The Effect of Gender and APOE ɛ4 Status on Brain Amyloid-β Deposition in Different Age Groups of Mild Cognitively Impaired Individuals: A PET-CT Study

Abstract

Background:

Gender, APOE ɛ4 status and age have different effects on brain amyloid deposition in patients with mild cognitively impaired (MCI).

Objective:

To investigate the effect of gender×APOE ɛ4 status interaction on Aβ deposition in the brains of individuals with MCI in different age groups by PET scanning.

Methods:

204 individuals with MCI were classified into younger or older groups based on whether they were under or over 65 years of age. APOE genotyping, structural MRI, amyloid PET scans, and neuropsychological tests were performed. The effect of gender×APOE ɛ4 status interaction on Aβ deposition was assessed in different age groups.

Results:

APOE ɛ4 carriers had higher amyloid deposition than noncarriers in the whole group. Females with MCI had more amyloid deposition in the medial temporal lobe than males in the whole cohort and younger group. Older individuals with MCI had higher amyloid deposition than younger individuals. In stratified analysis by age, female APOE ɛ4 carriers had significantly increased amyloid deposition compared to their male counterparts only in the medial temporal lobe in the younger group. Amyloid deposition was increased in female APOE ɛ4 carriers compared to noncarriers in the younger group, whereas higher amyloid deposition was observed in male APOE ɛ4 carriers in the older group.

Conclusion:

Women in the younger group with MCI who were APOE ɛ4 carriers had more amyloid deposition in the brain, while men in the older group with MCI who were APOE ɛ4 carriers had higher amyloid deposition.

Keywords

Alzheimer’s disease amyloid deposition gender mild cognitive impairment PET

INTRODUCTION

Alzheimer’s disease (AD) is the most common type of dementia in older people, and its prevalence sharply increases with age. It is important to note that AD increases exponentially after age 65, and its prevalence doubles every five years [1]. Pathologies associated with AD are characterized by abnormal accumulation of amyloid-β (Aβ) proteins and tau neurofibrillary tangles in the brain [2]. The apolipoprotein E (APOE) ɛ4 allele is the strongest sporadic genetic risk factor for late-onset AD (LOAD,>65 years old) [3, 4]. The APOE ɛ4 allele is associated with AD-related biological and clinical markers, including more severe cortical Aβ burden, tau neurofibrillary tangle deposition, and hippocampal atrophy [5]. The presence of the APOE ɛ4 allele is associated with an increased risk of MCI and AD [6].

Female gender has been identified as a high-risk factor for AD, particularly following menopause, due to factors including follicle-stimulating hormone and longevity [7, 8]. However, gender has a significant effect on the degree of medial temporal lobe atrophy in mild cognitively impaired (MCI) individuals and early AD patients, with longitudinal changes in hippocampal volume greater in females with stable MCI than in their male counterparts [9]. The prevalence of MCI increases with age and is higher in men [10]. Emerging evidence has highlighted the genetic drivers of AD, leading to striking gender differences in the clinical severity and neuropathological presentation of AD [11, 12]. There are gender×APOE ɛ4 status interaction effects in individuals with cognitive decline, with female gender displaying an APOE ɛ4 status effect on hippocampal volumes and cognition in MCI and AD [13, 14]. Female APOE ɛ4 carriers also have a higher Aβ burden and tau pathology than male APOE ɛ4 carriers, as measured by PET and cerebrospinal fluid (CSF) in patients with MCI and AD [5, 15]. Healthy older females and females with MCI who carry the APOE ɛ4 allele are more likely to develop AD than their male counterparts [16].

The Food and Drug Administration has approved [¹⁸F]florbetapir (also called [¹⁸F]AV-45) to image amyloid pathology in patients with AD, and [¹⁸F]florbetapir PET has been used to examine the effects of the APOE ɛ4 allele on brain Aβ deposition. PET-based research has found that while APOE ɛ4 is associated with hypometabolism and greater Aβ burden across both genders in individuals with MCI, it is associated with greater Aβ burden only in males among patients with AD [5]. A study showed that APOE ɛ4 is associated with high levels of [¹⁸F]florbetapir SUVR only in male participants with AD.

