12-17 and finally the Aβ-predominant ADNC-MSA as highlighted in this study.

Out of 21 cases in our MSA cohort, four cases (19%) exhibited the Aβ variant. The literature review revealed only three cases of Aβ-predominant ADNC-MSA (Table 4).^5,31,32 The prevalence of Aβ-predominant ADNC-MSA cases in our consecutive case collection is unexpectedly high (19%) compared with other studies (7.9%). Jellinger^12,13 and other groups^37-39 have reported Aβ alone co-pathology in MSA cases, but these reports did not specify the Thal phase; therefore, the Aβ-predominant ADNC-MSA might be higher in some cohorts. Although several studies evaluated a larger number of MSA cases, they either did not report ADNC^38,40,41 or reported only the mean or median values of Thal phases and Braak NFT stages for the pooled cohort^13-15,42 or did not report the ADNC score suggesting the discrepancy of extent and severity between Aβ and tau pathology has been under-recognized. A recent study reported Thal phases and Braak NFT stages¹⁷; however, a discrepancy between Thal phases and Braak stages in a degree reported here was not mentioned even in carriers of APOE ɛ4 allele. In a forensic cohort of young subjects (aged 30–65 years), mild Aβ pathology without any tau deposition was observed only in 23/431 subjects (5.3%), and the majority of these subjects carried the APOE ɛ4 allele.⁴³ This finding supports the notion that the presence of Aβ plaques in the cortex precedes NFT pathology and could be linked to genetic predisposition (e.g. APOE ɛ4). However, that forensic cohort did not report cases with Aβ pathology involving subcortical areas, brainstem and cerebellum with only minimal or no tau pathology. Cases with Aβ-predominant ADNC-MSA in our cohort carried the APOE ɛ4 allele. In the literature, only pooled data are available in connection to APOE genotypes, and a single case with APOE genotype (ɛ3/ɛ4) and Aβ pathology was reported.³² In our cohort, the MAPT haplotypes showed no association with Aβ-predominant ADNC-MSA cases, and the presence of pathogenic Alzheimer’s disease mutations in APP, PSEN1 or PSEN2 was excluded. The APOE ɛ4 allele is strongly associated with the typical constellation ADNC (i.e. plaques and tangles),^5,44 and both Aβ and tau pathologies typically advance concurrently.^45-47 Our investigation reveals that a significant proportion of APOE ɛ4 carriers, encompassing five out of eight cases within the MSA cohort and 50 of 53 cases within the non-MSA cohort, did not manifest the discrepancy between Aβ and tau pathologies. Consequently, the APOE ɛ4 alleles alone does not seem to be the driving force for the discrepancy between high Aβ Thal phases and low NFT Braak stages. Therefore, further genetic factors or ethnicity might contribute to variations in the reported frequencies of mixed pathologies. Furthermore, the reason for the high prevalence of Aβ-predominant ADNC-MSA in our cohort remains unclear since the age of our MSA patients is comparable with MSA cases reported from around the world. Unfortunately, larger cohorts, which report ADNC co-pathologies in MSA cases, do not specifically describe Aβ Thal phases and Braak NFT stages for each case, making it difficult to explore the frequency of Aβ-predominant ADNC-MSA cases. We believe that raising attention of this condition will facilitate collaborative efforts to explore whether there are peculiar aspects or genetic constellations that we might have missed due to the limited number of cases examined.

Importantly, the amyloid cascade hypothesis postulates that Aβ induces tau pathology⁴⁸; however, in Aβ-predominant ADNC cases, this pattern cannot be recognized. Indeed, Aβ-predominant ADNC cases are associated only with mild cognitive alterations, if any, supporting the notion that tau pathology is more associated with cognitive decline.⁴⁹ We are aware that the high Thal phase with low Braak NFT stage is not specific to MSA, as similar variants have been reported in other diseases, although they may have been under-recognized. Terry et al.⁵⁰ described ‘plaque-only dementia’ in 18 out of 60 (45%) Alzheimer’s disease cases in 1987, and later, they reported its association with Lewy pathology.⁵¹ A similar pathology has also been observed in 5 out of 29 (17.2%) Down syndrome cases.⁵² However, it is worth noting that these studies did not apply modern immunohistochemistry techniques including staining for Aβ, and ‘plaque-only dementia’ meant to represent cases with neuritic plaques without tangles in the cortex. Indeed, this is completely different from the concept of Aβ-predominant ADNC-MSA where the focus is on the distribution of Aβ deposits involving the striatum, brainstem and cerebellum as well. With the advancements in modern immunohistochemistry, cases with a predominant presence of Aβ plaques compared with tau pathology have rarely been reported, but their recognition remains limited. In population-representative cohorts in the UK, the prevalence of high Thal with low Braak stage co-pathologies ranged from 1.1% (six cases of Thal 4–5 with Braak NFT II in 186 cases)⁵³ to 1.9% (two cases of Thal 4–5 with Braak NFT I–II in 106 patients).⁵⁴ Additionally, this type of co-pathology has been observed in 2.6% of cases (five cases of Thal 4–5 with Braak NFT 0–II in 192 Alzheimer’s disease patients) in a multi-centre study in the USA.⁵⁵ In progressive supranuclear palsy cohorts, the prevalence of moderate to high Thal phase with low Braak stage co-pathology ranged from 3.4% (1/29 patients, Thal 3 with Braak I)⁵⁶ to 4.9% (4/81 patients, two cases of Thal 5 with Braak II and two cases of Thal 3 with Braak I).⁵⁷ In a community-based study from Austria (VITA study), a similar discrepancy was not found.⁴ A recent large international cohort evaluating the frequency of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) revealed that among cases without LATE-NC, 41 out of 2334 (1.7%) cases had Thal Phase 4 or 5 associated with Braak NFT Stages 0–II.¹¹

In Lewy body disease, the prevalence of high Thal phase and low Braak stage co-pathology has been reported to range from 3.2% (21/652 cases, Thal 4–5 with Braak Stage 0–II) to 4.5% (1/22 cases, Thal 4 with Braak II).^58,59 Kotzbauer et al.⁶⁰ reported that 19 of 32 patients (59%) with Parkinson’s disease dementia exhibited Aβ deposition (Braak amyloid Stages B and C) but little to moderate tau deposition (Braak NFT Stages 0–IV), although Thal phases were not reported in their cohort. Interestingly, Aβ accumulation in synucleinopathies appears to be more frequent than in tauopathies, suggesting a potential synergistic relationship between the pathological aggregation of α-syn and Aβ.^61-63 The accumulation of α-syn may further disrupt protein homoeostasis and contribute to the pathological accumulation of Aβ.^61,62 Understanding the mechanisms underlying this mixed pathology may shed light on specific interactions with α-syn and common mechanisms involving other proteins that contribute to neurodegeneration. Recent studies have identified distinct strains of Aβ,^19,64 and cryo-electron microscopy analysis has revealed polymorphisms in Aβ fibrils.^65,66 It is plausible that potential unknown interactions between α-syn and Aβ, or unidentified features of α-syn or Aβ, may contribute to the development of Aβ variant pathology.

