Impact of type 2 diabetes mellitus on differential cerebellar volume reduction in Alzheimer's disease trajectory

Abstract

Background

Alzheimer's disease (AD) is a neurodegenerative disorder linked to cognitive decline. Type 2 diabetes mellitus (T2DM) is a known risk factor for AD and may contribute to cerebellar atrophy, but their relationship remains unclear.

Objective

This study investigated the impact of T2DM on cerebellar gray matter (GM) volume across normal cognition (NC), preclinical AD, and AD mild cognitive impairment (AD MCI) groups to explore its role in AD progression.

Methods

Medical records of patients visiting St. Vincent's Hospital (September 2019–April 2024) were analyzed. Cerebellar GM volume was analyzed using voxel-based morphometry with SPM12. Group differences in cerebellar GM volume were assessed using rank analysis of covariance. Spearman's partial correlation was used to explore associations between cerebellar GM volume and cognitive function, and HbA1c levels in patients with T2DM.

Results

AD MCI patients with T2DM showed greater GM atrophy, particularly in the posterior lobe. In NC, T2DM was associated with Vermis VI volume reduction, while preclinical AD showed increased Left VIIIb volume. Amyloid-β positive (Aβ+) group has negative correlation HbA1c level and right Crus I volume. Cerebellar GM volume correlated with cognitive scores, particularly episodic memory in AD MCI patients with T2DM.

Conclusions

T2DM and AD pathology contribute to cerebellar changes linked to cognitive decline. Managing T2DM may mitigate its impact on AD progression.

Keywords

aged Alzheimer's disease cerebellum cognitive dysfunction diabetes mellitus type 2

Introduction

Alzheimer's disease (AD), a neurodegenerative disorder, leads to cognitive decline marked by amyloid plaques, neurofibrillary tangles, and neuronal loss in the hippocampus and cerebrum.^1,2 Various studies have been conducted to investigate risk factors for AD prevention, among which type 2 diabetes mellitus (T2DM) has been identified as a factor that increases the risk of developing AD in numerous previous studies.³ T2DM involves insulin resistance and hyperglycemia and is increasingly common among the elderly, with a rising incidence of T2DM patients developing dementia, including AD.^4,5 Growing evidence supports a link between AD and T2DM, as diabetes is closely associated with cognitive impairment.⁶ While the cerebellum is traditionally seen as stable in AD pathology,⁷ recent findings indicate cerebellar atrophy may occur by the mild cognitive impairment (MCI) stage and be linked to insulin resistance, impacting cognitive function.^8,9 However, the relationship among AD, T2DM, and cerebellar changes remains incompletely understood, further in-depth research is required.

Traditionally, the cerebellum has been known for its role in motor control and balance; however, recent studies have revealed that the cerebellum also contributes to the regulation of cognition and emotion.¹⁰ Moreover, evidence from positron emission tomography- computed tomography (PET-CT) and functional magnetic resonance imaging (fMRI) studies has demonstrated that the cerebellum is closely connected to brain regions involved in AD brain networks.¹¹ Notably, the neocerebellum, particularly lobules VII–VIII, has been shown to be functionally connected with various associative cortical regions, including the prefrontal, parietal, temporal, and occipital cortices.¹² This connectivity extends to multiple brain networks, such as the central executive, default mode, salience, dorsal and ventral attentional, and language-dedicated networks.^13,14 Such widespread network integration suggests that the cerebellum plays an essential role in coordinating cognitive functions beyond its traditional motor-related roles.¹⁵ Previous studies have shown that patients with AD have smaller gray matter volumes in the right and left superior posterior lobes and the right inferior posterior cerebellar lobe, compared to those with MCI and healthy controls.⁸ This may suggest that the degree of cerebellar volume reduction reflects cognitive decline. Furthermore, some studies have reported that cerebellar volume changes are detectable up to 12 months prior to an AD diagnosis, indicating early alterations in the disease process.^16,17 Based on these findings, it is plausible that disruptions in cerebello-cortical functional connectivity (FC) may precede and potentially contribute to the subsequent structural atrophy of the cerebellum, ultimately exacerbating cognitive decline in AD. Considering this, it is hypothesized that cerebellar volume changes may not only influence cognitive decline in AD but also emerge early in the disease process, potentially even at the initial stages of AD pathology.

