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Table 2 Clinical evidence supporting a role for α-synuclein in AD pathophysiology

From: α-synuclein in the pathophysiology of Alzheimer’s disease

Type of Analysis Cohort Findings Citation (Year)
• CSF N=80
- AD (n=13)
- DLB (n=38)
- PD (n=8)
- CJD (n=8)
- NC (n=13)
• CSF αSyn levels:
- higher in AD versus synucleinopathies
- no difference in AD versus NC
• Mollenhauer et al. 2008 [82]
• CSF N=151
- AD (n=66)
- DLB (n=15)
- PD (n=15)
- NC (n=55)
• CSF αSyn levels lower in AD patients versus NCs
• In AD patients, lowest CSF αSyn associated with MMSE<20
• Ohrfelt et al. 2009 [83]
• CSF N=86
- AD (n=31)
- DLB (n=34)
- other dementias (n=21)
• CSF αSyn levels:
- Lower in DLB versus AD and other dementia patients
- No difference in AD versus DLB or other dementia patients
• Kasuga et al. 2010 [84]
• CSF N=150
- AD (n=63)
- DLB (n=35)
- PD (n=18)
- subjective memory complaints (n=34)
• CSF αSyn levels did not differ between patient groups
• Lower CSF αSyn in DLB patients marginally associated with reduced cognitive performance
• Reesink et al. 2010 [85]
• CSF N=191
- AD (n=46)
- DLB (n=33)
- PDD (n=22)
- PD (n=38)
- NC (n=52)
• CSF αSyn levels higher in AD patients compared NCs
• CSF αSyn levels lower in synucleinopathies versus AD and NCs
• CSF αSyn levels were positively correlated with p-tau in all groups, and t-tau in all groups except PD/PDD
• Wennström et al. 2013 [81]
• CSF N=117
- AD (n=36)
- MCI (n=65)
- NC (n=16)
• Increased CSF αSyn in AD and MCI versus NC
• Increased CSF αSyn levels correlated to decreased MMSE score in combined AD and MCI patient group
• Korff et al. 2013 [86]
• CSF N=68
- AD (n=18)
- DLB (n=16)
- NC (n=22)
• Increased CSF αSyn levels in DLB versus AD and NC • Kapaki et al. 2013 [87]
• CSF N=389 (AD cohort)
- AD (n=92)
- MCI (n=187)
- NC (n=110)
N=102 (PD cohort)
- PD (n=63)
- NC (n=39)
• Increasing CSF αSyn levels negatively correlated to p-tau levels in AD cohort (AD and MCI patients combined), but not in the PD cohort.
• CSF αSyn and t-tau levels positively correlated in both cohorts and cohort patient groups
• Toledo et al. 2013 [88]
• CSF N=247
- AD (n=48)
- DLB (n=71)
- PDD (n=30)
- NC (n=98)
• CSF αSyn oligomer levels significantly higher in DLB and PDD versus AD patients • Hansson et al. 2014 [89]
• CSF N=262
- probable AD (n=94)
- AD (n=34)
- probable DLB (n=30)
- DLB (n=15)
- probable PDD (n=23)
- probable PD (n=30)
- probable MSA (n=7)
- MSA (n=1),
(ante-mortem) NC (n=29)
• CSF αSyn levels higher in AD patients versus synucleinopathy patients and HCs
• CSF αSyn levels correlated to CSF t-tau and p-tau in autopsy-confirmed AD patients
• CSF αSyn combined with CSF t-tau and p-tau may be able to differentially diagnose AD from DLB patients
• Slaets et al. 2014 [90]
• Meta-analysis N=10 research articles • CSF αSyn levels were significantly higher in AD versus DLB, PD and MSA patients • Wang et al. 2015 [91]
• CSF N=99
- AD (n=26),
- MCI converting to AD (n=25) MCI-stable (n=23)
- NC (n=25)
• In MCI patients who converted to AD within two years CSF αSyn levels were substantially higher and associated with an aggressive symptom onset • Berge et al. 2016 [92]
• CSF N=293
- AD (n=225)
- NC with other neurological diseases (n=68)
• In AD patients versus controls CSF αSyn:
̵ positively correlated to CSF t-tau and p-tau
̵ positively correlated to decreasing MMSE score