In our cases with Aβ-predominant ADNC-MSA, morphologically diffuse plaques predominated, with fewer cored plaques compared with Alzheimer’s disease. The median age at death in Aβ-predominant ADNC-MSA cases was 66.5 years old, which is younger than typical Alzheimer’s disease cases where dementia usually develops after age 65.⁴⁴ Diffuse plaques precede the development of cored plaques.^29,30,61,62 Additionally, the prevalence of NFT pathology increases with age.^33,34,67,68 Therefore, we cannot exclude the possibility that patients with Aβ variant of MSA have not lived long enough to develop significant NFT pathology.

Cerebral cortex and striatal Aβ deposition are important pathological findings closely associated with the development of dementia in individuals with Lewy body disease.^69,70 We have recently reported that the molecular signature of Aβ peptides differs among various neurodegenerative diseases.^18,19 Therefore, we conducted further analyses of the Aβ peptides in Aβ variant of MSA, which demonstrated significantly fewer cored plaques in the temporal cortex and striatum than Alzheimer’s disease cases using pan-Aβ, Aβ₄₀, Aβ₄₂, Aβ₄₃ and Aβ_Np3E antibodies. Additionally, we observed fewer diffuse plaques in the striatum compared with Alzheimer’s disease in Aβ₄₀ and Aβ₄₃ immunoreactivity. Notably, the severity of Aβ_pSer8-ir diffuse and cored plaques in Aβ variant of MSA was similar to Alzheimer’s disease. Regarding the biochemical maturation process of Aβ in Alzheimer’s disease and/or Down syndrome, Aβ₄₂ and Aβ₄₃ are the first Aβ species to accumulate in the human brain.^52,71,72 Aβ₄₀ is detected subsequently, followed by Aβ_Np3E and/or Aβ_Np11E,^52,71,72 and finally, Aβ_pSer8 accumulates.^67,72 In Alzheimer’s disease patients and transgenic mouse brains, Aβ₄₃ has been found in diffuse and cored plaques, with Aβ₄₃ having the strongest propensity to aggregate, followed by Aβ₄₂ and Aβ₄₀.⁷³ Aβ_pSer8 is mainly restricted to symptomatic Alzheimer’s disease.⁶⁷ Fewer cored plaques in cases of Aβ variant of MSA than Alzheimer’s disease suggest that Aβ plaques in this variant are premature. On the other hand, the Aβ_pSer8 burden was similar to Alzheimer’s disease, indicating that Aβ plaques in this variant still contain the peptide thought to be toxic at a biochemical level.⁶⁷ The molecular signature of Aβ peptides might be influenced by the local α-syn accumulation contributing to the development of the pathology of the Aβ variant and cognitive impairment.

Prominent capillary CAA in the cerebral cortices, particularly in the occipital cortex, characterizes the advanced Thal phase of Aβ variant of MSA. This distribution and severity of Aβ plaques and CAA pattern align with Type 3, as reported by Allen et al.⁶⁹ Previous studies have indicated that capillary CAA is strongly associated with the APOE ɛ4 allele and higher Thal phase.^53,74 In line with these findings, three out of four genotyped Aβ-predominant ADNC-MSA cases (one case lacked genetic testing) carried the APOE ɛ4 allele. The prevalence of APOE ɛ4 carriers in our total MSA cohort was 42.1% (8/19), which appears higher than previous reports of 22%.^5,75 The APOE ɛ4 allele is strongly associated with the typical constellation ADNC (i.e. plaques and tangles),^5,44 and CAA is also an independent contributor to cognitive impairment.⁷⁶ Although it is plausible that the APOE ɛ4 allele may influence the distribution and severity of Aβ plaques and CAA pathology in Aβ-predominant ADNC-MSA, however, we demonstrated that APOE ɛ4 alone might not account for the discrepancy between Aβ Thal phases and Braak NFT stages.

In our study, Aβ-predominant ADNC-MSA cases exhibited only mild or no cognitive impairment. Previous reports have suggested that cognitive impairment in MSA is associated with the load of α-syn-ir NCIs in the hippocampus.^14,41,42 Clinical features of frontotemporal lobar degeneration with abundant α-syn-ir NCIs in the frontotemporal cortices and limbic systems are referred to as ‘FTLD-synuclein’.^77,78 MSA patients with severe α-syn-ir NCIs in the hippocampus have been referred to as ‘hippocampal MSA’.⁴² Therefore, it is conceivable that a particular subset of individuals with MSA may demonstrate increased susceptibility to α-syn-ir NCIs in the limbic system. However, only one case (MSA 1) of Aβ-predominant ADNC-MSA showed mild α-syn-ir NCIs in the hippocampus, while all others did not. Therefore, the mild cognitive impairment in our cases appears to be independent of the hippocampal α-syn-ir NCIs.

In two cases of MSA where both α-syn and Aβ were present in the putamen, distinct kinetic curves were observed compared with other MSA cases with and without Aβ in α-syn seeding amplification assay. Given the reported cross-seeding effects between α-syn and Aβ,^61,79-82 we cannot exclude the possibility that the presence of Aβ could influence the unique α-syn kinetic curves. Although we did not observe any differences in the morphometry or co-localization between Aβ and α-syn in GCIs, the co-presence of fine granular Aβ deposits α-syn dots in the neuropil support the notion that these two proteins have the opportunity to interact. These aspects merit further studies when such cases will be identified in other cohorts.

In conclusion, this study has unveiled the neuropathological features of Aβ-predominant ADNC-MSA, which were previously unappreciated, raising awareness of this variant. The limitation of our study is the relatively small number of patients included. Therefore, the exact frequency and specific clinical signature of this variant cannot be determined. Further larger studies are needed to determine whether there is a yet unidentified genetic aspect or other reason for the clustering detected in our cohort. These cases originated from a racially very diverse population in Toronto Canada so a genetic founder effect accounting for the proportion of such cases in our sample is highly unlikely. The stratification of this variant may be crucial for clinicians to provide precise treatments for subtypes of MSA. We propose a novel two-tiered approach to the interpretation of mixed pathologies to address the questions of whether (i) the additional misfolded protein contributes to or alters the clinical phenotype and (ii) there is an anatomical overlap between the misfolded protein deposits that allow direct interaction. Indeed, the Aβ-predominant ADNC-MSA variant is the most prone to fulfil the second premise, which theoretically could lead to an altered response to α-syn-directed therapies. Furthermore, disease-modifying therapies targeting Aβ have been rapidly evolving^83,84 and could be considered for combined therapies in such cases. Furthermore, in the Aβ-predominant ADNC-MSA variant, tau pathology, which is the major reason for accelerated cognitive impairment in cases with typical ADNC,^34,49,55 does not have an impact on the clinical progression. Since biomarker studies are entering clinical practice, these cases will be recognized, and the clinicians have to be informed that the prognosis is not necessarily different than in pure MSA cases and also that the effects of potential α-syn-based therapies might be influenced by the co-presence of amyloid in regions where α-syn also aggregates. Therefore, we believe that informing the clinicians about this phenotype is important. If one envisions the future of personalized medicine, the identification of variants that can be diagnosed with in vivo tau, Aβ and synuclein-based biomarkers is of high importance. Our study contributes to the understanding of the full spectrum of mixed pathology variants in MSA (summarized in Fig. 4).