Meanwhile, insulin plays a critical role in neuronal growth and brain aging; however, insulin resistance in T2DM reduces insulin receptor density at the blood-brain barrier (BBB), thereby limiting insulin transport to the brain.⁴ This restriction may promote the accumulation of amyloid precursor proteins, potentially linking T2DM to the onset of AD.^18,19 Additionally, mitochondrial dysfunction and increased oxidative stress observed in T2DM can lead to pathological changes in amyloid-β and tau proteins, resulting in neural damage.²⁰ Inflammatory markers detected in T2DM patients may cross the BBB and contribute to cognitive decline either directly in the brain or indirectly via vascular disease.²¹ Furthermore, reductions in cerebellar volume and declines in cognitive function observed in T2DM patients suggest that such metabolic alterations may affect brain regions, including cerebellar atrophy, ultimately increasing the risk of AD progression.^9,22 However, despite the accumulating evidence, studies investigating the interplay among AD, the cerebellum, and T2DM remain limited.

Therefore, this study aimed to investigate the impact of T2DM on cerebellar volume reduction in AD by categorizing participants into groups with normal cognition (NC), preclinical AD, and AD MCI. This approach seeks to analyze how cerebellar volume reduction in AD patients with T2DM may contribute to the onset and progression of AD, offering insights into potential modifiable factors for disease management. In this study, we hypothesized that patients with AD pathology and T2DM would exhibit greater cerebellar volume reduction compared to those with AD pathology but without T2DM, and that this reduction would progressively worsen across the NC, preclinical AD, and AD MCI. Furthermore, we hypothesized that cerebellar volume reduction would correlate with a decline in cognitive function.

Methods

Participants

This study was a retrospective analysis based on collected medical records of patients who visited St. Vincent's Hospital between September 2019 and April 2024 with cognitive impairment as their chief complaint.

The inclusion criteria were as follows: patients with demographic data such as age, sex, education years, and diabetes status; those aged 55∼89 years, those who underwent amyloid PET-CT, brain MRI, and a comprehensive neuropsychiatric test battery including the Mini-Mental State Examination (MMSE),²³ the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K),²⁴ the Global Deterioration Scale (GDS),²⁵ the Clinical Dementia Rating (CDR),²⁶ Seoul-Activities of Daily Living (ADL),²⁷ Seoul-Instrumental Activities of Daily Living (S-IADL)²⁷ and the Neuropsychiatric Inventory (NPI)²⁸; and those with complete blood sample results, including apolipoprotein E ε4 (APOE ε4) genotype testing.

The exclusion criteria included the absence of properly documented demographic information; age below 55 or above 89 years old, missing imaging studies such as amyloid PET-CT or brain MRI, incomplete blood test results including APOE ε4 genotype testing, and the presence of psychiatric disorders affecting cognitive function (e.g., depression and bipolar disorder), neurological disorders, cerebrovascular history, or alcohol/substance use disorders. Additionally, patients with dementia, a CDR score of 1 or higher and functional impairments preventing independent living were excluded.

Based on previous chart records and test results performed at our institution, participants were classified into the following cognitive groups:

Normal cognition: A patient with a CDR score of 0, showing no clinical evidence of cognitive changes and negative findings on amyloid PET scan, showing no evidence of amyloid-β (Aβ) deposition.

Preclinical Alzheimer's disease: Patients with a CDR score of 0, showing no objective cognitive impairment on neuropsychiatric tests but with positive findings on amyloid PET-CT, indicating biomarker evidence.

Alzheimer's disease mild cognitive impairment : Considering the criteria proposed by Petersen, patients with objective cognitive impairment on neuropsychiatric testing for age and education, preserved general cognitive function, intact activities of daily living and positive amyloid PET-CT findings indicating biomarker evidence²⁹

Diabetes status was determined through self-reported history of physician-diagnosed diabetes at the initial clinical evaluation. Furthermore, the use of anti-diabetic medications at the time of the first clinical evaluation was also considered as confirmation of diabetes diagnosis. For participants with T2DM, blood samples for HbA1c measurement were collected at the initial evaluation.

