Reviewed: Zheng Y, Xie Y, Qi M, et al. Ginkgo biloba extract is comparable with donepezil in improving functional recovery in Alzheimer’s disease: Results from a multilevel characterized study based on clinical features and resting-state functional magnetic resonance imaging. Front Pharmacol. August 3, 2021;12:721216. doi: 10.3389/fphar.2021.721216.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder characterized by progressive cognitive and intellectual deficits. Pharmacological interventions include acetylcholinesterase inhibitors, N-methyl D-aspartate (NMDA) antagonists, and immunotherapy. Previously published reviews have found that the pharmaceutical donepezil can improve cognitive function, activities of daily living, and Clinical Global Impression scales in people with AD. AD progression follows a typical order, beginning with episodic memory loss, followed by semantic memory loss, aphasia (a disorder that affects language and communication), apraxia (a disorder that makes people unable to carry out certain motor movements), visuospatial symptoms, and other motor and visual deficits.

Ginkgo (Ginkgo biloba, Ginkgoaceae) extract (GBE) is thought to act on specific brain regions, and human clinical studies have shown some positive effects of GBE in people with AD. The purpose of this randomized, three-arm, parallel-group trial was to compare the efficacy of GBE versus donepezil and study the effects of their combination on cognition, behavioral function, psychological function, and quality of life (QOL). The study also used functional magnetic resonance imaging (fMRI*) to analyze spontaneous brain activity adaptations after pharmacological treatment with donepezil and/or GBE in people diagnosed with AD.

Participants were recruited at the First Affiliated Hospital of Nanjing Medical University in Nanjing, China. Eligible participants were 50 to 85 years old; right-handed; diagnosed with AD or mild cognitive impairment (MCI); had a computed tomography (CT) or MRI scan that indicated AD or MCI less than a year before recruitment; had a mini-mental state examination (MMSE) score of 27 or lower; and had the ability to follow medical guidance and provide informed consent. People were excluded if they were diagnosed with vascular dementia, major depression, schizophrenia, cerebrovascular disease, Parkinson’s disease, or other systemic and neurodegenerative diseases, or had a modified Hachinski ischemic score (MHIS, a tool used to distinguish among types of dementia) of 4 or higher.

A total of 150 eligible participants were randomly assigned to the GBE group, the donepezil group, or the combined group. fMRI was contraindicated for 19 participants in the GBE group, 22 in the donepezil group, and 22 in the combined group. Ten participants in the GBE group withdrew for various reasons, 18 withdrew in the donepezil group, and six withdrew in the combined group. The final analysis for neuropsychological testing included 40 participants in the GBE group, 32 in the donepezil group, and 44 in the combined group. fMRI testing was performed on 20 participants each in the GBE and combined groups and 17 in the donepezil group.

The GBE group received 150 mg three times daily. The donepezil group received 5 mg once daily. The combined group received both GBE (150 mg three times daily) and donepezil (5 mg once daily). All groups continued their interventions for six months.

Baseline assessments included demographics, AD/MCI history and family history, comorbidities, status of apolipoprotein E (ApoE) genotype (which increases the risk of developing AD), MHIS, Hamilton Anxiety Rating Scale (HAM-A) score, and Clinical Dementia Rating (CDR) score. Additional variables included MMSE, AD Assessment Scale-Cognitive Subscale (ADAS-Cog), Instrumental Activities of Daily Living (IADL), Geriatric Depression Scale (GDS), Neuropsychiatric Inventory (NPI), and QOL in AD (QOL-AD). All data were collected at baseline and at one, three, and six months. Resting state fMRI was performed at baseline and six months.

Baseline characteristics were similar for all parameters. During treatment, no significant differences were observed between the groups for any of the parameters except MMSE at one month. The GBE group had significantly higher MMSE scores (indicating less impairment) at one month (P = 0.019) compared to the donepezil group. All three groups showed significant improvements in MMSE and ADAS-Cog scores at one, three, and six months compared to baseline. IADL impairment was significantly reduced at three months compared to baseline in the GBE group (P = 0.017) and in the combined group (P = 0.041), and QOL-AD improved significantly in the combined group (P = 0.022). NPI scores significantly improved in the GBE (P = 0.044) and donepezil (P = 0.012) groups at six months compared to baseline. GDS scores in the combined group were significantly improved (P = 0.007) after six months compared to baseline.

Results of fMRI showed significant changes in brain activity in all three groups reflected by changes in four metrics: amplitude of low-frequency fluctuations (ALFF), percent amplitude of fluctuation (PerAF), regional homogeneity (ReHo), and degree centrality (DC). A significant positive correlation was observed between IADL changes and ALFF changes in the right gyrus rectus in the GBE group (P = 0.03), whereas a negative correlation was found in the left superior cerebellum gyrus in the donepezil group (P = 0.01). Negative correlations also were observed between: ALFF and GDS in the right middle temporal gyrus in the GBE group (P = 0.01); NPI changes and PerAF changes in the left fusiform gyrus in the GBE group (P = 0.03); and MMSE changes and ReHo changes in the right superior frontal gyrus in the GBE group (P = 0.04).

The authors concluded that GBE is comparable to donepezil in the improvement of cognitive, behavioral, psychological, and global functions in people diagnosed with AD. They also asserted that combined treatment with GBE and donepezil “seems to be unnecessary” and that “variations of imaging metrics in specific brain regions may serve as potential biomarkers in the monitoring of the therapeutic efficacy of GBE.” Well-designed studies are needed to fully investigate the efficacy and mechanisms of pharmacological treatments such as donepezil and GBE on functional recovery in people with AD, the authors noted.