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Table 1 Post-mortem evidence demonstrating involvement of α-synuclein in AD pathophysiology

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

Type of Analysis Cohort Findings Citation (Year)
• Brain tissue N=225
- AD (n=150)
- NC (n=75)
• 25% of AD cases had LBs (versus 5% of NCs)
- 11% of which had cortical LBs
- 3% of which had neocortical LBs and where re-classified as DLB
- LBs primarily in SNc, substantia innominata and locus coeruleus
• Inverse relationship between LBs and tau pathology
• Bergeron and Pollanen (1989) [50]
• Brain tissue
• Clinicopathological correlations
N=36
- AD (n=23)
- AD-LBV (n=13)
• AD-LBV patients had:
- more pronounced cognitive and movement symptoms versus AD
- less tau pathology
- increased spongiform vacuolization of the medial temporal lobe
- increased neurodegeneration of the SNc, substantia innominata, and locus coeruleus
• Hansen et al. (1990) [51]
• Brain tissue N=147 AD • 25% where “Aβ-plaque only” AD
- of which, 75% had LRP
• 28% were AD-LBV
- of which 66% were “Aβ-plaque only” AD
• Hansen et al. (1993) [52]
• Brain tissue N=16
- AD (n=8)
- AD-LBV (n=8)
• AD-LBV patients had:
- higher incidence of Parkinsonism
- increased frontal lobe atrophy
- reduced frontal lobe and limbic tau-tangles
- increased neuronal loss within the SNc and the nucleus basalis of Meynert which correlated with reduced cognitive function
• Förstl et al. (1993) [53]
• Brain tissue N=1x human cortical AD Aβ-plaque
N=1x AD brain section sections
• Found a novel 35-amino acid sequence in an Aβ-plaque
- named it the “non-amyloid component (NAC) of Aβ-plaques” (NAC)
- used novel antibodies to detect the NAC in hippocampal neuronal soma and neurites in AD brain sections
• Uéda et al. (1993) [54]
• Brain tissue N=137
- probable AD or AD-LBV
• 30 % of cohort confirmed as AD-LBV
• In AD-LBV, not AD, APOEe4 associated with enhanced NFTs
• Hansen et al. (1994) [55]
• Brain tissue N=75
- AD (n=68)
- NC (n=7)
• NAC immunoreactivity found:
- in 35% of diffuse Aβ-plaques
- in 55% of mature Aβ plaques
- primarily in the core of Aβ-plaques
• Masliah et al. (1996) [56]
• Brain tissue
• Clinicopathological correlations
N=50
- AD
Mild (n=4)
Moderate (n=16)
Severe (n=23)
- NC (n=7)
• NAC immunoreactivity:
- increased in frontal cortex of mild AD individuals - versus all other groups
- correlated negatively with NFTs
- did not correlate with Aβ-plaques
correlated negatively with cognitive decline
• Iwai et al. (1996) [57]
• Brain tissue N=74
- ADAD
PSEN1 (n=57)
APP (n=9)
PSEN2 (n=8)
• LRP immunoreactivity:
- found in 22% of all ADAD brains
- found in 63% (12/19) of ADAD amygdala samples
- frequently alongside tau-tangles in amygdala
- not influenced by APOEε4
• Lippa et al. (1998) [58]
• Database search N=188
- AD (n=148)
- AD-LBV (n=40)
• Compared to AD, AD-LBV patients had:
- more rapid cognitive decline
- shorter survival time after symptom onset
• Olichney et al. (1998) [59]
• Brain tissue N=20
- Down’s syndrome
with AD (n=16)
without AD (n=4)
• LRP in 50% of Down’s syndrome brains with AD
- primarily in the amygdala
• Lippa et al. (1999) [60]
• Brain tissue N=145
- AD
• LRP in 61% of AD brains
̵ primarily in the amygdala and entorhinal cortex
̵ rarely in the SNc
̵ frequently alongside NFTs
• R.L. Hamilton (2000) [23]
• Brain tissue N=25
- AD (n=23)
- Down’s syndrome with AD (n=2)
• LRP immunoreactivity:
- in 43% of AD and 100% of Down’s syndrome
- primarily in the amygdala
- frequently alongside NFTs
• Marui et al. (2000) [61]
• Brain tissue N=35
- AD (n=24)
- AD-LBV (n=8)
- NC (n=3)
• In AD-LBV patients LRP:
- primarily in hippocampus, less frequently in the frontal cortex
- often co-localized with Aβ-plaques in dystrophic neurites
• Wirths et al. (2000) [62]
• Brain tissue N=27
- AD
• LRP found in ~50% cases
- most frequently in the amygdala
- most non-LB LRP found in hippocampus
- frequently co-localized with NFTs
• Arai et al. (2001) [24]
• Brain tissue N=60
- AD (n=17)
- DLB (n=34)
- PD (n=9)
• In AD cases:
- LBs, not LNs, frequently found in amygdala
- no limbic or neocortical LRP
- 95% co-occurrence of LBs and NFTs in amygdala
• Iseki et al. (2004) [63]
• Brain tissue
• Clinicopathological correlations
N=3
- ADAD PSEN1 (S170F) mutation carrying family members
• Rapid decline in third decade of life
• Severe symptoms, i.e. myoclonus, rigidity and seizures
• Death in fourth decade or early fifth decade of life
• Florid LBs in neocortex, limbic system and brainstem
• Snider et al. (2005) [64]
• Brain tissue N=28
- AD
• LBs found in:
- hippocampus (54% of cases)
- amygdala (47%)
- SNc (42%)
- entorhinal cortex (33%)
• Correlation between LRP and Aβ pathology
• No correlation between LRP and NFTs
• Mikolaenko et al. (2005) [65]
• Brain tissue N= 39
- ADAD 14
PSEN1 (n=25)
PSEN2 (N141I) (n=14)
• In PSEN1 cases:
- 96% had amygdala LBs
- frequent neocortical and amygdala LBs versus PSEN2
• In both PSEN1 and PSEN2 cases:
- significant variability of Lewy body pathology between family members with same ADAD mutation.
• Leverenz et al. 2006 [25]
• Brain tissue
• Clinicopathological correlations
N=347
- AD
- In total 43% had some extent of LRP
- 25% diagnosed as AD-LBV
- 24% AD cases had amygdala LRP with sparse LRP in other limbic regions
- LBs and NFT frequently co-localize in same soma
- αSyn and tau frequently co-localize in the same lesion
- no clinical difference in AD with amygdala LRP versus AD cases
• Uchikado et al. 2006 [66]
• Brain tissue N=12
- AD (n=4),
- DLB (n=4)
- NC (n=4)
• In AD and DLB, but not NC brain samples, αSyn monomers, dimers, trimers and pentamers co-immunoprecipitated with Aβ monomers • Tsigelny et al. 2008 [67]
• CSF N=325
- AD (n=131),
- DLB (n=40),
- FTD (39),
- VsD (n=39),
- NC (n=112)
• CSF αSyn levels did not differ between dementia groups • Spies et al. 2009 [68]
• Brain tissue N=84
- AD (n=24)
- MCI (n=34)
- NC (n=26)
• In AD brains without LRP there was a twofold increase in soluble intracellular αSyn
• Significantly increased monomeric αSyn in inferior temporal cortex of AD cases versus MCI and NCs
• Larson et al. 2012 [69]
• Brain tissue N=542
- AD-LBV (n=308)
- DLB (n=13)
- PD (n=141)
- PD with AD-pathology (n=80)
• AD-LBV patients had distinct and prominent LRP in the amygdala, limbic and olfactory systems, with little/no brainstem LRP • Toledo et al. 2016 [70]
• Clinicopathological correlations N=59
- AD (n=19)
- DLB (n=18)
- AD+DLB (n=22)
• 50% of AD+DLB, 94% of DLB and 16% of AD cases had complex visual hallucinations
- thus, within the context of AD-type dementia, visual hallucinations may indicate possible LRP
• Thomas et al. 2018 [71]
  1. AD Alzheimer’s disease, αSyn α-synuclein, NC non-demented control, AD-LBV Alzheimer’s disease Lewy body variant, LBs Lewy bodies, LN Lewy neurites, DLB dementia with Lewy bodies, LRP Lewy related pathology, amyloid-β, SNc substantia nigra, APOEε4 apolipoprotein ε4 allele, NFTs neurofibrillary tangles, ADAD autosomal dominant Alzheimer’s disease, PSEN1 presenilin 1 allele, PSEN2 presenilin 2 allele, APP amyloid precursor protein allele, FTD frontotemporal dementia, VsD vascular dementia, MCI mild cognitive impairment, PD Parkinson’s disease, AD+DLB co-diagnosis of Alzheimer’s disease and dementia with Lewy bodies