Additionally, this study was conducted with the approval of the Catholic Institutional Review Board (VC24RISI0021).

Image and data acquisition

Brain imaging data were acquired using a 3T Siemens Skyra machine and 32 channel Siemens head coil (Siemens Medical Solutions, Erlangen, Germany) at St. Vincent's hospital in Korea. The image parameters for the T1-weighted volumetric magnetization-prepared rapid gradient echo scan sequences were as follows: echo time (TE) = 2.6 ms, repetition time (TR) = 1940 ms, inversion time = 979 ms, field of view (FOV) = 230 mm, matrix = 256 × 256, and voxel size = 1.0 × 1.0 × 1.0 mm³.

To confirm biomarker evidence, [¹⁸F]flutemetamol PET imaging was performed using a PET-CT scanner using (Philips healthcare, Andover, MA, USA) at St. Vincent's hospital in Korea. The amyloid PET-CT scan results for each patient were interpreted by an experienced nuclear medicine physician and categorized as either positive or negative based on the degree of biomarker deposition.

Voxel-based morphometry analysis was performed using SPM 12 and the CAT12 toolbox implemented in MATLAB 2024b. The spatially unbiased infratentorial template (SUIT) atlas was used to extract and normalize the GM and white matter (WM) of the cerebellum. SUIT provides a high-resolution, spatially unbiased template of the cerebellum and brainstem, allowing for more accurate inter-subject alignment compared to conventional whole-brain methods via automated non-linear normalization.³⁰ The images were smoothed with an 8-mm full-width at half maximum (FWHM) Gaussian kernel, and total intracranial volume (TICV) was calculated separately using CAT12,³¹ with these values used as covariates. GM volume values were obtained for cerebellar regions I-IV, V, VI, Crus I, Crus II, VIIb, VIIIa, VIIIb, IX, and X. Among these, regions I-V and V were defined as the anterior lobe, regions VI-IX as the posterior lobe, and region X as the flocculonodular lobe.³²

The CERAD-K was used to assess objective cognitive impairment in neuropsychiatric tests. Originally designed for the standardized clinical and neuropsychological evaluation of AD, the CERAD-K has been validated and shown to be reliable for use in the Korean.²⁴ Episodic memory was defined as the composite score of word list memory, word list recall, word list recognition, and constructional praxis recall.³³ Non-episodic memory was defined as the composite score of verbal fluency, the modified Boston naming test, MMSE, and constructional praxis.³³

Statistical analyses

To compare demographic and clinical characteristics across diagnostic groups, the Kruskal-Wallis test was used for continuous variables, and the Fisher's exact test was applied for categorical variables. Differences in cerebellar GM volume by T2DM status among the NC, preclinical AD, and AD MCI groups were examined using rank analysis of covariance (rank ANCOVA), with age, education year, sex, APOE ε4 genotype carrier status, and TICV as covariates. Among participants with T2DM, Spearman's partial correlation analyses were performed separately for the Aβ+ and Aβ- groups to assess the associations between HbA1c levels and cerebellar regional volumes, adjusting for age, sex, years of education, APOE ε4 carrier status, and TICV. Spearman's partial correlation analyses were performed for the AD MCI group with T2DM to explore associations between significantly different cerebellar GM region volumes and CERAD-K test scores, applying the same covariates. Statistical significance was set at p < 0.05 for both regional differences and correlation analyses. These statistical approaches provided a robust framework for evaluating relationships among cerebellar GM volume, T2DM status, and cognitive impairment. All statistical analyses were conducted using R software (Version 4.4.2).