Although age plays a key role in AD, the role of age in MCI has not been well investigated. A previous study found that in cognitively normal participants, amyloid deposition in the precuneus and lateral parietal cortex in older individuals is higher than that in younger adults [17]. Neuroimaging studies have shown that patients with early-onset AD (EOAD,<65 years old) have more severe amyloid and tau deposition and greater cortical atrophy than patients with LOAD [18–21]. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40–55 years for APOE ɛ4 carriers and 65-95 years for APOE ɛ4 noncarriers [22]. In view of the differences in amyloid deposition in the brain among different age groups, younger and older MCI patients could also have different patterns of amyloid deposition that have not been demonstrated. Given the effects of gender, APOE ɛ4 status, and age on amyloid deposition, we hypothesized that the effect of gender and APOE ɛ4 status on brain amyloid deposition is different in the younger and older MCI groups. Therefore, the main purpose of this study was to investigate the effect of the gender×APOE ɛ4 status interaction on region-specific Aβ deposition in MCI patients in different age groups by PET scanning.

MATERIALS AND METHODS

Participants

A total of 204 individuals with MCI were included from the memory clinic of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and communities in Shanghai, from September 2021 to February 2023. They volunteered to join the study cohort through an advertisement on a public board or they or their family members observed their memory decline. Participants were enrolled through the following methods: first, relevant medical history was obtained based on exclusion criteria; then, a comprehensive neuropsychological assessment was conducted. Each participant was enrolled only once, and the enrolment process was not continuous. This study was approved by the Institutional Ethics Reviewing Board of Huashan Hospital and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. Written informed consent was obtained from participants or their family members.

The exclusion criteria were as follows: 1) current major psychiatric diagnoses such as severe depression or anxiety; 2) a diagnosis of other neurological conditions that could cause cognitive decline (e.g., cerebrovascular disease, brain tumors, Parkinson’s disease, or epilepsy) rather than AD spectrum disorders; 3) a diagnosis of other diseases that could cause cognitive decline (e.g., thyroid dysfunction, severe anemia, syphilis, or HIV); 4) a history of psychosis or congenital psychological growth retardation; 5) cognitive decline caused by traumatic brain injury; and 6) an inability to complete the study protocol or contraindications for MRI [23].

Genotyping of APOE

Peripheral blood samples from individuals were obtained for APOE ɛ4 genotyping. Genomic DNA was extracted from peripheral blood samples using a Blood Genomic DNA Extraction Kit (TIANGEN, Shanghai, People’s Republic of China). The APOE genotypes were determined by multiplex amplification refractory mutation system polymerase chain reaction according to the method previously described [24]. The APOE ɛ4 status depends on the presence or absence of the APOE ɛ4 allele. Although the APOE ɛ4 allele is a well-established risk factor for AD, the APOE ɛ2 allele has a positive influence on cognitive health. The effect of the APOE ɛ2/ɛ4 alleles on AD is controversial. Therefore, individuals with the APOE ɛ2/ɛ4 allele, a putative protective allele for AD, were excluded [25].

Neuropsychology

All participants received a comprehensive neuropsychological assessment revised for use in the Chinese population [26, 27]. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Basic (MoCA-B) were used to assess global cognition, and six neuropsychological tests in three cognitive domains were administered. The AVLT 30-minute-long delayed free recall of the auditory verbal learning test (AVLT-LDR, 12 items) and the AVLT-recognition (24 items) for the memory domain; the animal fluency test (AFT, total score) and Boston naming test (BNT, 30 items) for the language domain; and the shape trails test (STT), parts A and B (time to completion) for the executive function domain [28, 29].

The diagnosis of all patients was made on clinical grounds according to corresponding international criteria. The diagnosis of MCI was based on the actuarial neuropsychological method proposed by Jak and Bondi after the exclusion of AD based on the 2011 National Institute of Ageing and Alzheimer’s Association (NIA-AA) diagnostic criteria for probable AD dementia [30–32]. A diagnosis of MCI was given if the participant met one of the following standards: 1. impaired scores (defined as > 1 standard deviation (SD) below the age-corrected normative mean) on two of the six neuropsychological tests in the same cognitive domain; and 2. impaired scores (>1 SD) in each of the three cognitive domains [33, 34].

Imaging scanning

High-resolution 3D MRI was performed on a 3T MRI scanner (Prisma 3.0 T, Siemens, Erlangen, Germany) at Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. MRI T1 images were acquired with a 3-dimensional magnetization-prepared rapid gradient-echo sequence with the following parameters: repetition time = 3000 ms, echo time = 2.56 ms, flip angle = 7, acquisition matrix = 320×320, in-plane resolution = 0.8 mm×0.8 mm, slice thickness = 0.8 mm, and 208 sagittal slices.

