APOE4 Linked to Parkinson's Disease Dementia

Pauline Anderson

November 20, 2012

The APOE (apolipoprotein E) ε4 allele, long associated with the development of Alzheimer's disease (AD) through amyloid-β metabolism, could be a risk factor for dementia in Parkinson's disease (PD) and other synucleinopathies, a new study suggests.

Researchers found a highly significant overrepresentation of the ε4 allele not only in patients with AD and those with Lewy body dementia AD (LBD-AD) but also in those with PD with dementia (PDD) and pure dementia with Lewy bodies (pDLB).

"While the ε4 allele is a well established risk factor for AD, and several studies have reported an association between APOE and LBD-AD, the finding that ε4 was overrepresented in pDLB and PDD was unexpected," the authors, led by Debby Tsuang, MD, Veterans Affairs Puget Sound Health Care System and Departments of Psychiatry and Behavioral Sciences, University of Washington, Seattle, conclude.

The results suggest that APOE might contribute to neurodegeneration through mechanisms other than amyloid processing.

Their findings were published online November 19 in the Archives of Neurology.

Overrepresentation of ε4

For this study, researchers genotyped APOE in deceased patients who came to autopsy, diagnosed with AD (n = 244), LBD-AD (n = 224), pDLB (n = 91), or PDD (n = 81), and controls who were cognitively healthy elderly adults (n = 269).

DNA was extracted from peripheral leukocytes or brain tissue, and the presence of APOE ε2, ε3 and ε4 alleles was determined by genotyping.

In a model adjusting for sex and age at death, with controls as the reference, the researchers found a highly significant overrepresentation of the ε4 allele in all case groups, including PDD and pDLB.

Table. Odds of Carrying ε4 Allele in Case Groups vs Controls

Case Group Odds Ratio (95% Confidence Interval)
AD 9.9 (6.4 - 15.3)
LBD-AD 12.6 (8.1 - 19.8)
pDLB 6.1 (3.5 - 10.5)
PDD 3.1 (1.7 - 5.6)


Within the groups with synucleinopathy, the ε4 allele frequency was significantly lower in patients with PDD (19%) than those with pDLB (31.9%) or LBD-AD (40.6%).

"[O]ur observation of an elevated ε4 frequency in the pDLB and PDD groups in which the overall brain neuritic plaque burden is low suggests the possibility that apoE isoforms also might modulate neurodeneneration by nonamyloidogenic mechanisms," the authors write.

Although PD is clinically defined by motor symptoms, more than 50% of patients develop dementia within 10 years of diagnosis.

"Whether APOE acts as a modifier gene by influencing the manifestation of cognitive dysfunction in PD is still a matter of debate," the authors note. To address this issue, researchers could, for example, assess whether APOE genotypes differ in frequency between patients with PDD and controls or cognitively intact patients with PD, or they could evaluate whether these genotypes influence the rate of progression to dementia in PD cohorts, they said.

With the results of this study, taken together with other recent research, "we believe that the preponderance of the evidence indicates that APOE is a risk factor for cognitive dysfunction in PD," the authors conclude. "However, in our data set, the magnitude of the APOE &epsilon4;4 effect was smaller for PDD than for LBD-AD and pDLB."

Most of the patients died before publication of the consensus clinical criteria for DLB, so the authors were unable to fully apply these criteria retrospectively, they note.

The study was supported by grants from the Department of Veterans Affairs and the National Institutes of Health. The work of one of the authors was funded by grants from the National Institutes of Health. The authors have disclosed no relevant financial relationships.

Arch Neurol. Published online November 19, 2012. Abstract