APOE ϵ4 Increases Risk for Dementia in Pure Synucleinopathies

Tsuang, Debby W.; Leverenz, James B.; López, Oscar L.; Hamilton, Ronald L.; Bennett, David A.; Schneider, Julie A.; Buchman, Aron S.; Larson, Eric B.; Crane, Paul K.; Kaye, Jeffrey; Kramer, Patricia L.; Woltjer, Randy; Trojanowski, John Q.; Weintraub, Daniel; Chen‐Plotkin, Alice S.; Irwin, David J.; Rick, Jacqueline; Schellenberg, Gerard D.; Watson, G. Stennis; Kukull, Walter A.; Nelson, Peter T.; Jicha, Gregory A.; Neltner, Janna H.; Galasko, Doug; Masliah, Eliezer; Quinn, Joseph F.; Chung, Kathryn A.; Yearout, Dora; Mata, Ignacio; Wan, Jia; Edwards, Karen L.; Montine, Thomas J.; Zabetian, Cyrus P.

doi:10.1001/jamaneurol.2013.600

Cited by 321 publications

(350 citation statements)

References 37 publications

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“…Overall, the NPI-Q scores indicated more behavioral problems, and the UPDRS motor scores poorer motor performance, among participants who had AD with Lewy bodies compared with participants who had AD without Lewy bodies. As captured on the NPI-Q, delusions, hallucinations, aberrant motor behaviors, and sleep behavior problems were more severe among participants who had AD with Lewy bodies than among participants who had AD without Lewy bodies.In contrast to our results, most neuropathological AD studies 8,14,15,17,19,22,23,40 have found no significant differences in age at symptomatic onset of AD or in age at death between participants who had AD with Lewy bodies and participants who had AD without Lewy bodies. With one exception, 22 all of these other studies 8,14,15,17,19,23,40 had a sample size less than half of our sample size, which could explain why there were no statistically significant differences in age at onset of cognitive symptoms or in age at death.…”

contrasting

confidence: 99%

“…With one exception, 22 all of these other studies 8,14,15,17,19,23,40 had a sample size less than half of our sample size, which could explain why there were no statistically significant differences in age at onset of cognitive symptoms or in age at death. In the study by Weiner et al 22 with a sample size similar to our own, participants were selected based on a clinical diagnosis of dementia while they were living.…”

Section: Discussionmentioning

confidence: 86%

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P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

Chung

Babulal

Monsell

et al. 2015

Alzheimer's & Dementia

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edu).Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Supplemental content at jamaneurology.com Author Contributions: Dr Morris had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of Interest Disclosures:Dr Morris has participated or is currently participating in clinical trials of antidementia drugs sponsored by the following companies and studies: Janssen Immunotherapy, Pfizer, Eli Lilly/Avid Radiopharmaceuticals, the SNIFF (Study of Nasal Insulin to Fight Forgetfulness) study, and the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. Dr Morris has served as a consultant for Lilly USA, ISIS Pharmaceuticals, and the Charles Dana Foundation. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by National Institutes of Health grants P50AG005681, P01AG003991, P01AG026276, and U19AG032438.Additional Information: The NACC database is funded by NIA/National Institutes of Health grant U01 AG016976. The NACC data were obtained from the NIA-funded AD centers (grants P30 AG019610 [PI Eric Reiman, MD] EXPOSURES-Standardized neuropathologic assessment and then brain autopsy after death. HHS Public Access MAIN OUTCOMES AND MEASURES-Clinical and neuropsychiatric test scores.RESULTS-The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). CONCLUSIONS AND RELEVANCE-Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE ε4 allele suggest potential common mechanisms for AD and Lewy body pathologies.The 2 neuropathological hallmarks of Alzheimer disease (AD) are the extracellular Aβ plaques and the intracellular neurofibrillary tangles, of which the latter is composed of hyperphosphorylated tau protein. 1 Lewy bodies are intraneuronal cytoplasmic inclusions comprising aggregates of α-synuclein 2,3 and are readily detected by immunohistochemistry using anti-α-synuclein antibodies. In up to 50% of cases of sporadic late-onset AD, comorbid Lewy bodies are found. 2 Lewy bodies are frequent in the setting of moderate-tosevere levels of A...