Results

Demographic and clinical characteristics

Supplemental Table 1 presents the demographic and clinical characteristics of the study population. The mean age of the participants was 73.1 years, with 39 males and 86 females, and the mean of education year was 8.64. Among the participants, 4 were APOE ε4 homozygotes, 40 were heterozygotes, and 81 were non-carriers. The mean TICV was 1388. Table 1 presents the demographic and clinical characteristics of the participants categorized by diagnostic group. A total of 66 individuals were classified as the NC group, 22 as the preclinical AD group, and 37 as the AD MCI group. Among these, 18 participants in the NC group, 3 in the preclinical AD group, and 11 in the AD MCI group were diagnosed with T2DM. To assess homogeneity according to diagnostic groups, a Kruskal-Wallis test was conducted for continuous variables, including age (p < 0.001), education year (p = 0.607), and TICV (p = 0.234). For categorical variables, including sex (p = 0.055), APOE ε4 status (p = 0.006), and T2DM diagnosis (p = 0.370), Fisher's exact test applied. There was statistical significance in age and APOE ε4 status (Table 1).

Table 1.

Demographic and clinical characteristics of participants according to diagnosis.

	NC(N = 66)	Preclinical AD(N = 22)	AD MCI(N = 37)	p
Age ± SD	70.2 ± 8.30	77.0 ± 7.27	75.8 ± 5.99	<0 . 001
Sex (Female, %)	24 (42,63.6)	9 (13,59.1)	6 (31,83.8)	0.055
Education year ± SD	188.32 ± 5.48	9.14 ± 4.37	8.92 ± 4.77	0.607
T2DM (%)	18 (27.3)	3 (13.6)	11 (29.7)	0.370
APOE ε4 genotype				0 . 006
Homozygotes (%)	2 (3.0)	0 (0)	2 (5.4)
Heterozygotes (%)	13 (19.7)	12 (54.5)	15 (40.5)
Non-carrier (%)	51 (77.3)	10 (45.5)	20 (54.1)
TICV ± SD	1402 ± 160	1394 ± 123	1361 ± 126	0.234

NC: normal cognition; Preclinical AD: preclinical Alzheimer's disease; AD MCI: Alzheimer's disease mild cognitive impairment; SD: standard deviation; T2DM: type 2 diabetes mellitus; APOE ε4: apolipoprotein E ε4; TICV: total intracranial volume

Regional variations in cerebellar GM atrophy based on T2DM status

As shown in Figure 1 and Supplemental Table 2, in the NC group, the volume of Vermis VI was smaller in individuals with T2DM compared to those without T2DM (p = 0.030), whereas in the preclinical AD group, individuals with T2DM exhibited a larger volume of Left VIIIb compared to those without T2DM. (p = 0.044) In the AD MCI group, significant differences in cerebellar GM volume reduction were observed between T2DM status (Figure 2, Supplemental Table 2).

Figure 1.

Box plots of cerebellar gray matter volume differences between the normal cognition group (left) and preclinical Alzheimer's disease patients (right) with and without type 2 diabetes mellitus. T2DM: type 2 diabetes mellitus.

Figure 2.

Box plots of cerebellar gray matter volume differences the Alzheimer's disease mild neurocognitive impairment patients with and without type 2 diabetes mellitus. T2DM: type 2 diabetes mellitus.

Figure 3.

Cerebellar gray matter regions with significant volume changes in participants with and without type 2 diabetes mellitus.

Among AD MCI patients, those with T2DM exhibited significantly smaller GM volumes in cerebellar regions, including the right VI (p = 0.019), left Crus I (p = 0.035), lobule Crus II (p = 0.012, 0.025, 0.003), lobule VIIb (p = 0.002, 0.014, 0.019), left and right VIIIa (p = 0.003, 0.026), left and right VIIIb (p = 0.004, 0.017), and left IX (p = 0.027), as well as the total posterior lobe GM volume (p = 0.003), compared to the AD MCI group without T2DM (Figure 2, Supplemental Table 2). Additionally, while no differences were observed in the individual regions of the flocculonodular lobe, the composite volume of the flocculonodular region showed a difference (p = 0.027) (Supplemental Tables 2 and 3). In the NC group, only the Vermis VI region showed significantly smaller volume in individuals with T2DM (Figure 3). In contrast, in the preclinical AD group, the volume of Left VIIIb was larger in patients with T2DM compared to those without T2DM (Figure 3). Importantly, in T2DM patients, all volume changes were localized to the posterior lobe of the cerebellum, except for the total volume of the flocculonodular region (Figure 3). Other cerebellar regions that did not show statistical significance according to T2DM status are presented in Supplemental Table 3.

