Alzheimer's Disease-related Cognitive Impairment Research Articles

Comparison of Enlarged Perivascular Spaces in Early-Onset and Late-Onset Alzheimer Disease-related Cognitive Impairment: A Single Clinic-based Study in South Korea.

We examined whether there were differences in the presence of centrum semiovale-enlarged perivascular spaces (CSO-ePVS) and basal ganglia-ePVS (BG-ePVS) among patients with Alzheimer disease-related cognitive impairment (ADCI) based on their age of onset. Out of a total of 239 patients with cognitive impairment, 155 with positive amyloid-PET results were included. Among these, 43 had early-onset ADCI (EOADCI) and 112 had late-onset ADCI (LOADCI). Patients with LOADCI exhibited a higher prevalence of hypertension, lacunes, white matter hyperintensities, and BG-ePVS than those with EOADCI. BG-ePVS showed a significant correlation with age at the onset and the number of lacunes, whereas CSO-ePVS did not exhibit any association. The higher prevalence of BG-ePVS in patients with LOADCI might be attributable to vascular risk factors (hypertension) and cerebral small vessel disease (CSVD). These findings support the hypothesis that BG-ePVS is associated with CSVD and vascular risk factors, whereas CSO-ePVS is associated with cerebral amyloid angiopathy.

Distinct changes in brain metabolism in patients with dementia and hearing loss.

Previous studies have reported that hearing loss (HL) is associated with dementia, although the mechanistic underpinnings remain elusive. This study aimed to evaluate the changes in brain metabolism in patients with HL and different types of dementia. Patients with cognitive impairment (CI) and HL treated at the university-based memory clinic from May 2016 to October 2021 were included. In total, 108 patients with CI and HL prospectively underwent audiometry, neuropsychological test, magnetic resonance imaging, and 18 F-fluorodeoxyglucose positron emission tomography. Twenty-seven individuals without cognitive impairment and hearing loss were enrolled as a control group. Multivariable regression was performed to evaluate brain regions correlated with each pathology type after adjusting for confounding factors. Multivariable regression analyses revealed that Alzheimer's disease-related CI (ADCI) was associated with hypometabolic changes in the right superior temporal gyrus (STG), right middle temporal gyrus (MTG), and bilateral medial temporal lobe. Lewy body disease-related CI (LBDCI) and vascular CI were associated with hypermetabolic and hypometabolic changes in the ascending auditory pathway, respectively. In the pure ADCI group, the degree of HL was positively associated with abnormal increase of brain metabolism in the right MTG, whereas it was negatively associated with decreased brain metabolism in the right STG in the pure LBDCI group. Each dementia type is associated with distinct changes in brain metabolism in patients with HL.

Feature extraction of time series data on functional near-infrared spectroscopy and comparison of deep learning performance for classifying patients with Alzheimer's-related mild cognitive impairment: a post-hoc analysis of a diagnostic interventional trial.

This study aimed to define a method of classifying patients with mild cognitive impairment caused by Alzheimer's disease by the retrieval of functional near-infrared spectroscopy (fNIRS) signal characteristics obtained during olfactory stimulation and the validation of deep learning findings. Participants were recruited for the study from March 02 and August 30, 2021. A total of 78 participants met the criteria for categorization. The Mini-Mental State Examination and the Seoul Neuropsychological Scale were used to distinguish between patients with mild Alzheimer's disease-related cognitive impairment and healthy controls. fNIRS data received during olfactory stimulation were used to create 1,680 time-series sample values. A total of 150 indices with a p-value ≤ 0.1 were used as deep learning features to construct the result values for 120 models accounting for all conceivable combinations of data ratios. For this trial, 78 participants were recruited for the original intervention trial. The average accuracy of the 120 deep-learning models for classifying patients with Alzheimer's-related mild cognitive impairment ranged from 0.78 to 0.90. Sensitivity ranged from 0.88 to 0.96 for the 120 models, while specificity ranged from 0.86 to 0.94. The F1 scores ranged from 0.74 to 0.88. At 0.78 to 0.90, the precision and recall were equivalent. This trial using a deep-learning model found that the representative value extracted from the time series data of each channel could distinguish between healthy people and patients with mild cognitive impairment caused by Alzheimer's disease.

Neuroprotective properties of DPP-4i: A therapeutic target for dementia prevention in elderly diabetic patients?

Possible mechanisms of Alzheimer's disease-related cognitive impairment in patients with diabetes mellitus are shown in this figure. DPP-4i may modulate Aβ accumulation in the process of AD-related cognitive impairment.

