LIGHT-MCI Trial: GLP-1 Agonist, SGLT2 Inhibitor, and DPP-4 Inhibitor for MCI Remission in Type 2 Diabetes

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Change in the RBANS index score of immediate memory

The RBANS (Chinese version) is a brief neuropsychological screening battery with established test-retest reliability and age-appropriate normative data. The RBANS includes 12 sub-tests that generate five age-adjusted index scores and a total score. The five indices include immediate memory (consisting of list learning and story memory tests), visuospatial/constructional domain (consisting of figure copying and line orientation tests), language (consisting of picture naming and semantic fluency tests), attention (consisting of digit span and coding tests) and delayed memory (consisting of list recall, story recall, figure recall and list recognition tests). Generally, a higher index score reflects a better cognitive subdomain function.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in the RBANS index score of visuospatial/constructional

Measurements and instruments are the same as the RBANS index score of immediate memory.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in the RBANS index score of language

Measurements and instruments are the same as the RBANS index score of immediate memory.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in the RBANS index score of attention

Measurements and instruments are the same as the RBANS index score of immediate memory.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in the RBANS index score of delayed memory

Measurements and instruments are the same as the RBANS index score of immediate memory.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in aggregate time to test completion for Trail Making Test (TMT)

The TMT is a validated timed measure of processing speed, which consists of part A and part B (TMT-A and TMT-B). The time limits for performing the TMT-A and TMT-B are 180 and 300 seconds, respectively. Processing speed is estimated by the aggregate time in seconds to complete TMT-A and TMT-B such that less time indicate faster processing speed.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in aggregate time to test completion for Victoria Stroop Color-Word Test

The Victoria Stroop Color-Word Test is a well-known measure of executive function. There are three indices including Stroop-dot, Stroop-word and Stroop-color word in the test. The color task consists of colored dots; the word task comprises ordinary words that are unrelated to the meaning of color; the color-word task consists of words written in color that indicate the meaning of the color, but the color of these words differs from the meaning of the word itself. The participants were asked to quickly read the color of the dots or Chinese words on the cards. The sum of consuming time taken to read the three cards is used as an index of executive function performance. Less time indicates better executive function.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived total brain volume

Philips TX 3.0T superconducting clinical MRI will be used for magnetic resonance scanning (Philips Achieva 3T TX Medical Systems, Eindhoven, the Netherlands). T1 images were processed using Freesurfer software (version 8.1.0, https://surfer.nmr.mgh.harvard.edu) to calculate intracranial volume, total gray matter volume, total white matter volume, cerebrospinal fluid volume and volumes of 68 cortical and 14 subcortical regions based on the Desikan-Killiany atlas23. The total brain volume was calculated as the sum of the gray matter and white matter volumes.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived total gray matter volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived total white matter volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived cerebrospinal fluid volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived white matter hyperintensity volume (WMH)

Total white matter hyperintensity volume was measured from FLAIR images using the Lesion Segmentation Tool for Statistical Parametric Mapping (SPM) 12.0.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived frontal gray matter volume

Measurements and instruments are the same as total brain volume. Frontal gray matter volume was calculated as the sum of all frontal lobe regions parcellated by FreeSurfer (Desikan-Killiany atlas).

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived parietal gray matter volume

Measurements and instruments are the same as total brain volume. Parietal gray matter volume was calculated as the sum of all parietal lobe regions parcellated by FreeSurfer (Desikan-Killiany atlas).

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived temporal gray matter volume

Measurements and instruments are the same as total brain volume. Temporal gray matter volume was calculated as the sum of all temporal lobe regions parcellated by FreeSurfer (Desikan-Killiany atlas).

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived occipital gray matter volume

Measurements and instruments are the same as total brain volume. Occipital gray matter volume was calculated as the sum of all occipital lobe regions parcellated by FreeSurfer (Desikan-Killiany atlas).

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived insula gray matter volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived hippocampal volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived parahippocampal volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived entorhinal cortex volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived inferior parietal lobule volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived precuneus volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived cuneus volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived thalamus volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived caudate nucleus volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived putamen volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived pallidum volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived amygdala volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in MRI-derived accumbens volume

Measurements and instruments are the same as total brain volume.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in mean fractional anisotropy (FA) in white matter derived from diffusion tensor imaging (DTI)

Diffusion Toolbox in FMRIB Software Library (FSL, version 6.0.7, http://fsl.fmrib.ox.ac.uk/fsl/fslwiki) was used to process all DTI-scans, and generate FA maps. FA from DTI assessment is a global microstructural integrity measure, with higher value indicating better integrity.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in mean diffusivity (MD) in white matter derived from DTI

Measurement and instruments are the same as FA. MD describes the overall diffusion and motion of water molecules, with higher MD values reflect more water mobility.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in fractional volume of free water in white matter (FW-WM)