Correlations between HbA1c level and cerebellar GM atrophy in patients with T2DM

We compared HbA1c levels and cerebellar GM volumes across Aβ+ groups (preclinical AD, AD MCI) and Aβ- normal cognitive group in patients with T2DM. In the Aβ- normal cognitive group, no significant associations were observed between cerebellar volumes and HbA1c levels (Supplemental Table 4). However, in the Aβ+ groups, a significant negative correlation was identified between the volume of the right Crus I region and HbA1c levels, indicating that higher HbA1c concentrations were associated with greater atrophy in the right Crus I (p = 0.037, adjusted Spearman's rho = −0.70, Supplemental Table 5).

Correlations between neuropsychological test scores and cerebellar GM atrophy in Aβ+ MCI with T2DM

In AD MCI patients with T2DM, significant correlations were observed between cerebellar GM volumes and neuropsychological test scores (Supplemental Table 6). Positive correlations were identified in regions such as the right VIIIa (r = 0.85, p = 0.032), right VIIIb (r = 0.84, p = 0.038), and the posterior lobe (r = 0.98, p < 0.001), with cognitive test domains including word list memory and the composite episodic memory scores (Figure 4). Meanwhile, the NC group with T2DM presented no correlation between the GM volume of Vermis VI and cognitive function test scores, and the sample size of the preclinical AD group with T2DM was insufficient to evaluate correlations between neuropsychological test scores and cerebellar GM atrophy.

Figure 4.

Correlation between cognitive function test score and cerebellar gray matter volume reduction in Alzheimer's disease mild cognitive impairment with type 2 diabetes mellitus.

Discussion

This study investigated the clinical relationship between T2DM and AD pathology by examining cerebellar GM volume changes based on T2DM status. The findings provide significant insights, highlighting the cerebellum and T2DM as potential targets for early diagnosis and intervention in AD.

The results revealed that cerebellar GM atrophy was significantly more pronounced in AD MCI with T2DM patients, particularly in the posterior lobe. Among AD MCI patients, those with T2DM exhibited reduced GM volumes in several regions, including the right VI, left Crus I, lobules Crus II, lobules VIIb, left and right VIIIa, left and right VIIIb, and left IX, as well as the total posterior lobe GM volume and the total floccunodular lobe GM volume. Furthermore, in the NC group, the volume of Vermis VI was smaller in individuals with T2DM, whereas in the preclinical AD group, the volume of Left VIIIb was larger in those with T2DM. These findings challenge the traditional perspective that the cerebellum primarily supports motor control,³⁴ instead underscoring its critical role in cognitive functions and its vulnerability to AD pathology. Moreover, these results indicate that the cerebellum, traditionally considered a stable region in the AD trajectory,⁸ undergoes structural changes influenced by modifiable factors like T2DM, which may affect the stages of AD progression.

The effects of T2DM on the cerebellum differed across diagnostic groups—NC, preclinical AD, and AD MCI—and became more pronounced with advancing AD pathology. This suggests that T2DM impacts not only AD pathology but also the cerebellum. While previous studies have explored the cerebellum in AD or the connection between AD and T2DM, this study is the first to investigate the interplay among the cerebellum, AD, and T2DM simultaneously. Importantly, our findings uniquely reveal the impacts of T2DM on AD pathology and the cerebellum.

