GBA and APOE Mutations Linked to Cognitive Decline, Dementia Risk

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Among Parkinson’s patients, those carrying GBA and APOE gene mutations have a significantly faster cognitive decline and a higher risk of progression to dementia, a study in more than 1,000 patients across Northern Europe reported.

Notably, the dementia risk was even higher when mutations in both genes were present. No significant associations were detected for other common Parkinson’s-associated genes, such as MAPT or SNCA.

These findings of GBA and APOE mutations as risk factors for cognitive impairment may help to better inform future clinical trials and aid doctors in managing a patient’s potential disease progression, the researchers noted.

The study, “GBA and APOE Impact Cognitive Decline in Parkinson’s Disease: A 10-Year Population-Based Study,” was published in the journal Movement Disorders.

Besides its well-known motor symptoms, Parkinson’s is characterized by non-motor symptoms that include cognitive impairment. But cognitive decline’s progression is highly variable among patients, “limiting the recruitment of relevant participants into clinical trials,” the researchers wrote.

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Genetic factors have been proposed as potential predictors of cognitive decline and dementia in people with Parkinson’s, which could help identify those at high risk and improve the design of future trials. Among the strongest candidates are common genetic changes in the GBA, APOE, MAPT, and SNCA genes.

Notably, the APOE4 variant has been linked to Lewy body dementias (LBDs) like Parkinson’s, while GBA is one of the most common genetic risk factors for Parkinson’s and LBD. Studies into possible associations between MAPT and SNCA mutations and cognitive decline report inconsistent results.

“Large studies with prospective follow-up from the time of PD [Parkinson’s disease] diagnosis are scarce,” the scientists also noted.

An international research team analyzed clinical and genetic data covering 1,002 newly-diagnosed Parkinson’s patients (611 men and 391 women) who were followed for up to 10 years within the Parkinson’s Incidence Cohorts Collaboration (PICC).

PICC is a project that pools data from six longitudinal (observational), non-selective, population-based studies of people newly diagnosed with Parkinson’s in Northern Europe.

Patients’ mean age at diagnosis was 69.1 years. They entered one of the six studies a median of 1.2 months after diagnosis, and were followed for a median of 7.2 years. During these years, 34.3% of the patients died and 17.7% left the study for other reasons.

Most patients (92.6%) had genetic information covering the four relevant genes. The researchers assessed the effect of these mutations on patients’ rate of cognitive decline and risk of dementia, also known as Parkinson’s disease dementia (PDD).

Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) scale, while dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, or Movement Disorder Society criteria.

Patients carrying the APOE4 variant (282 people) or any GBA mutation (102 people) were significantly younger — by about two to 2.5 years — at the time of both Parkinson’s diagnosis and onset of motor symptoms, compared with those without such mutations, the team reported.

Moreover, carriers of either the APOE4 variant or a GBA mutation showed significantly faster cognitive decline than non-carriers. Patients with either mutation were estimated to lose an average of 0.5 MMSE points per year, which “is substantially higher than estimates of 0.1–0.2 points per year in other longitudinal studies,” the researchers wrote.

Cognitive function declined most quickly among the 23 patients with both genes carrying mutations (drop of about 11 vs. three MMSE points over 10 years).

In line with a faster decline, patients carrying any of these mutations had a significantly higher risk of progression to dementia relative to those without such mutations.

Specifically, patients with the APOE4 variant showed a 3.5-fold higher risk, but this risk fell over time with no significant link being observed 10 years after diagnosis. This risk also showed what the researchers called a dose-dependent effect, “with about a threefold increased risk of dementia per [APOE4 gene variant].”

These findings support “the importance of early initiation of neuroprotective treatment (when available) in [APOE4] carriers,” particularly those “with a younger age at onset who are not traditionally identified as of high risk of rapid cognitive decline,” the scientists added.

Patients with any GBA mutation were also nearly two times more likely to develop PDD than non-carriers. Severe GBA mutations were linked to greater cognitive impairments at study start and an almost three times higher risk of PDD.

Both mild and severe GBA mutations contribute to the cognitive variability among patients with mutations in this gene, with “the clinical continuum linked to GBA mutations … apparent already at diagnosis,” the researchers wrote.

Notably, carrying both of these genetic variants associated with a five times higher risk of progression to dementia relative to carrying none, which may be associated with “the combination of neurodegenerative mechanisms mediated by these [genetic changes],” the study reported.

No significant effects were observed for mutations in the MAPT or SNCA genes in terms of age at diagnosis and motor symptom onset, rate of cognitive decline, or risk of PDD.

These findings highlight that “both [APOE4] and GBA mutations have an independent and additive effect on cognitive outcomes, adding to mounting evidence that these variants are key drivers of cognitive decline in PD, whilst common variants in SNCA and MAPT showed no significant impact,” the researchers wrote.

“Understanding the role of common variants on the pattern of cognitive decline over the natural course of PD will support more accurate disease prognosis [likely outcomes] and should be considered when designing clinical trials,” they added.

In this study, “36% of patients were carriers of either [APOE4] or GBA, which places many individuals at risk of a more severe disease course, and the importance of these results is augmented by the additional effect of GBA and APOE carrier status on reducing the age at disease onset,” the team concluded.