**Spectrum of mixed pathology of ADNC in MSA.** Five constellations are shown: the most frequent is pure MSA pathology or MSA pathology associated with NFTs in the entorhinal cortex and hippocampus as in PART followed by low or less frequently intermediate and high levels of ADNC. The bar graph shows the case frequency of each subgroup. The dashed-line square represents the anatomical meeting points of multiple proteins. Regarding the consideration of using α-syn-targeted therapy in patients with high-level ADNC would largely be excluded due to the severe cognitive decline (indicated by a dash in the row indicating α-syn therapy trial). In contrast, cases of MSA with PART, MSA with low-level ADNC and Aβ-predominant ADNC-MSA groups might be included since the clinical phenotype is not significantly different (indicated by a ‘+’ in the row indicating α-syn therapy trial). Importantly, in Aβ-predominant ADNC-MSA cases, the possibility of an interaction between α-syn and Aβ is the highest, and therefore, this might have an effect on the outcome of the α-syn therapy trial and might justify the consideration of combined therapies separately targeting the two proteinopathies.

Supplementary Material

fcae141_Supplementary_Data

fcae141_supplementary_data.pdf^{(1MB, pdf)}

Acknowledgements

The authors particularly acknowledge the patients and their families for their donations.

Contributor Information

Tomoya Kon, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada; Department of Neurology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.

Shojiro Ichimata, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada; Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan.

Daniel G Di Luca, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA.

Ivan Martinez-Valbuena, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada.

Ain Kim, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada.

Koji Yoshida, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada; Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan.

Abdullah A Alruwaita, Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada; Neurology Department, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.

Galit Kleiner, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada; Movement Disorders and Spasticity Management Clinic, Pamela and Paul Austin Centre for Neurology and Behavioral Support, Baycrest Centre for Geriatric Care, Toronto, ON M6A 2E1, Canada.

Antonio P Strafella, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada; Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada.

Shelley L Forrest, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada; Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, ON M5T 0S8, Canada; Faculty of Medicine, Health and Human Sciences, Dementia Research Centre, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia.

Christine Sato, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada.

Ekaterina Rogaeva, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada.

Susan H Fox, Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada.

Anthony E Lang, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada; Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada.

Gabor G Kovacs, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 0S8, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada; Edmund J Safra Program in Parkinson’s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada; Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, ON M5T 0S8, Canada; Faculty of Medicine, Health and Human Sciences, Dementia Research Centre, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.

Supplementary material

Supplementary material is available at Brain Communications online.

Funding

This study was supported by the Rossy Family Foundation, Edmond J. Safra Philanthropic Foundation, Canada Foundation for Innovation John Evans Leaders Fund program (Award Number 40480), Ontario Research Fund and a grant from the Multiple System Atrophy Coalition (Nr: MSAC-2022-12-003). G.G.K. holds Rossy Chair in progressive supranuclear palsy research.

Competing interests

G.G.K. holds a shared patent for the 5G4 antibody and received royalty for 5G4 synuclein antibody. Other authors report no competing interests in relation to the work described.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