[¹⁸F]florbetapir PET/CT imaging was conducted using PET/CT scanners (Biograph mCT Flow, Siemens, Erlangen, Germany), with previously described parameters [35, 36], at Fudan University Huashan Hospital. For [¹⁸F]florbetapir PET scanning, participants were intravenously injected with a dose of 7.4 MBq/kg [¹⁸F]florbetapir and then rested quietly for 50 min. Then, a 20-min PET acquisition was performed with a low-dose CT scan. After acquisition, the PET images were reconstructed by a filtered back projection algorithm with corrections for decay, normalization, dead time, photon attenuation, scatter, and random coincidences. The reconstructed PET image matrix size was 168×168×148 with a voxel size of 2.04×2.04×1.5 mm³.

Image preprocessing

The [¹⁸F]florbetapir PET images were processed using SPM12 (Welcome Trust Centre for Neuroimaging, London, UK; https://www.fil.ion.ucl.ac.uk/spm). In brief, PET images were first coregistered to their individual structural MRI. Then, the T1 images were warped into the standard Montreal Neurological Institute (MNI) stereotactic space and segmented into grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF), and the tissue-labelled images were applied for the partial volume correction (PVC) of PET images using the Muller-Gartner method. All PET images were further warped into the standard MNI stereotactic space by using transformative parameters from warping the MRI images; finally, a Gaussian kernel of full width at half maximum was used for smoothing the PET data [16]. The smoothed and normalized images were used for region of interest (ROI) extraction. A total of 7 cortical ROIs were defined in the frontal, lateral parietal, lateral temporal, medial temporal, and occipital lobes and the posterior cingulate, precuneus, and global cortex (the sum of the above 7 ROIs) [37]. Standardized uptake value ratios (SUVr) of [¹⁸F]florbetapir were calculated using the mean intensity with the bilateral cerebellar crus as the reference region.

Statistical analysis

Voxelwise analyses were conducted by SPM12, and clinical characteristic and ROI-based analyses were conducted using SPSS 23. The differences between the two groups in physiological variables and SUVr values were determined using independent t tests, education years, age, or gender as covariates. The group differences in demographics were analyzed using chi-square tests. In age stratified analyses, the differences among multiple groups of female and male (APOE ɛ4 noncarriers and carriers) in SUVr values were assessed using one-way analysis of variance with covariance (ANCOVA) with education years and age as covariates. We used multiple regression with all covariates to calculate the unstandardized residuals for SUVr and then obtained the absolute value of the unstandardized residual value (rSUVr). When comparing the difference in SUVr between groups, we used the unstandardized residual value of SUVr. We used voxelwise analyses to evaluate differences in [¹⁸F]florbetapir between APOE ɛ4 carriers and noncarriers, male and female APOE ɛ4 carriers, and male and female APOE ɛ4 noncarriers. For voxelwise analyses, the significance level was set at p < 0.05 with cluster-level false discovery rate (FDR) correction, and the cluster-defining voxel threshold was defaulted to 0.001, with education years, age or gender as covariates. For other analyses, the significance level was set at p < 0.05 (two-sided). FDR correction was used for multiple comparisons.

RESULTS

Study population demographics and clinical assessments

A total of 204 individuals with MCI, comprising 134 APOE ɛ4 noncarriers and 70 carriers, were included in our study. In the whole cohort, the age range was 52 to 79, and patients were divided into younger and older groups by the mean age of 65. Table 1 demonstrates the demographics and clinical characteristics of all participants. The younger and older groups showed no significant differences in APOE ɛ4 status, years of education, or comprehensive neuropsychological scores. In the younger group, only APOE ɛ4 carriers had lower MMSE scores than noncarriers (24.52 ± 4.06 versus 26.40±2.61, p = 0.028), and there were no differences in age, years of education, or comprehensive neuropsychological scores between APOE ɛ4 carriers and noncarriers. In the older group, there were no significant differences in population demographics or comprehensive neuropsychological scores between APOE ɛ4 carriers and noncarriers.