FW-WM maps were constructed from preprocessed diffusion-weighted images using a regularized bi-tensor model and the open-source software package Diffusion Imaging in Python (also known as Dipy) algorithm (https://dipy.org/). Elevated FW -WM suggests the stagnation of fluid drainage caused by glymphatic dysfunction.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in diffusion tensor image analysis along the perivascular space (DTI-ALPS) index

The ALPS index was analyzed on DTI images using a method developed and validated by Taoka et al. ALPS index = (mean (Dxxproj, Dxxassoc)) ∕ (mean (Dyyproj, Dzzassoc)). The ALPS indices in the bilateral hemispheres were calculated, respectively, and the mean was used in further analyses. The DTI-ALPS index is calculated from the diffusivity along the deep medullary vein at the level of the lateral ventricle body, as a measure of perivascular clearance activity in the human brain. It is validated as a non-invasive proxy for glymphatic functioning, with higher value indicating better function.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in perivascular space volume fraction in white matter (PVSVF-WM)

PVSs were mapped from T2W images using an automated and highly reliable quantification method, following the pipeline of previous studies. The PVS volume fraction (PVSVF) = PVS volume/intracranial volume. The PVSVF-WM is a quantitative metric that reflects the distribution and dilatation of perivascular spaces within cerebral white matter. An elevated volume fraction may suggest impaired clearance function of brain interstitial fluid.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in functional MRI-derived odor-induced brain activation

Task-evoked activation was assessed using FSL FEAT (version 6.0.7), which use general linear modelling to estimate scent effects on brain activation. Bilateral parahippocampus, amygdala, piriform cortex, insula, orbitofrontal cortex, and hippocampus in Automated Anatomical Labeling templates and Brodmann areas 28 and 34 (entorhinal cortices) were extracted and merged as olfactory regions of interest (ROIs) (total cluster size 5,029 voxels) for further analyses.

Time frame: from baseline to the 48 weeks of treatment.

Changes in plasma amyloid beta (Aβ)42/Aβ40 concentration

Plasma Aβ40 and Aβ42 concentration were measured using the Neurology 4-plex E assay kit from Quanterix.

Time frame: from baseline to the 48 weeks of treatment.

Changes in plasma phosphorylated tau (p-tau)181 concentration

Plasma p-tau 181 concentration was measured using the p-Tau181 Advantage PLUS kit from Quanterix.

Time frame: from baseline to the 48 weeks of treatment.

Changes in plasma p-tau 217 concentration

Plasma p-tau 217 concentration was measured using the ALZpath p-Tau217 Advantage PLUS kit from Quanterix.

Time frame: from baseline to the 48 weeks of treatment.

Changes in plasma neurofilament light chain (NfL) concentration

Plasma NfL concentration was measured using the Neurology 4-plex E assay kit from Quanterix.

Time frame: from baseline to the 48 weeks of treatment.

Changes in plasma glial fibrillary acidic protein (GFAP) concentration

Plasma GFAP concentration was measured using the Neurology 4-plex E assay kit from Quanterix.

Time frame: from baseline to the 48 weeks of treatment.

Changes in resting-state functional MRI-derived brain network connectivity

The whole-brain network functional connectivity analysis was carried out using the CONN Toolbox (v.22.v2407). The Schaefer-Yeo 7-network functional atlas was used to parcellate the cortex into 400 volumetric functional parcels, and the Melbourne Subcortical Atlas was used to parcellate the subcortex into 54 functional nuclei, yielding a total of 454 regions. For each participant, the pre-processed resting-state fMRI time series was spatially averaged across all voxels composing each region, yielding an averaged time series for each region. The Pearson correlation coefficient was computed between all pairs of regions from the combined cortical and subcortical atlases to provide a measure of functional connectivity, yielding a 454\*454 symmetric connectivity matrix for each individual.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in olfactory threshold scores

Olfactory Function Assessment by Computerized Testing (OLFACT®, Osmic Enterprises, Inc.) was administered to assess olfactory threshold, identification, and memory. The olfactory threshold test (score range, 1-14) was a forced-choice paradigm based on serial dilutions of N-butanol solutions. Higher scores indicate better olfactory function.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in olfactory identification scores

Olfactory Function Assessment by Computerized Testing (OLFACT®, Osmic Enterprises, Inc.) was administered to assess olfactory threshold, identification, and memory. The olfactory identification (score 0-30) and memory (score 0-20) subtests consisted of two sequential phases separated by a 10-min interval. During task A, participants performed forced-choice identification of 10 distinct odors. In task B, they were presented with 20 odors (10 from task A and 10 novel distractors) and required to complete two tasks per odor: identify the odor, then classify it as 'old' or 'new' (relative to task A). Higher scores indicate better olfactory function.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in olfactory memory scores

Olfactory Function Assessment by Computerized Testing (OLFACT®, Osmic Enterprises, Inc.) was administered to assess olfactory threshold, identification, and memory. The olfactory identification (score 0-30) and memory (score 0-20) subtests consisted of two sequential phases separated by a 10-min interval. During task A, participants performed forced-choice identification of 10 distinct odors. In task B, they were presented with 20 odors (10 from task A and 10 novel distractors) and required to complete two tasks per odor: identify the odor, then classify it as 'old' or 'new' (relative to task A). Higher scores indicate better olfactory function.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in olfactory assessment total scores

The sum of the olfactory threshold, identification, and memory scores was referred to as the olfactory assessment total scores, which ranged from 0 to 64 points. Higher scores indicate better olfactory function.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in glycated haemoglobin (HbA1c) levels

Glycated haemoglobin A1c (HbA1c).