1. Wenning GK, Stankovic I, Vignatelli L, et al. The movement disorder society criteria for the diagnosis of multiple system atrophy. Mov Disord. 2022;37:1131–1148. [DOI] [PMC free article] [PubMed] [Google Scholar]
2. Stefanova N, Wenning GK. Multiple system atrophy: At the crossroads of cellular, molecular and genetic mechanisms. Nat Rev Neurosci. 2023;24:334–346. [DOI] [PubMed] [Google Scholar]
3. Forrest SL, Kovacs GG. Current concepts of mixed pathologies in neurodegenerative diseases. Can J Neurol Sci. 2023;50:329–345. [DOI] [PubMed] [Google Scholar]
4. Kovacs GG, Milenkovic I, Wohrer A, et al. Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: A community-based autopsy series. Acta Neuropathol. 2013;126:365–384. [DOI] [PubMed] [Google Scholar]
5. Robinson JL, Lee EB, Xie SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018;141:2181–2193. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Robinson JL, Xie SX, Baer DR, et al. Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated. Brain. 2023;146:2557–2569. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–259. [DOI] [PubMed] [Google Scholar]
8. Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791–1800. [DOI] [PubMed] [Google Scholar]
9. Montine TJ, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol. 2012;123:1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age-related tauopathy (PART): A common pathology associated with human aging. Acta Neuropathol. 2014;128:755–766. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Nelson PT, Brayne C, Flanagan ME, et al. Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: Combined data from 13 community-based or population-based autopsy cohorts. Acta Neuropathol. 2022;144:27–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
12. Jellinger KA. More frequent Lewy bodies but less frequent Alzheimer-type lesions in multiple system atrophy as compared to age-matched control brains. Acta Neuropathol. 2007;114:299–303. [DOI] [PubMed] [Google Scholar]
13. Jellinger KA. Neuropathological findings in multiple system atrophy with cognitive impairment. J Neural Transm (Vienna). 2020;127:1031–1039. [DOI] [PubMed] [Google Scholar]
14. Koga S, Parks A, Uitti RJ, et al. Profile of cognitive impairment and underlying pathology in multiple system atrophy. Mov Disord. 2017;32:405–413. [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Koga S, Cheshire WP, Tipton PW, et al. Clinical features of autopsy-confirmed multiple system atrophy in the Mayo Clinic Florida brain bank. Parkinsonism Relat Disord. 2021;89:155–161. [DOI] [PubMed] [Google Scholar]
16. Miki Y, Bettencourt C, Jaunmuktane Z, Holton JL, Warner TT, Wakabayashi K. Alzheimer’s disease pathology concomitant with memory impairment in late-onset multiple system atrophy. Neuropathol Appl Neurobiol. 2023;49:e12878. [DOI] [PubMed] [Google Scholar]
17. Sekiya H, Koga S, Murakami A, et al. Frequency of comorbid pathologies and their clinical impact in multiple system atrophy. Mov Disord. 2024;39:380–390. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Ichimata S, Yoshida K, Li J, Rogaeva E, Lang AE, Kovacs GG. The molecular spectrum of amyloid-beta (Abeta) in neurodegenerative diseases beyond Alzheimer’s disease. Brain Pathol. 2024;34:e13210. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Ichimata S, Martinez-Valbuena I, Lee S, Li J, Karakani AM, Kovacs GG. Distinct molecular signatures of amyloid-beta and tau in Alzheimer’s disease associated with down syndrome. Int J Mol Sci. 2023;24:11596. [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2002;61:282–293. [DOI] [PubMed] [Google Scholar]
21. Skrobot OA, Attems J, Esiri M, et al. Vascular cognitive impairment neuropathology guidelines (VCING): The contribution of cerebrovascular pathology to cognitive impairment. Brain. 2016;139:2957–2969. [DOI] [PubMed] [Google Scholar]
22. Schneider JA. Neuropathology of dementia disorders. Continuum (Minneap Minn). 2022;28:834–851. [DOI] [PMC free article] [PubMed] [Google Scholar]
23. Ichimata S, Yoshida K, Visanji NP, Lang AE, Nishida N, Kovacs GG. Patterns of mixed pathologies in Down syndrome. J Alzheimers Dis. 2022;87:595–607. [DOI] [PubMed] [Google Scholar]
24. Tanaka H, Hird MA, Tang-Wai DF, Kovacs GG. Significant contralaterality of temporal-predominant neuroastroglial tauopathy and FTLD-TDP type C presenting with the right temporal variant FTD. J Neuropathol Exp Neurol. 2023;82:187–191. [DOI] [PubMed] [Google Scholar]
25. Richard E, Carrano A, Hoozemans JJ, et al. Characteristics of dyshoric capillary cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2010;69:1158–1167. [DOI] [PubMed] [Google Scholar]
26. Kim A, Yoshida K, Kovacs GG, Forrest SL. Computer-based evaluation of α-synuclein pathology in multiple system atrophy as a novel tool to recognize disease-subtypes. Manuscript under review. [DOI] [PubMed]
27. Martinez-Valbuena I, Swinkin E, Santamaria E, et al. Alpha-synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders. Acta Neuropathol. 2022;144:167–185. [DOI] [PubMed] [Google Scholar]
28. Martinez-Valbuena I, Visanji NP, Kim A, et al. Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy. Transl Neurodegener. 2022;11:7. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Forrest SL, Tartaglia MC, Kim A, et al. Progressive supranuclear palsy syndrome associated with a novel tauopathy: Case study. Neurology. 2022;99:1094–1098. [DOI] [PubMed] [Google Scholar]
30. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30:1591–1601. [DOI] [PubMed] [Google Scholar]
31. Coughlin DG, Dryden I, Goodwill VS, et al. Long-standing multiple system atrophy-Parkinsonism with limbic and FTLD-type alpha-synuclein pathology. Neuropathol Appl Neurobiol. 2022;48:e12783. [DOI] [PMC free article] [PubMed] [Google Scholar]
32. Koga S, Li F, Zhao N, et al. Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease. Brain Pathol. 2020;30:766–778. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70:960–969. [DOI] [PubMed] [Google Scholar]
34. Ferrer I. Hypothesis review: Alzheimer’s overture guidelines. Brain Pathol. 2023;33:e13122. [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Bujan B, Hofer MJ, Oertel WH, Pagenstecher A, Burk K. Multiple system atrophy of the cerebellar type (MSA-C) with concomitant beta-amyloid and tau pathology. Clin Neuropathol. 2013;32:286–290. [DOI] [PubMed] [Google Scholar]
36. Terni B, Rey MJ, Boluda S, et al. Mutant ubiquitin and p62 immunoreactivity in cases of combined multiple system atrophy and Alzheimer's disease. Acta Neuropathol. 2007;113:403–416. [DOI] [PubMed] [Google Scholar]
37. Shibuya K, Nagatomo H, Iwabuchi K, Inoue M, Yagishita S, Itoh Y. Asymmetrical temporal lobe atrophy with massive neuronal inclusions in multiple system atrophy. J Neurol Sci. 2000;179:50–58. [DOI] [PubMed] [Google Scholar]
38. Cykowski MD, Coon EA, Powell SZ, et al. Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain. 2015;138:2293–2309. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Homma T, Mochizuki Y, Komori T, Isozaki E. Frequent globular neuronal cytoplasmic inclusions in the medial temporal region as a possible characteristic feature in multiple system atrophy with dementia. Neuropathology. 2016;36:421–431. [DOI] [PubMed] [Google Scholar]
40. Ozawa T, Paviour D, Quinn NP, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: Clinicopathological correlations. Brain. 2004;127:2657–2671. [DOI] [PubMed] [Google Scholar]
41. Miki Y, Foti SC, Hansen D, et al. Hippocampal alpha-synuclein pathology correlates with memory impairment in multiple system atrophy. Brain. 2020;143:1798–1810. [DOI] [PubMed] [Google Scholar]
42. Ando T, Riku Y, Akagi A, et al. Multiple system atrophy variant with severe hippocampal pathology. Brain Pathol. 2022;32:e13002. [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Pletnikova O, Kageyama Y, Rudow G, et al. The spectrum of preclinical Alzheimer’s disease pathology and its modulation by ApoE genotype. Neurobiol Aging. 2018;71:72–80. [DOI] [PubMed] [Google Scholar]
44. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–118. [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Baek MS, Cho H, Lee HS, Lee JH, Ryu YH, Lyoo CH. Effect of APOE epsilon4 genotype on amyloid-beta and tau accumulation in Alzheimer's disease. Alzheimers Res Ther. 2020;12:140. [DOI] [PMC free article] [PubMed] [Google Scholar]
46. Farfel JM, Yu L, De Jager PL, Schneider JA, Bennett DA. Association of APOE with tau-tangle pathology with and without beta-amyloid. Neurobiol Aging. 2016;37:19–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Sabbagh MN, Malek-Ahmadi M, Dugger BN, et al. The influence of apolipoprotein E genotype on regional pathology in Alzheimer’s disease. BMC Neurol. 2013;13:44. [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Hardy JA, Higgins GA. Alzheimer’s disease: The amyloid cascade hypothesis. Science. 1992;256:184–185. [DOI] [PubMed] [Google Scholar]
49. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J Neuropathol Exp Neurol. 2012;71:362–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
50. Terry RD, Hansen LA, DeTeresa R, Davies P, Tobias H, Katzman R. Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles. J Neuropathol Exp Neurol. 1987;46:262–268. [DOI] [PubMed] [Google Scholar]
51. Hansen LA, Masliah E, Galasko D, Terry RD. Plaque-only Alzheimer disease is usually the Lewy body variant, and vice versa. J Neuropathol Exp Neurol. 1993;52:648–654. [DOI] [PubMed] [Google Scholar]
52. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: Implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996;3:16–32. [DOI] [PubMed] [Google Scholar]
53. Wharton SB, Wang D, Parikh C, et al. Epidemiological pathology of Abeta deposition in the ageing brain in CFAS: Addition of multiple Abeta-derived measures does not improve dementia assessment using logistic regression and machine learning approaches. Acta Neuropathol Commun. 2019;7:198. [DOI] [PMC free article] [PubMed] [Google Scholar]
54. Robinson AC, Roncaroli F, Davidson YS, et al. Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer’s disease pathology at death. Int J Geriatr Psychiatry. 2021;36:713–721. [DOI] [PMC free article] [PubMed] [Google Scholar]
55. Serrano-Pozo A, Qian J, Muzikansky A, et al. Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease Continuum. J Neuropathol Exp Neurol. 2016;75:516–526. [DOI] [PMC free article] [PubMed] [Google Scholar]
56. Yoshida K, Hata Y, Kinoshita K, Takashima S, Tanaka K, Nishida N. Incipient progressive supranuclear palsy is more common than expected and may comprise clinicopathological subtypes: A forensic autopsy series. Acta Neuropathol. 2017;133:809–823. [DOI] [PubMed] [Google Scholar]
57. Kovacs GG, Lukic MJ, Irwin DJ, et al. Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol. 2020;140:99–119. [DOI] [PMC free article] [PubMed] [Google Scholar]
58. Colom-Cadena M, Gelpi E, Charif S, et al. Confluence of alpha-synuclein, tau, and beta-amyloid pathologies in dementia with Lewy bodies. J Neuropathol Exp Neurol. 2013;72:1203–1212. [DOI] [PubMed] [Google Scholar]
59. Dickson DW, Heckman MG, Murray ME, et al. APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology. 2018;91:e1182–e1195. [DOI] [PMC free article] [PubMed] [Google Scholar]
60. Kotzbauer PT, Cairns NJ, Campbell MC, et al. Pathologic accumulation of alpha-synuclein and Abeta in Parkinson disease patients with dementia. Arch Neurol. 2012;69:1326–1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
61. Ono K, Takahashi R, Ikeda T, Yamada M. Cross-seeding effects of amyloid beta-protein and alpha-synuclein. J Neurochem. 2012;122:883–890. [DOI] [PubMed] [Google Scholar]
62. Shim KH, Kang MJ, Youn YC, An SSA, Kim S. Alpha-synuclein: A pathological factor with Abeta and tau and biomarker in Alzheimer’s disease. Alzheimers Res Ther. 2022;14:201. [DOI] [PMC free article] [PubMed] [Google Scholar]
63. Obi K, Akiyama H, Kondo H, et al. Relationship of phosphorylated alpha-synuclein and tau accumulation to Abeta deposition in the cerebral cortex of dementia with Lewy bodies. Exp Neurol. 2008;210:409–420. [DOI] [PubMed] [Google Scholar]
64. Maxwell AM, Yuan P, Rivera BM, et al. Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer's disease pathology in down syndrome. Acta Neuropathol Commun. 2021;9:201. [DOI] [PMC free article] [PubMed] [Google Scholar]
65. Kollmer M, Close W, Funk L, et al. Cryo-EM structure and polymorphism of Abeta amyloid fibrils purified from Alzheimer’s brain tissue. Nat Commun. 2019;10:4760. [DOI] [PMC free article] [PubMed] [Google Scholar]
66. Yang Y, Arseni D, Zhang W, et al. Cryo-EM structures of amyloid-beta 42 filaments from human brains. Science. 2022;375:167–172. [DOI] [PMC free article] [PubMed] [Google Scholar]
67. Rijal Upadhaya A, Kosterin I, Kumar S, et al. Biochemical stages of amyloid-beta peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain. 2014;137:887–903. [DOI] [PubMed] [Google Scholar]
68. Braak H, Zetterberg H, Del Tredici K, Blennow K. Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-beta changes occur before increases of tau in cerebrospinal fluid. Acta Neuropathol. 2013;126:631–641. [DOI] [PubMed] [Google Scholar]
69. Shah N, Frey KA, Muller ML, et al. Striatal and cortical beta-amyloidopathy and cognition in Parkinson’s disease. Mov Disord. 2016;31:111–117. [DOI] [PMC free article] [PubMed] [Google Scholar]
70. Hepp DH, Vergoossen DL, Huisman E, et al. Distribution and load of amyloid-beta pathology in Parkinson disease and dementia with Lewy bodies. J Neuropathol Exp Neurol. 2016;75:936–945. [DOI] [PubMed] [Google Scholar]
71. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43). Neuron. 1994;13:45–53. [DOI] [PubMed] [Google Scholar]
72. Thal DR, Walter J, Saido TC, Fandrich M. Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer’s disease. Acta Neuropathol. 2015;129:167–182. [DOI] [PubMed] [Google Scholar]
73. Saito T, Suemoto T, Brouwers N, et al. Potent amyloidogenicity and pathogenicity of Abeta43. Nat Neurosci. 2011;14:1023–1032. [DOI] [PubMed] [Google Scholar]
74. Allen N, Robinson AC, Snowden J, Davidson YS, Mann DM. Patterns of cerebral amyloid angiopathy define histopathological phenotypes in Alzheimer's disease. Neuropathol Appl Neurobiol. 2014;40:136–148. [DOI] [PubMed] [Google Scholar]
75. Ogaki K, Martens YA, Heckman MG, et al. Multiple system atrophy and apolipoprotein E. Mov Disord. 2018;33:647–650. [DOI] [PMC free article] [PubMed] [Google Scholar]
76. Boyle PA, Yu L, Nag S, et al. Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology. 2015;85:1930–1936. [DOI] [PMC free article] [PubMed] [Google Scholar]
77. Aoki N, Boyer PJ, Lund C, et al. Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: Frontotemporal lobar degeneration associated with alpha-synuclein. Acta Neuropathol. 2015;130:93–105. [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Rohan Z, Rahimi J, Weis S, et al. Screening for alpha-synuclein immunoreactive neuronal inclusions in the hippocampus allows identification of atypical MSA (FTLD-synuclein). Acta Neuropathol. 2015;130:299–301. [DOI] [PubMed] [Google Scholar]
79. Murakami K, Ono K. Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration. FASEB J. 2022;36:e22493. [DOI] [PubMed] [Google Scholar]
80. Masliah E, Rockenstein E, Veinbergs I, et al. beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson’s disease. Proc Natl Acad Sci U S A. 2001;98:12245–12250. [DOI] [PMC free article] [PubMed] [Google Scholar]
81. Mandal PK, Pettegrew JW, Masliah E, Hamilton RL, Mandal R. Interaction between Abeta peptide and alpha synuclein: Molecular mechanisms in overlapping pathology of Alzheimer’s and Parkinson’s in dementia with Lewy body disease. Neurochem Res. 2006;31:1153–1162. [DOI] [PubMed] [Google Scholar]
82. Tsigelny IF, Crews L, Desplats P, et al. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson’s diseases. PLoS One. 2008;3:e3135. [DOI] [PMC free article] [PubMed] [Google Scholar]
83. Perneczky R, Jessen F, Grimmer T, et al. Anti-amyloid antibody therapies in Alzheimer’s disease. Brain. 2023;146:842–849. [DOI] [PubMed] [Google Scholar]
84. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330:512–527. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

