Table 1.

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

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]

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, Aβ 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