Table 1

Demographic information and clinical characteristics of the overall study cohort

	Younger group	Older group	p₁	Younger group			Older group
				APOE ɛ4+	APOE ɛ4-	p₂	APOE ɛ4+	APOE ɛ4-	p₃
Number of MCI	100	104		32	68		38	66
Age	57.54±5.93	70.28±3.79	<0.001^a	56.78±4.22	58.54±5.33	0.243^a	71.15±3.83	69.78±6.68	0.138^a
Female (%)	58/100 (58%)	51/104 (49%)	0.210^b	21/32 (66%)	37/68 (54%)		19/38 (50%)	32/66 (48%)
APOE ɛ4 carriers	32/100 (32%)	38/104 (36%)	0.296^b	32	68		38	66
Homozygotes	11/100 (11%)	12/104 (12%)	0.540^b	11/32 (34%)			12/38 (32%)		0.502^b
Education (y)	10.86±3.19	10.48±3.91	0.448^a	10.41±3.72	11.07±2.91	0.332^a	10.05±4.05	10.73±3.84	0.407^a
MMSE	25.68±3.29	25.50±3.47	0.705^a	24.52±4.06	26.40±2.61	0.028^a	24.68±4.31	25.97±2.81	0.105^a
MoCA-B	21.92±3.59	21.80±3.13	0.732^a	21.22±5.43	22.21±3.47	0.213^a	22.76±2.47	21.77±2.51	0.089^a
AVLT-LDR	1.98±2.446	1.69±1.71	0.066^a	1.88±3.76	2.13±1.45	0.324^a	1.57±1.43	1.79±1.33	0.254^a
AVLT-recognition	18.17±2.78	17.56±2.52	0.147^a	16.24±3.34	18.36±2.13	0.096^a	17.25±2.33	17.78±2.56	0.675^a
AFT	12.65±3.62	13.23±3.29	0.516^a	11.65±1.45	13.28±3.19	0.147^a	13.12±2.61	13.31±2.79	0.783^a
BNT	21.02±4.12	21.79±3.86	0.233^a	22.09±2.75	20.79±4.12	0.187^a	22.13±4.37	21.36±3.95	0.678^a
STT-A	58.77±24.83	59.19±21.59	0.790^a	56.74±25.73	59.16±27.95	0.364^a	57.73±29.33	60.14±23.71	0.169^a
STT-B	153.41±46.62	161.55±48.57	0.354^a	160.77±56.34	148.96±63.47	0.239^a	149.23±40.91	166.21±48.79	0.176^a

Bolded text indicates statistical significance at p < 0.05. ^a: independent t test and ^b: chi-square test. p₁ value: younger group versus older group, p₂ value: younger group APOE ɛ4 carriers versus APOE ɛ4 noncarriers, p₃ value: older group APOE ɛ4 carriers versus APOE ɛ4 noncarriers. Only APOE ɛ4 carriers had lower MMSE scores than noncarriers in the younger group, with no other differences in population demographics or neuropsychological scores between the younger and older groups or APOE ɛ4 carriers and noncarriers in the younger and older groups. APOE ɛ4+, APOE ɛ4 carriers; APOE ɛ4 -, APOE ɛ4 noncarriers; MMSE, Mini-Mental State Examination; MoCA-B, Montreal Cognitive Assessment-Basic; AVLT, Verbal learning test; AVLT-LDR, long-delayed free recall of the auditory verbal learning test; AFT, animal fluency test, BNT, Boston naming test for language domain; STT_A and STT_B, shape trails test parts A and B.

Table 2 shows the demographics and clinical characteristics of males and females with MCI in both the younger and older groups. We observed that APOE ɛ4 carriers had lower MMSE scores in both males (24.65±4.75 versus 26.58±2.86, p = 0.038) and females (24.48±4.32 versus 26.38±2.76, p = 0.041) than noncarriers only in the younger group. There were no other differences in patient number, years of education, and comprehensive neuropsychological assessment results between APOE ɛ4 carriers and noncarriers in males and females with MCI in the younger and older groups. Supplementary Table 1 shows the demographics and clinical characteristics of APOE ɛ4 carrier and noncarrier individuals with MCI in both the male and female groups. Only the younger APOE ɛ4 carriers had lower AVLT recognition (11.60±3.24 versus 17.57±2.40, p = 0.032) and AFT (10.77±0.45 versus 14.86±3.61, p = 0.044) scores than the older APOE ɛ4 carriers in the male group. In both the female and male groups, there were no other differences in population demographics or neuropsychological scores between the younger group of APOE ɛ4 carriers and the older group of APOE ɛ4 carriers or between the younger group of APOE ɛ4 noncarriers and the older group of APOE ɛ4 noncarriers.