fcae141_Supplementary_Data

fcae141_supplementary_data.pdf^{(1MB, pdf)}

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

[fcae141-B1] 1. Wenning GK, Stankovic I, Vignatelli L, et al. The movement disorder society criteria for the diagnosis of multiple system atrophy. Mov Disord. 2022;37:1131–1148. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B2] 2. Stefanova N, Wenning GK. Multiple system atrophy: At the crossroads of cellular, molecular and genetic mechanisms. Nat Rev Neurosci. 2023;24:334–346. [DOI] [PubMed] [Google Scholar]

[fcae141-B3] 3. Forrest SL, Kovacs GG. Current concepts of mixed pathologies in neurodegenerative diseases. Can J Neurol Sci. 2023;50:329–345. [DOI] [PubMed] [Google Scholar]

[fcae141-B4] 4. Kovacs GG, Milenkovic I, Wohrer A, et al. Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: A community-based autopsy series. Acta Neuropathol. 2013;126:365–384. [DOI] [PubMed] [Google Scholar]

[fcae141-B5] 5. Robinson JL, Lee EB, Xie SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018;141:2181–2193. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B6] 6. Robinson JL, Xie SX, Baer DR, et al. Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated. Brain. 2023;146:2557–2569. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B7] 7. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–259. [DOI] [PubMed] [Google Scholar]

[fcae141-B8] 8. Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791–1800. [DOI] [PubMed] [Google Scholar]

[fcae141-B9] 9. Montine TJ, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol. 2012;123:1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B10] 10. Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age-related tauopathy (PART): A common pathology associated with human aging. Acta Neuropathol. 2014;128:755–766. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B11] 11. Nelson PT, Brayne C, Flanagan ME, et al. Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: Combined data from 13 community-based or population-based autopsy cohorts. Acta Neuropathol. 2022;144:27–44. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B12] 12. Jellinger KA. More frequent Lewy bodies but less frequent Alzheimer-type lesions in multiple system atrophy as compared to age-matched control brains. Acta Neuropathol. 2007;114:299–303. [DOI] [PubMed] [Google Scholar]

[fcae141-B13] 13. Jellinger KA. Neuropathological findings in multiple system atrophy with cognitive impairment. J Neural Transm (Vienna). 2020;127:1031–1039. [DOI] [PubMed] [Google Scholar]

[fcae141-B14] 14. Koga S, Parks A, Uitti RJ, et al. Profile of cognitive impairment and underlying pathology in multiple system atrophy. Mov Disord. 2017;32:405–413. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B15] 15. Koga S, Cheshire WP, Tipton PW, et al. Clinical features of autopsy-confirmed multiple system atrophy in the Mayo Clinic Florida brain bank. Parkinsonism Relat Disord. 2021;89:155–161. [DOI] [PubMed] [Google Scholar]

[fcae141-B16] 16. Miki Y, Bettencourt C, Jaunmuktane Z, Holton JL, Warner TT, Wakabayashi K. Alzheimer’s disease pathology concomitant with memory impairment in late-onset multiple system atrophy. Neuropathol Appl Neurobiol. 2023;49:e12878. [DOI] [PubMed] [Google Scholar]

[fcae141-B17] 17. Sekiya H, Koga S, Murakami A, et al. Frequency of comorbid pathologies and their clinical impact in multiple system atrophy. Mov Disord. 2024;39:380–390. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B18] 18. Ichimata S, Yoshida K, Li J, Rogaeva E, Lang AE, Kovacs GG. The molecular spectrum of amyloid-beta (Abeta) in neurodegenerative diseases beyond Alzheimer’s disease. Brain Pathol. 2024;34:e13210. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B19] 19. Ichimata S, Martinez-Valbuena I, Lee S, Li J, Karakani AM, Kovacs GG. Distinct molecular signatures of amyloid-beta and tau in Alzheimer’s disease associated with down syndrome. Int J Mol Sci. 2023;24:11596. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B20] 20. Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2002;61:282–293. [DOI] [PubMed] [Google Scholar]

[fcae141-B21] 21. Skrobot OA, Attems J, Esiri M, et al. Vascular cognitive impairment neuropathology guidelines (VCING): The contribution of cerebrovascular pathology to cognitive impairment. Brain. 2016;139:2957–2969. [DOI] [PubMed] [Google Scholar]

[fcae141-B22] 22. Schneider JA. Neuropathology of dementia disorders. Continuum (Minneap Minn). 2022;28:834–851. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B23] 23. Ichimata S, Yoshida K, Visanji NP, Lang AE, Nishida N, Kovacs GG. Patterns of mixed pathologies in Down syndrome. J Alzheimers Dis. 2022;87:595–607. [DOI] [PubMed] [Google Scholar]

[fcae141-B24] 24. Tanaka H, Hird MA, Tang-Wai DF, Kovacs GG. Significant contralaterality of temporal-predominant neuroastroglial tauopathy and FTLD-TDP type C presenting with the right temporal variant FTD. J Neuropathol Exp Neurol. 2023;82:187–191. [DOI] [PubMed] [Google Scholar]

[fcae141-B25] 25. Richard E, Carrano A, Hoozemans JJ, et al. Characteristics of dyshoric capillary cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2010;69:1158–1167. [DOI] [PubMed] [Google Scholar]

[fcae141-B26] 26. Kim A, Yoshida K, Kovacs GG, Forrest SL. Computer-based evaluation of α-synuclein pathology in multiple system atrophy as a novel tool to recognize disease-subtypes. Manuscript under review. [DOI] [PubMed]

[fcae141-B27] 27. Martinez-Valbuena I, Swinkin E, Santamaria E, et al. Alpha-synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders. Acta Neuropathol. 2022;144:167–185. [DOI] [PubMed] [Google Scholar]

