Alzheimer's Pathologies in Synucleinopathies Indicates Dementia Course

A mixture of Alzheimer's pathologies may help indicate the clinical course of dementia.
A mixture of Alzheimer's pathologies may help indicate the clinical course of dementia.

A high burden of Alzheimer's disease (AD) pathology seems to promote a greater degree of α-synuclein pathology in patients with primary Lewy body disease (LBD), according to data reported in The Lancet.1 The degree of neurofibrillary tangles present in addition to ß-amyloid plaques and α-synuclein pathology were strongly predictive of both the timing of progression from motor symptoms to dementia as well as survival.

This large scale multicenter retrospective study led by David Irwin, MD, of the Center for Neurodegenerative Disease Research and the Penn Frontotemporal Degeneration Center at the University of Pennsylvania, compiled data from 213 patients with LBD confirmed on autopsy to have α-synuclein pathology and classified them into 4 levels of AD neuropathology: 23% had negligible or no AD (n=49), 26% had low-level AD (n=56), 21% had intermediate AD (n=45) and 30% had high-level AD (n=63).

These groupings were marked by the increased presence of neurofibrillary tangles, neuritic plaques, and alpha-synuclein pathology in the cerebrum and basal ganglia at each new level. Cerebral amyloid angiopathy scores increased as well.  Although there was a significantly higher frequency of patients with a clinical diagnosis of dementia with Lewy bodies as compared to a clinical diagnosis of Parkinson's disease with later occurring dementia reported among the patients who had higher levels of AD neuropathology, there was no clear genetic or pathological finding to support the clinical distinction between these two clinical phenotypes.

The cohort was also examined according to the known genetic variants for synucleinopathies.2-4 The frequency of the GBA pE326K risk allele or GBA mutation was more frequent in those patients without significant Alzheimer's disease pathology. There was no correlation between APOE ε4 allele frequency and the 4 categories of AD pathology, although the researchers noted that this allele was more frequent in patients in the intermediate or high AD pathology group compared to those in the low-level or no AD group.

Increasing severity of AD pathology also appeared to inversely correlate to decreases in the time from motor symptoms to the onset of dementia and death, with the most significant trends seen in the intermediate- and high-level AD groups compared with the low-level and no AD groups. Multivariate regression models found that tau pathology was the strongest predictor of a shorter time to dementia and to death in this cohort. Alzheimer's disease pathology was also higher in patients who were older at the time of onset of motor symptoms and dementia.

Dr Irwin suggested a possible “synergistic effect” between AD and α-synuclein pathologies. “We found that patients with a higher burden of AD neuropathology also had higher burden of cortical alpha-synuclein pathology,” he told Neurology Advisor. “We inferred based on these findings that there could be a potential synergism between the pathophysiological processes in AD and LBD but this will need to be confirmed using cell and animal models of disease and also with vivo molecular imaging in humans where we can study the longitudinal progression of tau, amyloid, and alpha-synuclein pathology.”

As effective treatment for dementia remains elusive, the most important application of these findings is to appropriate patient selection for clinical trials. The results of this study suggest that “Lewy body pathology (ie, α-synuclein) is the primary driver of the neurodegenerative process, whereas Alzheimer's disease pathology (ie, amyloid ß and tau) has an impact later in the disease,” wrote Johannes Attems, of the Institute of Neuroscience at Newcastle University, Newcastle on Tyne, UK, in an accompanying commentary.5

References

  1. Irwin DJ, Grossman M, Weintraub D, et al.   Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis.  Lancet Neurol. 2017;16:55-65.
  2. Tsuang D, Leverenz JB, Lopez OL, et al. APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013;70: 223–28.
  3. Tsuang D, Leverenz JB, Lopez OL, et al. GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology. 2012;79:1944–50.
  4. Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014;46: 989–93.
  5. Attems J. Alzheimer's disease pathology in synucleinopathies.  Lancet Neurol. 2017;16:22-23.
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