Table 2

Demographic information and clinical characteristics of the males and females with MCI

	Male			Female
APOE ɛ4 status	Carriers	Noncarriers	p₁	Carriers	Noncarriers	p₂
Younger group
Number of individuals with MCI	11	31		21	37	0.200^b
Homozygotes	4/11 (36%)			7 (33%)		0.582^b
Education (y)	10.78±4.35	11.25±2.85	0.567^a	9.90±3.43	10.81±2.94	0.293^a
MMSE	24.65±4.75	26.58±2.86	0.038 ^a	24.48±4.32	26.38±2.76	0.041 ^a
MoCA-B	21.43±5.78	22.34±3.42	0.843^a	21.00±3.19	22.42±3.71	0.246^a
AVLT-LDR	2.17±4.24	2.26±2.79	0.493^a	1.62±1.50	1.33±2.445	0.268^a
AVLT-recognition	11.60±3.24	18.55±2.57	0.806^a	16.83±3.01	18.48±2.64	0.081^a
AFT	10.77±0.45	13.88±3.29	0.102^a	12.00±4.00	12.88±3.74	0.497^a
BNT	22.77±3.45	21.35±3.68	0.473^a	20.42±3.50	20.45±4.56	0.979^a
STT-A	51.46±13.47	66.57±33.68	0.439a	63.08±23.74	56.12±20.99	0.347^a
STT-B	189.33±77.39	164.38±57.86	0.542^a	156.83±27.07	147.15±46.17	0.499^a
Older group
MCI Number	19	34		19	32	0.522^b
Homozygotes	5/19 (26%)			7/19 (37%)		0.364^b
Education (y)	11.00±3.85	10.75±4.21	0.832^a	9.11±4.12	10.70±3.46	0.144^a
MMSE	24.97±4.22	26.06±2.60	0.157^a	24.68±4.37	25.88±3.05	0.258^a
MoCA-B	23.21±2.45	21.93±3.38	0.212^a	21.50±2.53	21.11±3.31	0.699^a
AVLT-LDR	1.57±1.28	1.37±1.56	0.672^a	1.57±1.95	2.14±1.91	0.371^a
AVLT-recognition	17.57±2.40	16.70±1.95	0.207^a	17.00±2.14	18.75±2.91	0.376^a
AFT	14.86±3.61	13.47±3.57	0.238^a	12.57±3.32	12.50±2.57	0.554^a
BNT	24.07±3.38	21.87±4.10	0.088^a	21.21±2.91	20.86±3.94	0.766^a
STT-A	55.71±28.94	54.33±13.56	0.829^a	60.59±19.68	65.46±24.61	0.516^a
STT-B	146.21±42.12	154.80±39.12	0.512^a	151.07±32.10	181.68±61.52	0.090^a

Bolded text indicates statistical significance at p < 0.05. ^aindependent t test and ^bChi-square test. p₁, male APOE ɛ4 carriers versus APOE ɛ4 noncarriers; p₂, female APOE ɛ4 carriers versus APOE ɛ4 noncarriers. APOE ɛ4 carriers had lower MMSE scores than noncarriers among both males and females with MCI only in the younger group. In both the younger and older groups, there were no other differences in population demographics or neuropsychological scores between APOE ɛ4 carriers and noncarriers in males and females with MCI.