[fcae141-B28] 28. Martinez-Valbuena I, Visanji NP, Kim A, et al. Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy. Transl Neurodegener. 2022;11:7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B29] 29. Forrest SL, Tartaglia MC, Kim A, et al. Progressive supranuclear palsy syndrome associated with a novel tauopathy: Case study. Neurology. 2022;99:1094–1098. [DOI] [PubMed] [Google Scholar]

[fcae141-B30] 30. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30:1591–1601. [DOI] [PubMed] [Google Scholar]

[fcae141-B31] 31. Coughlin DG, Dryden I, Goodwill VS, et al. Long-standing multiple system atrophy-Parkinsonism with limbic and FTLD-type alpha-synuclein pathology. Neuropathol Appl Neurobiol. 2022;48:e12783. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B32] 32. Koga S, Li F, Zhao N, et al. Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease. Brain Pathol. 2020;30:766–778. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B33] 33. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70:960–969. [DOI] [PubMed] [Google Scholar]

[fcae141-B34] 34. Ferrer I. Hypothesis review: Alzheimer’s overture guidelines. Brain Pathol. 2023;33:e13122. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B35] 35. Bujan B, Hofer MJ, Oertel WH, Pagenstecher A, Burk K. Multiple system atrophy of the cerebellar type (MSA-C) with concomitant beta-amyloid and tau pathology. Clin Neuropathol. 2013;32:286–290. [DOI] [PubMed] [Google Scholar]

[fcae141-B36] 36. Terni B, Rey MJ, Boluda S, et al. Mutant ubiquitin and p62 immunoreactivity in cases of combined multiple system atrophy and Alzheimer's disease. Acta Neuropathol. 2007;113:403–416. [DOI] [PubMed] [Google Scholar]

[fcae141-B37] 37. Shibuya K, Nagatomo H, Iwabuchi K, Inoue M, Yagishita S, Itoh Y. Asymmetrical temporal lobe atrophy with massive neuronal inclusions in multiple system atrophy. J Neurol Sci. 2000;179:50–58. [DOI] [PubMed] [Google Scholar]

[fcae141-B38] 38. Cykowski MD, Coon EA, Powell SZ, et al. Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain. 2015;138:2293–2309. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B39] 39. Homma T, Mochizuki Y, Komori T, Isozaki E. Frequent globular neuronal cytoplasmic inclusions in the medial temporal region as a possible characteristic feature in multiple system atrophy with dementia. Neuropathology. 2016;36:421–431. [DOI] [PubMed] [Google Scholar]

[fcae141-B40] 40. Ozawa T, Paviour D, Quinn NP, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: Clinicopathological correlations. Brain. 2004;127:2657–2671. [DOI] [PubMed] [Google Scholar]

[fcae141-B41] 41. Miki Y, Foti SC, Hansen D, et al. Hippocampal alpha-synuclein pathology correlates with memory impairment in multiple system atrophy. Brain. 2020;143:1798–1810. [DOI] [PubMed] [Google Scholar]

[fcae141-B42] 42. Ando T, Riku Y, Akagi A, et al. Multiple system atrophy variant with severe hippocampal pathology. Brain Pathol. 2022;32:e13002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B43] 43. Pletnikova O, Kageyama Y, Rudow G, et al. The spectrum of preclinical Alzheimer’s disease pathology and its modulation by ApoE genotype. Neurobiol Aging. 2018;71:72–80. [DOI] [PubMed] [Google Scholar]

[fcae141-B44] 44. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–118. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B45] 45. Baek MS, Cho H, Lee HS, Lee JH, Ryu YH, Lyoo CH. Effect of APOE epsilon4 genotype on amyloid-beta and tau accumulation in Alzheimer's disease. Alzheimers Res Ther. 2020;12:140. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B46] 46. Farfel JM, Yu L, De Jager PL, Schneider JA, Bennett DA. Association of APOE with tau-tangle pathology with and without beta-amyloid. Neurobiol Aging. 2016;37:19–25. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B47] 47. Sabbagh MN, Malek-Ahmadi M, Dugger BN, et al. The influence of apolipoprotein E genotype on regional pathology in Alzheimer’s disease. BMC Neurol. 2013;13:44. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B48] 48. Hardy JA, Higgins GA. Alzheimer’s disease: The amyloid cascade hypothesis. Science. 1992;256:184–185. [DOI] [PubMed] [Google Scholar]

[fcae141-B49] 49. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J Neuropathol Exp Neurol. 2012;71:362–381. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B50] 50. Terry RD, Hansen LA, DeTeresa R, Davies P, Tobias H, Katzman R. Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles. J Neuropathol Exp Neurol. 1987;46:262–268. [DOI] [PubMed] [Google Scholar]

[fcae141-B51] 51. Hansen LA, Masliah E, Galasko D, Terry RD. Plaque-only Alzheimer disease is usually the Lewy body variant, and vice versa. J Neuropathol Exp Neurol. 1993;52:648–654. [DOI] [PubMed] [Google Scholar]

[fcae141-B52] 52. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: Implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996;3:16–32. [DOI] [PubMed] [Google Scholar]

[fcae141-B53] 53. Wharton SB, Wang D, Parikh C, et al. Epidemiological pathology of Abeta deposition in the ageing brain in CFAS: Addition of multiple Abeta-derived measures does not improve dementia assessment using logistic regression and machine learning approaches. Acta Neuropathol Commun. 2019;7:198. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B54] 54. Robinson AC, Roncaroli F, Davidson YS, et al. Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer’s disease pathology at death. Int J Geriatr Psychiatry. 2021;36:713–721. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B55] 55. Serrano-Pozo A, Qian J, Muzikansky A, et al. Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease Continuum. J Neuropathol Exp Neurol. 2016;75:516–526. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B56] 56. Yoshida K, Hata Y, Kinoshita K, Takashima S, Tanaka K, Nishida N. Incipient progressive supranuclear palsy is more common than expected and may comprise clinicopathological subtypes: A forensic autopsy series. Acta Neuropathol. 2017;133:809–823. [DOI] [PubMed] [Google Scholar]

[fcae141-B57] 57. Kovacs GG, Lukic MJ, Irwin DJ, et al. Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol. 2020;140:99–119. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B58] 58. Colom-Cadena M, Gelpi E, Charif S, et al. Confluence of alpha-synuclein, tau, and beta-amyloid pathologies in dementia with Lewy bodies. J Neuropathol Exp Neurol. 2013;72:1203–1212. [DOI] [PubMed] [Google Scholar]