• Majbour et al. 2017 [93]
• Brain tissue N=84
• AD (n=24), MCI (n=34), NC (n=26)
• AD brain samples without LRP had increased intracellular monomeric and oligomeric αSyn with weights varying from 17- to 54-kDa • Larson et al. 2018 [73]
• CSF N=367 Clinical cohort
- AD (n=114), MCI (n=63), DLB (n=10), PD (n=32), bvFTD (n=48), CBS (n=8), PSP (n=9), ALS (n=35), NC (n=48)
N=71 Autopsy cohort
- AD (n=29), PD (n=3), PD with AD pathology (n=4), AD with LRP (n=12), LRP-TDP (n=2), FTLD (n=12), FTLD-AD (n=4), ALS (n=5)
• CSF αSyn levels were higher in clinical AD and autopsy-confirmed AD cohorts
• The addition of CSF αSyn to the standard CSF AD biomarker panel improved the differential diagnosis of AD versus synucleinopathies (PD, PDD, DLB) and FTD
• Shi et al. 2018 [94]
• CSF
• Neuroimaging
N=36
subjective memory complaint patients
- PET-Aβ(+) (n=8)
- PET-Aβ(-) (n=28)
• Increased CSF αSyn associated with increased brain Aβ deposition
• CSF αSyn positively correlated to CSF t-tau and p-tau
• Vergallo et al. 2018 [26]
• CSF
• Neuroimaging
N=136 AD cohort
- AD (n=27)
- MCI converting to AD (n=27)
- MCI remaining MCI (n=27)
- NC (n=57)
N=142 ADAD cohort
- APP (n=24)
- PSEN1 (n=50)
- PSEN2 (n=18)
- related non-ADAD mutation carriers (n=50)
• In the sporadic AD cohort:
- at baseline CSF αSyn levels were increased in MCI patients who converted to AD after two years (MCI-AD)
- MCI-AD patients also exhibited a positive dose-dependent association between CSF αSyn levels and the APOEε4 allele
• CSF αSyn levels were positively associated with t-tau and p-tau in all investigated groups
• In the ADAD cohort:
- asymptomatic ADAD mutation carriers, and APOEε4 positive ADAD mutation carriers had significant positive association between increased CSF αSyn levels and brain Aβ deposition in regions know to exhibit early Aβ deposition
- CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus asymptomatic ADAD mutation carriers
- CSF αSyn levels positively correlated with estimated years from symptom onset in ADAD mutation carriers
• CSF αSyn levels were positively correlated with t-tau in non-mutation and ADAD mutation carriers, and with p-tau in non-mutation carriers and PSEN1 mutation carriers only (not APP or PSEN2 mutation carriers)
• Twohig et al. 2018 [27]
  1. AD Alzheimer’s disease, DLB dementia with Lewy bodies, PD Parkinson’s disease, CJD Creutzfeldt-Jakob Disease, NC non-demented control, CSF cerebrospinal fluid, αSyn α-synuclein, MMSE Mini Mental State Examination, MSA multiple system atrophy, PDD Parkinson’s disease with dementia, MCI mild cognitive impairment, p-tau phosphorylated tau, t-tau total tau, bvFTD behavioral variant frontotemporal dementia, CBS corticobasal syndrome, PSP progressive supranuclear palsy, ALS amyotrophic lateral sclerosis, FTD frontotemporal dementia, LRP-TDP Lewy body related pathology with transactive response DNA-binding protein 43 pathology, LRP-AD Lewy body related pathology with Alzheimer’s disease pathology, FTLD frontotemporal lobar degeneration, FTLD-AD frontotemporal lobar degeneration with Alzheimer’s disease pathology, LB Lewy body, LRP Lewy related pathology, VaD vasculature dementia, ADAD autosomal dominant Alzheimer’s disease, PSEN1 presenilin 1 allele , PSEN2 presenilin 2 allele, APP amyloid precursor protein allele, Aβ amyloid-β, PET positron emission tomography, APOEε4 apolipoprotein ε4 allele