APOE ɛ4 status, gender, and age effect on amyloid deposition

We investigated the effects of APOE ɛ4 status on regional Aβ deposition. APOE ɛ4 carriers displayed higher global amyloid deposition than APOE ɛ4 noncarriers in the whole cohort and in the younger and older groups as identified by voxelwise analysis (Fig. 1). In the whole cohort and younger group, APOE ɛ4 carriers had higher amyloid deposition in the frontal, lateral parietal, lateral temporal, posterior cingulate, precuneus, and occipital lobes than noncarriers. In the older group, APOE ɛ4 carriers had higher amyloid deposition in the frontal, lateral temporal, and precuneus lobes than noncarriers. The ROI analysis results were similar to the voxelwise analysis results, as shown in Supplementary Figure 1. Significantly higher amyloid deposition in the medial temporal lobe in females than in males was observed in the overall cohort (rSUVr: 1.22±0.12 versus 1.16±0.14, p = 0.004) and younger group (rSUVr: 1.23±0.11 versus 1.14±0.13, p = 0.001), as shown in Supplementary Figure 1. However, there was no significant difference in global or regional amyloid deposition between males and females with MCI in the older group. The older MCI group had higher amyloid deposition than the younger MCI group in the posterior cingulate (rSUVr: 1.53±0.23 versus 1.46±0.21, p = 0.020), occipital lobe (rSUVr: 1.33±0.18 versus 1.27±0.14, p = 0.044), and precuneus (rSUVr: 1.35±0.23 versus 1.27±0.20, p = 0.026), as shown in Supplementary Figure 2.

Fig. 1

Group differences between APOE ɛ4 carriers and noncarriers in the amyloid deposition by voxelwise analysis (A) in the overall cohort; (B) in the younger group; (C) in the older group. A) In the whole cohort, APOE ɛ4 carriers had higher amyloid deposition in the frontal, lateral parietal, lateral temporal, and occipital lobes and the posterior cingulate and precuneus than noncarriers. B) In the younger group, APOE ɛ4 carriers had higher amyloid deposition in the frontal, lateral parietal, lateral temporal, and occipital lobes and the posterior cingulate and precuneus than noncarriers. C) In the older group, APOE ɛ4 carriers had higher amyloid deposition in the frontal and lateral temporal lobes and the precuneus than noncarriers. The color bar in the voxelwise results represents the T value of the differences among groups with the statistical threshold of p < 0.05, with cluster-level FDR correction and adjusted for the covariates age, gender, and education years.

Fig. 2

Group differences in amyloid deposition between female APOE ɛ4 carriers and male APOE ɛ4 carriers and between female APOE ɛ4 noncarriers and male APOE ɛ4 noncarriers as determined by voxelwise analysis (A) in the overall cohort; (B) in the younger group; (C) in the older group. A) In the overall cohort, there was no significant difference between female and male APOE ɛ4 carriers in amyloid deposition in the brain (A1). Female APOE ɛ4 noncarriers displayed higher amyloid deposition in the bilateral medial temporal lobe and right posterior cingulate than male APOE ɛ4 noncarriers (A2). B) In the younger group, female APOE ɛ4 carriers displayed higher amyloid deposition in the bilateral medial temporal lobe than male APOE ɛ4 carriers (B1). There was no difference between female and male APOE ɛ4 noncarriers in amyloid deposition in the brain (B2). C) In the older group, there was no significant difference between female and male APOE ɛ4 carriers or between female and male APOE ɛ4 noncarriers in the amyloid deposition in the brain (C1-2). The color bar in the voxelwise results represents the T value of the differences among groups with the statistical threshold of p < 0.05, cluster-level FDR correction, adjusted age, and education years as covariates.

APOE ɛ4 status and gender stratified analyses in different age groups

We analyzed the effect of the APOE ɛ4 status×gender interaction on amyloid deposition stratified by age. After adjusting for education years and age through voxelwise analysis, we observed that female APOE ɛ4 noncarriers displayed significant amyloid deposition in the bilateral medial temporal lobe and right posterior cingulate compared with male APOE ɛ4 noncarriers, but there was no difference between female and male carriers in the overall cohort. Female APOE ɛ4 carriers displayed significant amyloid deposition in the bilateral medial temporal lobe compared with male APOE ɛ4 carriers in the younger group, as shown in Fig. 2. This finding was also confirmed by ROI analysis (rSUVr: 1.27±0.12 versus 1.17±0.13, p = 0.048) in Fig. 3A. However, the older group showed no differences between female and male carriers. No difference in amyloid deposition was observed between male and female APOE ɛ4 noncarriers in either the younger or older group.