Insulin resistance observed in T2DM is hypothesized to serve as a connecting link between T2DM and AD.⁴ Insulin plays an essential neurotrophic role in the brain, influencing cognitive functions by activating various secondary signaling pathways.^35–37 Chronic hyperinsulinemia in T2DM patients may lead to downregulation of insulin receptors at BBB, potentially reducing insulin transport to the brain.⁴ These receptors, distributed throughout the brain, are densely located in the cerebellum.^38,39 Based on our findings, the pronounced cerebellar GM atrophy observed in AD MCI with T2DM patients suggests that T2DM may accelerates the progression of AD through insulin resistance. This study highlights that such acceleration affects not only the cerebrum but also the cerebellum, with posterior lobe atrophy detected even in the early stages of the AD, providing significant clinical insights. On the other hand, in the NC group, a reduction in the volume of Vermis VI was observed, whereas in the preclinical AD group, an increase in the volume of Left VIIIb was noted. These findings suggest that T2DM may exert differential effects on the cerebellum depending on the stage of AD progression. While both the preclinical AD and AD MCI groups showed GM volume changes in Left VIIIb, the NC group exhibited volume reductions in Vermis VI, a distinct region. This observation suggests that the cerebellum may be more vulnerable to structural changes in individuals with T2DM. Nevertheless, as this study is cross-sectional in design, it remains unclear whether T2DM exerts a direct effect on cerebellar atrophy or whether the observed changes result from secondary neurodegenerative processes. However, numerous studies have highlighted shared pathological mechanisms between T2DM and AD, particularly chronic inflammation and vascular dysfunction.⁴⁰ In patients with T2DM, elevated levels of inflammatory mediators such as C-reactive protein (CRP), interleukin-6 (IL-6),⁴¹ and proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α) have been reported, which contribute to insulin resistance and systemic inflammation.⁴⁰ Similarly, in AD, the accumulation of Aβ peptides triggers microglial activation, leading to the release of proinflammatory cytokines including TNF-α and IL-6, as well as elevated CRP levels, thereby promoting neuroinflammation.^42,43 Moreover, chronic inflammation in both conditions has been linked to vascular dysfunction, which can exacerbate neurodegenerative processes.⁴⁴ Considering previous findings that chronic systemic inflammation and vascular dysfunction contribute to brain atrophy,⁴⁵ it is plausible that the shared inflammatory and vascular pathology of T2DM and AD may have contributed to the cerebellar atrophy observed in our study. This study may provide a foundation for future research investigating cerebellar changes in patients with T2DM. Furthermore, longitudinal and blood biomarker-based studies are warranted to clarify the underlying mechanisms more clearly, and our findings could serve as a valuable basis for such future investigations.

In the NC group with T2DM, a reduction in the volume of vermis VI was observed. It is well known that damage to the cerebellar vermis results in deficits in whole-body posture and locomotion, and that the vermis receives somatosensory inputs related to proximal body parts via spinal pathways.⁴⁶ Specifically, vermis VI has been shown, in studies using monkeys, to interact with the motor cortex in the frontal lobe and regulate whole-body posture and locomotion.⁴⁷ Meanwhile, gait abnormalities and altered gait velocity are well-documented in patients with T2DM.⁴⁸ The structural changes in vermis VI observed in the NC group with T2DM in this study may reflect the impact of T2DM.

In the preclinical AD group, an increase in the volume of the left VIIIb was observed in individuals with T2DM, whereas a decrease in the left VIIIb volume was noted in the MCI group with T2DM. Previous studies have suggested that neuronal damage and compensatory mechanisms coexist in the early stages of AD.⁴⁹ For instance, FC deficits between the posterior cingulate cortex and regions of the default mode network(DMN) are accompanied by increased connectivity between the medial prefrontal cortex and anterior cingulate cortex.⁵⁰ Similarly, increased blood flow in brain regions, including the medial temporal lobe, has been observed alongside decreased blood flow in other AD-related regions during the early stages of the disease.⁵¹ Additionally, studies have reported that increased FC may lead to an increase in GM volume in associated brain regions.⁵²

Considering these findings, it is plausible that in the preclinical AD group with T2DM, the increased volume of the left VIIIb may reflect a compensatory response to reduced cerebellar FC. Once the neurodegenerative burden exceeds a certain threshold, these compensatory mechanisms might fail to function. This suggests that T2DM could accelerate FC decline, potentially promoting AD progression.