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in fasting plasma glucose levels

Fasting plasma glucose.

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in 2-hour postprandial plasma glucose levels

2-hour postprandial plasma glucose.

Time frame: from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in fasting insulin

Fasting insulin.

Time frame: from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in fasting C-peptide levels

Fasting C-peptide levels.

Time frame: from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in 2-hour postprandial insulin

2-hour postprandial insulin.

Time frame: from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in 2-hour postprandial C-peptide levels

2-hour postprandial C-peptide levels.

Time frame: from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in pancreatic islet function (HOMA2-β)

Pancreatic islet function (HOMA2-β) was estimated from fasting C-peptide via HOMA2 Calculator (v2.2.3, http://www.dtu.ox.ac.uk/homacalculator/) .

Time frame: from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in insulin sensitivity (HOMA2-S)

Insulin sensitivity (HOMA2-S) was estimated from fasting C-peptide via HOMA2 Calculator (v2.2.3, http://www.dtu.ox.ac.uk/homacalculator/) .

Time frame: from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in insulin resistance indexes (HOMA2-IR)

Insulin resistance indexes (HOMA2-IR) was estimated from fasting C-peptide via HOMA2 Calculator (v2.2.3, http://www.dtu.ox.ac.uk/homacalculator/) .

Time frame: from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in fasting serum triglyceride levels

Fasting serum triglyceride levels

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in fasting serum total cholesterol levels

Fasting serum total cholesterol levels

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in fasting serum high-density lipoprotein-cholesterol levels

Fasting serum high-density lipoprotein-cholesterol levels

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in fasting serum low-density lipoprotein-cholesterol levels

Fasting serum low-density lipoprotein-cholesterol levels

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in visceral fat area

Visceral fat area was measured by Inbody 720 analyser.

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in percent body fat

Percent body fat was measured by Inbody 720 analyser.

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in liver stiffness

Liver stiffness measurement was quantified by FibroTouch® system

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in liver fat controlled attenuation parameter

Liver fat controlled attenuation parameter was quantified by FibroTouch® system

Time frame: from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Change in blood pressure

Systolic and diastolic blood pressure

Time frame: from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).

Change in body weight

Body weight

Time frame: from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).

Change in body mass index

Body mass index

Time frame: from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).

Change in waist circumference

Waist circumference

Time frame: from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).

Change in hip circumference

Hip circumference

Time frame: from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).

Change in waist to hip ratio

Waist circumference to hip circumference ratio

Time frame: from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase).

Changes in Barthel index

Basic activities of daily living (BADL) ability measured by the Barthel index. The Barthel Index (Chinese version) measures dependence in 10 basic personal activities of daily living such as showering, feeding, and walking. Ten items are rated, for a maximum score of 100 representing total independence. A "good" score is ≥ 60 points, which indicates that the patient is capable of basic self-care. Moderate dysfunction is defined as a score between 40 and 60, indicating that the patient needs help in daily life. Severe dysfunction is defined as a score between 20 and 40, indicating that the patient is significantly dependent on help in daily living. A score below 20 indicates a total disability in which the patient depends on help for all aspects of daily living. The measure is completed based on input from the direct care worker providing care to the participants on the day testing.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Changes in FAQ score

Instrumental activities of daily living (IADL) ability measured by FAQ scores. The Functional Activities Questionnaire (FAQ, Chinese version) is a standardized assessment of instrumental activities of daily living such as preparing balanced meals and managing personal finances. Sum scores range from 0 to 30, with higher scores indicating worse function. Functional dependence is considered with scores ≥5 points.

Time frame: from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase).

Mild cognitive impairment (MCI) remission rate at week76

MCI mitigation is defined by three criteria: an education-adjusted score of the Montreal Cognitive Assessment (MoCA) ≥26, no cognitive deficits in any explored cognitive subdomain, including processing speed, executive function, immediate memory, visuospatial construction ability, language, attention and delayed memory, evaluated by Trail-Making Test, Stroop Color-Word Test and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively, and preservation of ability to perform instrumental activity of daily living (IADL) with a Functional Activities Questionnaire (FAQ) score \<5.

Time frame: from baseline to week 76 of treatment (the week 76 assessment will be analyzed and reported after the extension phase).