[fcae141-B59] 59. Dickson DW, Heckman MG, Murray ME, et al. APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology. 2018;91:e1182–e1195. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B60] 60. Kotzbauer PT, Cairns NJ, Campbell MC, et al. Pathologic accumulation of alpha-synuclein and Abeta in Parkinson disease patients with dementia. Arch Neurol. 2012;69:1326–1331. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B61] 61. Ono K, Takahashi R, Ikeda T, Yamada M. Cross-seeding effects of amyloid beta-protein and alpha-synuclein. J Neurochem. 2012;122:883–890. [DOI] [PubMed] [Google Scholar]

[fcae141-B62] 62. Shim KH, Kang MJ, Youn YC, An SSA, Kim S. Alpha-synuclein: A pathological factor with Abeta and tau and biomarker in Alzheimer’s disease. Alzheimers Res Ther. 2022;14:201. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B63] 63. Obi K, Akiyama H, Kondo H, et al. Relationship of phosphorylated alpha-synuclein and tau accumulation to Abeta deposition in the cerebral cortex of dementia with Lewy bodies. Exp Neurol. 2008;210:409–420. [DOI] [PubMed] [Google Scholar]

[fcae141-B64] 64. Maxwell AM, Yuan P, Rivera BM, et al. Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer's disease pathology in down syndrome. Acta Neuropathol Commun. 2021;9:201. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B65] 65. Kollmer M, Close W, Funk L, et al. Cryo-EM structure and polymorphism of Abeta amyloid fibrils purified from Alzheimer’s brain tissue. Nat Commun. 2019;10:4760. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B66] 66. Yang Y, Arseni D, Zhang W, et al. Cryo-EM structures of amyloid-beta 42 filaments from human brains. Science. 2022;375:167–172. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B67] 67. Rijal Upadhaya A, Kosterin I, Kumar S, et al. Biochemical stages of amyloid-beta peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain. 2014;137:887–903. [DOI] [PubMed] [Google Scholar]

[fcae141-B68] 68. Braak H, Zetterberg H, Del Tredici K, Blennow K. Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-beta changes occur before increases of tau in cerebrospinal fluid. Acta Neuropathol. 2013;126:631–641. [DOI] [PubMed] [Google Scholar]

[fcae141-B69] 69. Shah N, Frey KA, Muller ML, et al. Striatal and cortical beta-amyloidopathy and cognition in Parkinson’s disease. Mov Disord. 2016;31:111–117. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B70] 70. Hepp DH, Vergoossen DL, Huisman E, et al. Distribution and load of amyloid-beta pathology in Parkinson disease and dementia with Lewy bodies. J Neuropathol Exp Neurol. 2016;75:936–945. [DOI] [PubMed] [Google Scholar]

[fcae141-B71] 71. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43). Neuron. 1994;13:45–53. [DOI] [PubMed] [Google Scholar]

[fcae141-B72] 72. Thal DR, Walter J, Saido TC, Fandrich M. Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer’s disease. Acta Neuropathol. 2015;129:167–182. [DOI] [PubMed] [Google Scholar]

[fcae141-B73] 73. Saito T, Suemoto T, Brouwers N, et al. Potent amyloidogenicity and pathogenicity of Abeta43. Nat Neurosci. 2011;14:1023–1032. [DOI] [PubMed] [Google Scholar]

[fcae141-B74] 74. Allen N, Robinson AC, Snowden J, Davidson YS, Mann DM. Patterns of cerebral amyloid angiopathy define histopathological phenotypes in Alzheimer's disease. Neuropathol Appl Neurobiol. 2014;40:136–148. [DOI] [PubMed] [Google Scholar]

[fcae141-B75] 75. Ogaki K, Martens YA, Heckman MG, et al. Multiple system atrophy and apolipoprotein E. Mov Disord. 2018;33:647–650. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B76] 76. Boyle PA, Yu L, Nag S, et al. Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology. 2015;85:1930–1936. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B77] 77. Aoki N, Boyer PJ, Lund C, et al. Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: Frontotemporal lobar degeneration associated with alpha-synuclein. Acta Neuropathol. 2015;130:93–105. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B78] 78. Rohan Z, Rahimi J, Weis S, et al. Screening for alpha-synuclein immunoreactive neuronal inclusions in the hippocampus allows identification of atypical MSA (FTLD-synuclein). Acta Neuropathol. 2015;130:299–301. [DOI] [PubMed] [Google Scholar]

[fcae141-B79] 79. Murakami K, Ono K. Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration. FASEB J. 2022;36:e22493. [DOI] [PubMed] [Google Scholar]

[fcae141-B80] 80. Masliah E, Rockenstein E, Veinbergs I, et al. beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson’s disease. Proc Natl Acad Sci U S A. 2001;98:12245–12250. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B81] 81. Mandal PK, Pettegrew JW, Masliah E, Hamilton RL, Mandal R. Interaction between Abeta peptide and alpha synuclein: Molecular mechanisms in overlapping pathology of Alzheimer’s and Parkinson’s in dementia with Lewy body disease. Neurochem Res. 2006;31:1153–1162. [DOI] [PubMed] [Google Scholar]

[fcae141-B82] 82. Tsigelny IF, Crews L, Desplats P, et al. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson’s diseases. PLoS One. 2008;3:e3135. [DOI] [PMC free article] [PubMed] [Google Scholar]

[fcae141-B83] 83. Perneczky R, Jessen F, Grimmer T, et al. Anti-amyloid antibody therapies in Alzheimer’s disease. Brain. 2023;146:842–849. [DOI] [PubMed] [Google Scholar]

[fcae141-B84] 84. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330:512–527. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Multiple system atrophy with amyloid-β-predominant Alzheimer’s disease neuropathologic change

Tomoya Kon

Shojiro Ichimata

Daniel G Di Luca

Ivan Martinez-Valbuena

Ain Kim

Koji Yoshida

Abdullah A Alruwaita

Galit Kleiner

Antonio P Strafella

Shelley L Forrest

Christine Sato

Ekaterina Rogaeva

Susan H Fox

Anthony E Lang

Gabor G Kovacs

Abstract

Graphical Abstract

Graphical Abstract.

Introduction

Materials and methods

Case materials

Neuropathologic assessment

Morphometry of α-syn-ir GCIs

Double-labelled immunofluorescent staining

α-syn seeding amplification assay

Genetic analysis

ADNC density plot

Literature review

Statistical analysis

Results

Summary of the demographic and clinical features of the cohort

Table 1.

Pathological findings of MSA with divergent Aβ phase and NFT stage

Figure 1.

Table 2.

Table 3.

Double-labelled immunofluorescent staining

Morphometry of α-syn-ir GCIs

Figure 2.

α-syn seeding amplification assay

Impact of APOE ɛ4 allele on Aβ-predominant ADNC pathology

Figure 3.

Literature review

Table 4.

Discussion

Figure 4.

Supplementary Material

Acknowledgements

Contributor Information

Supplementary material

Funding

Competing interests

Data availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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