In the AD MCI group with T2DM, atrophy was observed in the posterior lobe, including the right VI, left Crus I, lobule Crus II, lobule VIIb, left and right VIIIa, left and right VIIIb, and left IX, compared to the AD MCI group without T2DM. The posterior lobe of the cerebellum is known to be associated with cognitive functions, and previous studies have reported a link between cerebellar posterior structural abnormalities and cognitive impairment.³⁴ Therefore, it is possible that the posterior lobe, which is involved in cognition, is more affected in cases of T2DM as AD progresses, reflecting the broader cerebellar involvement observed across the NC, preclinical AD, and AD MCI groups.

Also, we observed that higher HbA1c levels were significantly associated with reduced GM volume in the right Crus I of the cerebellum among Aβ+ T2DM patients. But there wasn’t an association between HbA1c levels and cerebellar volume in the Aβ- normal cognitive group. Previous neuroimaging studies have consistently reported that atrophy of the cerebellar Crus I region is a common feature in neurodegenerative diseases such as frontotemporal dementia and AD.^53,54 Notably, Crus I is recognized as a critical hub within the frontoparietal executive network and the DMN, with the potential to serve as a functional bridge between these two networks.¹² Consistent with this, recent findings in patients with T2DM have demonstrated that the right Crus I is particularly vulnerable in those with high insulin resistance, exhibiting reduced GM volume that is associated with impaired executive and visuospatial performance.⁵⁵ In the present study, we further extended these findings by examining the relationship between chronic hyperglycemia, as reflected by HbA1c levels—an indirect marker of insulin resistance⁵⁶—and cerebellar atrophy in T2DM patients stratified by amyloid status. Importantly, while no significant associations were observed between HbA1c levels and cerebellar volume in the Aβ- normal cognitive group. In contrast, higher HbA1c levels were associated with greater atrophy of the right Crus I region, suggesting that chronic hyperglycemia and underlying insulin resistance may exacerbate cerebellar neurodegeneration, in the presence of amyloid pathology. These findings underscore the selective vulnerability of the right Crus I to the combined impact of metabolic dysfunction and amyloid burden.

Meanwhile, this study demonstrated a significant correlation between cerebellar GM volume reduction and cognitive decline, particularly episodic memory and word list memory, in AD MCI patients with T2DM. Notably, the affected subregions were identified as lobules right VIIIa, VIIIb. Previous studies have reported that damage to lobules VIIIa is associated with disruptions in functional connectivity with the cerebrum, particularly the DMN, which supports cognitive functions including working memory.⁵⁷ Furthermore, larger volumes of lobule VIIIb have been associated with higher scores in verbal memory and mental flexibility, particularly the composition volumes of lobules VIIIb and IX have been linked to overall cognitive function.⁵⁸

Additionally, cerebro- cerebellar structural and FC impairments in T2DM patients have been well-documented, with evidence showing reduced connectivity between the cerebellum and the frontal and parietal cortices.⁵⁹ Specifically, the DMN, a network critical for episodic memory retrieval, self-referencing, and emotion regulation,⁶⁰ is known to exhibit progressively diminished functional connectivity as AD progresses.⁶¹ Similarly, in T2DM, the DMN has demonstrated abnormal FC, including disruptions in cerebro-cerebellar circuits.^62,63

Our findings align with these observations, revealing a close association between cerebellar volume reduction and cognitive decline in T2DM patients with AD MCI. Significantly, lobules VIIIa and VIIIb play key roles in regulating cognitive functions, including episodic memory. This study highlights that FC impairments in these cerebellar subregions may underlie cognitive decline in T2DM patients with Aβ+.

This study has several limitations.