Fig. 3

Scatter plots showing ROI rSUVr of amyloid PET imaging between APOE ɛ4 carriers and noncarriers in the male and female cohorts in different regions. In both the younger and older groups, group differences (APOE ɛ4 noncarriers and carriers) in [¹⁸F]florbetapir rSUVr at the ROIs were assessed for females and males with MCI using one-way analysis of variance with covariates (ANCOVA), with age and education years as covariates. All p values less than 0.05 are marked in the figure. * and ** indicate significant differences between the two groups with p < 0.05 and p < 0.01, respectively. False discovery rate (FDR) correction was used for multiple comparisons. rSUVr: the unstandardized residual value of SUVr. A) In the younger group, APOE ɛ4 carriers had higher amyloid deposition than noncarriers in the global cortex; the lateral parietal, lateral temporal, frontal, and occipital lobes; and the posterior cingulate and precuneus only in females. Female APOE ɛ4 carriers had higher amyloid deposition than male APOE ɛ4 carriers in the medial temporal lobe. B) In the older group, APOE ɛ4 carriers had higher amyloid deposition than noncarriers in the global cortex; the lateral parietal, lateral temporal, and frontal lobes; and the posterior cingulate and precuneus only in males.

As shown in Fig. 3A, among APOE ɛ4 carriers, significantly increased amyloid deposition was observed compared to noncarriers in the global cortex (rSUVr: 1.35±0.16 versus 1.23±0.13, p = 0.022), lateral parietal lobe (rSUVr: 1.33±0.17 versus 1.20±0.13, p = 0.043), lateral temporal lobe (rSUVr: 1.32±0.16 versus 1.21±0.13, p = 0.041), frontal lobe (rSUVr: 1.36±0.19 versus 1.22±0.13, p = 0.017), occipital lobe (rSUVr: 1.37±0.11 versus 1.27±0.12, p = 0.035), posterior cingulate (rSUVr: 1.59±0.24 versus 1.43±0.16, p = 0.030), and precuneus (rSUVr: 1.39±0.23 versus 1.24±0.15, p = 0.031) in females in the younger group. However, there was no difference between APOE ɛ4 carriers and noncarriers in global or regional amyloid deposition in males in this group.

However, the opposite result was observed in the older group. APOE ɛ4 carriers exhibited significantly increased amyloid deposition compared to noncarriers in the global cortex (rSUVr: 1.39±0.20 versus 1.22±0.16, p = 0.010), lateral parietal lobe (rSUVr: 1.37±0.20 versus 1.18±0.19, p = 0.007), lateral temporal lobe (rSUVr: 1.37±0.20 versus 1.21±0.15, p = 0.014), frontal lobe (rSUVr: 1.41±0.22 versus 1.21±0.18, p = 0.006), posterior cingulate (rSUVr: 1.65±0.20 versus 1.46±0.21, p = 0.019), and precuneus (rSUVr: 1.47±0.18 versus 1.27±0.22, p = 0.023) in the male group, but no such difference was present in the female group (Fig. 3B). This is also shown in Supplementary Table 2.

DISCUSSION

The APOE ɛ4 allele is the strongest genetic risk factor for AD and is associated with AD-related biological markers, such as Aβ plaque burden and tau deposition [38]. The effects of APOE ɛ4 status on Aβ deposition may differ between males and females. The main finding from this study is that in individuals with MCI, females and males in different age groups display different patterns of APOE ɛ4 status-related amyloid deposition. Specifically, in the whole cohort, female APOE ɛ4 noncarriers had higher amyloid deposition in the brain than male noncarriers. Female APOE ɛ4 carriers also showed higher amyloid deposition than male carriers among younger individuals with MCI. More importantly, APOE ɛ4 carriers displayed increased amyloid deposition in younger females with MCI and older males with MCI.

First, increased global amyloid deposition was observed in APOE ɛ4 carriers in the whole cohort and in the younger and older MCI groups compared to APOE ɛ4 noncarriers. APOE ɛ4 increases brain amyloid burden in a dose-dependent manner in cognitively normal individuals and individuals in the prodromal stages of AD, but this is less observed in individuals with AD dementia [37, 39]. This could be partially interpreted by the hypothesized effect of the APOE ɛ4 alleles on Aβ clearance and aggregation [40]. Biochemical evidence has shown that the APOE ɛ4 alleles might impact the Aβ clearance rate [41, 42]. Neuropathological evidence has also shown that APOE ɛ4 dosage is associated with increased Aβ peptide, Aβ oligomers, and plaque accumulation in the brains of patients [43].