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contrasting

confidence: 99%

Section: Discussionmentioning

confidence: 86%

P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

Chung

Babulal

Monsell

et al. 2015

Alzheimer's & Dementia

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“…Several studies have found that the presence of one or more APOE-4 alleles not only increases the A plaque load, but also the -syn pathology burden in PD cases (183,200,201). Interestingly, when a relatively large group of PD cases was stratified pathologically and cases with concomitant A pathology were excluded (leaving a cohort with pure -syn pathology), APOE-4 was still strongly associated with dementia and even more strongly associated with early development of dementia (202). Taken together, these findings suggest that the impact of APOE genotype on synucleinopathy and dementia is likely multifactorial and that apoE may directly influence -syn pathology.…”

Section: Apoe and -Synucleinmentioning

confidence: 99%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

184

145

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In 1907, the German psychiatrist, Alois Alzheimer, published a case report, "On an unusual illness of the cerebral cortex," in which he described what we now know as Alzheimer's disease (AD) (1). More than a century after this landmark discovery, AD is now recognized as the most common cause of late-life dementia. AD pathology is characterized by the cerebral accumulation of amyloid plaques and neurofibrillary tangles, both of which consist predominantly of specific insoluble protein aggregates. The majority of AD cases are sporadic and have a relatively late onset, predominantly after the age of 65. This form of AD is known as late-onset AD (LOAD), in contrast to early-onset AD, which has a strong genetic component, is often autosomal dominant, and accounts for less than 1% of AD cases (2). While most genetic risk factors for LOAD identified in the past two decades have a relatively small impact on AD risk, extensive epidemiological, clinical, and pathological studies have established the APOE gene on chromosome 19 as the most important genetic risk factor for developing LOAD (3-5). This locus encodes a 299 amino acid glycoprotein (apoE) that is expressed in several cell types, with highest expression levels found in the liver and the brain, where it is expressed predominantly by astrocytes (6) and, to a lesser extent, microglia (7,8). The human APOE gene Abstract Alzheimer's disease (AD) is one of the fastestgrowing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified APOE as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid- (A). Here, we discuss the role of apoE on the biophysical properties and metabolism of the A peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including A) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond A, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.

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“…The precise role of APOE genotype in dementia pathogenesis and TBI-related dementia is not fully understood, but likely impacts type, rate, and distribution of misfolded protein accumulation, especially b-amyloid (6,41). The APOE E4 allele, though, has also been associated with pure synucleinopathies, dual AD-DLB pathology and FTD with motor neuron disease (FTLD-MND) (42,43).…”

Section: Discussionmentioning

confidence: 99%

Dementia After Moderate-Severe Traumatic Brain Injury: Coexistence of Multiple Proteinopathies

Kenney¹,

Iacono

Edlow

et al. 2017

Journal of Neuropathology &Amp; Experimental Neurology

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We report the clinical, neuroimaging, and neuropathologic characteristics of 2 patients who developed early onset dementia after a moderate-severe traumatic brain injury (TBI). Neuropathological evaluation revealed abundant b-amyloid neuritic and cored plaques, diffuse b-amyloid plaques, and frequent hyperphosphorylated-tau neurofibrillary tangles (NFT) involving much of the cortex, including insula and mammillary bodies in both cases. Case 1 additionally showed NFTs in both the superficial and deep cortical layers, occasional perivascular and depth-of-sulci NFTs, and parietal white matter rarefaction, which corresponded with decreased parietal fiber tracts observed on ex vivo MRI. Case 2 additionally showed NFT predominance in the superficial layers of the cortex, hypothalamus and brainstem, diffuse Lewy bodies in the cortex, amygdala and brainstem, and intraneuronal TDP-43 inclusions. The neuropathologic diagnoses were atypical Alzheimer disease (AD) with features of chronic traumatic encephalopathy and white matter loss (Case 1), and atypical AD, dementia with Lewy bodies and coexistent TDP-43 pathology (Case 2). These findings support an epidemiological association between TBI and dementia and further characterize the variety of misfolded proteins that may accumulate after TBI. Analyses with comprehensive clinical, imaging, genetic, and neuropathological data are required to characterize the full clinicopathological spectrum associated with dementias occurring after moderate-severe TBI.

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APOE ϵ4 Increases Risk for Dementia in Pure Synucleinopathies

Cited by 321 publications

References 37 publications

P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Dementia After Moderate-Severe Traumatic Brain Injury: Coexistence of Multiple Proteinopathies

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