First, there was an imbalance in sample sizes between the T2DM and non-T2DM groups, with the T2DM group having a smaller sample size, which may limit the interpretability and generalizability of the findings. Second, the cross-sectional design of this study precludes the investigation of dynamic changes in cerebellar structure during the course of AD progression in T2DM patients. Future studies involving larger cohorts and longitudinal follow-up are warranted to validate and extend these findings. Third, while this study identified cerebellar anatomical volume reduction, it did not assess the functional consequences of this atrophy on cortical network activity. Further investigations incorporating functional and network-level analyses will be essential to evaluate the influence of cerebellar structural changes on cerebro-cerebellar network dysfunction. Fourth, most participants were elderly and on various medications. In particular, the effects of diabetes medications in the T2DM group could not be fully controlled. Fifth, while Aβ+ was diagnosed based on interpretation reports from nuclear medicine specialists, precise Standardized Uptake Value Ratio (SUVR) values were not available. However, a Korean study reported a concordance rate of 93.5% between SUVR values and physician interpretations.⁶⁴

Lastly, this study excluded patients already diagnosed with dementia due to AD, limiting the assessment of T2DM's impact on the cerebellum in advanced stages of AD.

Despite these limitations, this study provides robust evidence that T2DM accelerates cerebellar degeneration in AD, contributing to cognitive decline through its effects on the cerebellum. The identification of cerebellar atrophy in T2DM patients as a significant factor in AD progression underscores the potential of targeting both the cerebellum and T2DM for early diagnosis and therapeutic intervention.

This study demonstrated that both T2DM and AD pathology contribute to structural and functional changes in the cerebellum, which are closely associated with cognitive decline. Interestingly, greater posterior cerebellar volume reduction was associated with the progression of cognitive impairment, suggesting that T2DM may accelerate AD progression. Furthermore, in the presence of AD pathology, higher levels of chronic hyperglycemia were linked to more pronounced cerebellar atrophy. These findings underscore the critical role of the cerebellum in the trajectories of both AD and T2DM, highlighting its potential as a novel target for diagnosis and therapeutic intervention. This study also emphasizes the importance of proactive prevention and management of T2DM in the aging population to mitigate its impact on neurodegenerative diseases.

Supplemental Material

sj-docx-1-alz-10.1177_13872877251352208 - Supplemental material for Impact of type 2 diabetes mellitus on differential cerebellar volume reduction in Alzheimer's disease trajectory

Supplemental material, sj-docx-1-alz-10.1177_13872877251352208 for Impact of type 2 diabetes mellitus on differential cerebellar volume reduction in Alzheimer's disease trajectory by Suhyung Kim, Sheng-Min Wang, Dong Woo Kang, Sunghwan Kim, Jong-Hyun Jeong, Hyukjin Yoon, Hyun Kook Lim and Yoo Hyun Um in Journal of Alzheimer's Disease

Footnotes

Acknowledgements

The authors have no acknowledgments to report.

ORCID iDs

Suhyung Kim

Sheng-Min Wang

Dong Woo Kang

Sunghwan Kim

Jong-Hyun Jeong

Hyukjin Yoon

Hyun Kook Lim

Yoo Hyun Um

Ethical considerations

This study received ethical approval from the approval of the Catholic Institutional Review Board. (VC24RISI0021) on October 02, 2024. This is an Institutional Review Board-approved retrospective study, all patient information was de-identified and patient consent was not required. Patient data will not be shared with third parties.

Consent to participate

The requirement for informed consent was waived by the Institutional Review Board due to the retrospective nature of the study.

Author contributions

Suhyung Kim: Conceptualization; Data curation; Investigation; Formal analysis; Methodology; Visualization; Writing – original draft.

Sheng-Min Wang: Conceptualization; Data curation; Methodology; Validation; Writing – review & editing.

Dong Woo Kang: Conceptualization; Data curation; Methodology; Validation; Writing – review & editing.

Sunghwan Kim: Conceptualization; Data curation; Methodology; Validation; Writing – review & editing.

Jong-Hyun Jeong: Conceptualization; Writing – review & editing; Supervision.

Hyukjin Yoon: Methodology; Writing – review & editing.

Hyun Kook Lim: Conceptualization; Writing – review & editing; Supervision.

Yoo Hyun Um: Conceptualization; Validation; Formal analysis; Methodology; Visualization; Writing – review & editing; Supervision; Funding acquisition.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the St. Vincent's hospital, research Institute of Medical Science (SVHR-DH-2024-01) and the Korean Sleep Society of Sleep Medicine Research Fund.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data are not publicly available due to privacy or ethical restrictions.

Supplemental material

Supplemental material for this article is available online.

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