In the stratified analysis, we observed significantly higher amyloid deposition in females than males only in the medial temporal lobe in both the overall cohort and the younger group. However, a previous meta-analysis of the PET studies revealed no gender differences in amyloid positivity among individuals with subjective cognitive impairment or MCI [22]. Postmortem studies displayed no clear gender differences in the occurrence and distribution of Aβ plaques in the hippocampus and neocortices of individuals with MCI and patients with AD [44]. However, our results indicated higher amyloid deposition in the medial temporal lobe in females, and whether this means that females are vulnerable to amyloid deposition in the MCI stage requires further investigation. The medial temporal lobe is also considered a signature region for brain atrophy. The medial temporal lobe, especially the hippocampus, is one of the earliest affected brain regions in AD-related pathologies, such as atrophy and hypometabolism [45, 46]. Therefore, further investigations about the effect of the gender×APOE ɛ4 status interaction on amyloid deposition in individuals with MCI are critical for the personalized management of these patients.

Female APOE ɛ4 carriers exhibited significantly increased amyloid deposition in the medial temporal lobe compared to male APOE ɛ4 carriers only in the younger group. Previous studies have suggested that APOE ɛ4 confers a greater risk for AD, tau pathology, glucose hypometabolism, and Aβ burden in females than in males [4, 5]. Female APOE ɛ4 carriers have more risk of converting from MCI into AD as compared to noncarriers or males with any APOE ɛ4 status [47]. The APOE ɛ4 allele also has a greater deleterious effect on hippocampal volume, cortical thickness, and memory performance in women than in men at different stages of AD [48, 49]. Other studies have suggested that females have a higher risk of AD than males, not only because of their greater longevity but also because females are more susceptible to the APOE ɛ4 allele [4, 50]. Among individuals with MCI, younger age, female gender, and APOE ɛ4 allele carrier status are associated with higher amyloid deposition, which may increase the risk of progression to AD, requiring further follow-up studies. These findings have important clinical implications for developing gender- and genotype-guided management in AD.

Our study indicated that the APOE ɛ4 allele was associated with higher global amyloid deposition in females in the younger group and was associated with higher amyloid deposition only in males in the older group in stratified analyses. This is in line with a previous report that the APOE ɛ4 allele-associated risk of MCI peaked earlier in women than in men, leading to a significant increase in MCI between the ages of 55 and 70 among women, while the APOE ɛ4 allele-associated risk for MCI among men peaked in the 75- to 85-year-old group [7, 44]. Taken together, our data indicate that during the MCI stage, the impact of APOE ɛ4 status and gender on brain amyloid deposition varies across different age groups. In the younger group, female APOE ɛ4 carriers demonstrated higher amyloid deposition in the brain than noncarriers. However, in the older group, male APOE ɛ4 carriers displayed higher amyloid deposition in the brain than noncarriers.

Limitations

This study has several limitations. First, our sample size was small. In the younger group, there were only 11 male APOE ɛ4 carriers, which may have limited the power of the analysis. Second, we classified APOE ɛ4 status into only two groups: carriers and noncarriers. We did not further divide carriers into heterozygous and homozygous groups, nor did we further explore the effect of APOE ɛ4 dosage on Aβ deposition in the brain. Third, the severity of MCI and how long participants had been in this stage were not taken into account. Finally, our study was cross-sectional and lacked a systematic and comprehensive observation of the longitudinal changes in Aβ deposition in different age groups.

Conclusions

This quantitative [¹⁸F]florbetapir PET study showed that age is an important influencing factor for the effect of the gender×APOE ɛ4 status interaction on amyloid deposition in individuals with MCI. An APOE ɛ4 status effect on brain region-specific Aβ deposition existed in females in the younger group and in males in the older group. Young females with MCI, particularly those who carry the APOE ɛ4 allele, are associated with more amyloid deposition in the brain.

Footnotes

ACKNOWLEDGMENTS

The authors want to thank Jianfei Xiao, Xiangqing Xie, Zhiwei Pan, Yue Qian, and Dan Zhou for their assistance in patient arrangement.

FUNDING

This research was sponsored by the National Science Foundation of China (82001143, 82071962, 82171473); the Shanghai Sailing Program (18YF1403200, 19YF1405300); the startup fund of Huashan Hospital, Fudan University (2017QD081); the Shanghai Municipal Key Clinical Specialty (3030247006); and the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01).

CONFLICT OF INTEREST

The authors have no conflicts of interest to report.

DATA AVAILABILITY

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

The supplementary material is available in the electronic version of this article: .

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