Clinical outcomes of increased regional amyloid uptake in patients with subthreshold global amyloid levels

AbstractBackgroundAlthough the standardized uptake value ratio (SUVR) method is objective and simple, cut‐off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to regionally increased β‐amyloid (Aβ) uptake and global Aβ status.MethodWe recruited 973 patients with Alzheimer's disease ‐related cognitive impairment (ADCI). All patients underwent neuropsychological tests and 501 18F‐florbetaben (FBB) amyloid positron emission tomography (PET) and 472 18F‐flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (frontal, temporal, parietal, posterior cingulate, and striatum) by regional quantitative SUVR‐based cutoff values for each region using an iterative outlier approach.ResultA total of 64 (6.6%) subjects showed increased regional Aβ uptake with subthreshold global Aβ status [focal (+) and global (‐) Aβ group, F(+)G(‐) group]. The F(+)G(‐) group showed worse performance in memory impairment (P < 0.001) and greater hippocampal atrophy (P = 0.024) but not global cognition and cortical thickness, compared to those in the F(‐)G(‐). Participants with diffuse Aβ involvement in the whole region [diffuse (+) and global (+) Aβ group, D(+)G(+)] showed worse neuropsychological (P = 0.008‐0.042) and neuroimaging features (P <0.015) than those with focal Aβ involvement F(+)G(+).Conclusion] Our findings suggest that individuals show distinctive clinical outcomes according to regionally increased Aβ uptake and global Aβ status. Thus, clinicians should pay more attention to regional increased Aβ uptake in addition to global Aβ status.

Association of Dipeptidyl Peptidase-4 Inhibitor Use and Amyloid Burden in Patients With Diabetes and AD-Related Cognitive Impairment.

To investigate whether dipeptidyl peptidase-4 inhibitors (DPP-4i) have beneficial effects on amyloid aggregation and longitudinal cognitive outcome in diabetic Alzheimer disease-related cognitive impairment (ADCI). We retrospectively reviewed 282 patients with ADCI with positive 18F-florbetaben amyloid PET images. Patients were classified into 3 groups according to prior diagnosis of diabetes and DPP-4i use: diabetic patients being treated with (ADCI-DPP-4i+, n = 70) or without DPP-4i (ADCI-DPP-4i-, n = 71) and nondiabetic patients (n = 141). Multiple linear regression analyses were performed to determine intergroup differences in global and regional amyloid retention using standardized uptake value ratios calculated from cortical areas. We assessed longitudinal changes in Mini-Mental State Examination (MMSE) score using a linear mixed model. The ADCI-DPP-4i+ group had lower global amyloid burden than the ADCI-DPP-4i- group (β = 0.075, SE = 0.024, p = 0.002) and the nondiabetic ADCI group (β = 0.054, SE = 0.021, p = 0.010) after adjusting for age, sex, education, cognitive status, and APOE ε4 carrier status. The ADCI-DPP-4i+ group had lower regional amyloid burden in temporo-parietal areas than either the ADCI-DPP-4i- group or the nondiabetic ADCI group. The ADCI-DPP-4i+ group showed a slower longitudinal decrease in MMSE score (β = 0.772, SE = 0.272, p = 0.005) and memory recall subscore (β = 0.291, SE = 0.116, p = 0.012) than the ADCI-DPP-4i- group. These findings suggest that DPP-4i use is associated with low amyloid burden and favorable long-term cognitive outcome in diabetic patients with ADCI.

MRI-Visible Perivascular Spaces in the Centrum Semiovale Are Associated with Brain Amyloid Deposition in Patients with Alzheimer Disease-Related Cognitive Impairment.

The association of perivascular spaces in the centrum semiovale with amyloid accumulation among patients with Alzheimer disease-related cognitive impairment is unknown. We evaluated this association in patients with Alzheimer disease-related cognitive impairment and β-amyloid deposition, assessed with [18F] florbetaben PET/CT. MR imaging and [18F] florbetaben PET/CT images of 144 patients with Alzheimer disease-related cognitive impairment were retrospectively evaluated. MR imaging-visible perivascular spaces were rated on a 4-point visual scale: a score of ≥3 or <3 indicated a high or low degree of MR imaging-visible perivascular spaces, respectively. Amyloid deposition was evaluated using the brain β-amyloid plaque load scoring system. Compared with patients negative for β-amyloid, those positive for it were older and more likely to have lower cognitive function, a diagnosis of Alzheimer disease, white matter hyperintensity, the Apolipoprotein E ε4 allele, and a high degree of MR imaging-visible perivascular spaces in the centrum semiovale. Multivariable analysis, adjusted for age and Apolipoprotein E status, revealed that a high degree of MR imaging-visible perivascular spaces in the centrum semiovale was independently associated with β-amyloid positivity (odds ratio, 2.307; 95% CI, 1.036-5.136; P = .041). A high degree of MR imaging-visible perivascular spaces in the centrum semiovale independently predicted β-amyloid positivity in patients with Alzheimer disease-related cognitive impairment. Thus, MR imaging-visible perivascular spaces in the centrum semiovale are associated with amyloid pathology of the brain and could be an indirect imaging marker of amyloid burden in patients with Alzheimer disease-related cognitive impairment.

Association between APOE ε2 and Aβ burden in patients with Alzheimer- and vascular-type cognitive impairment.

To investigate the association between APOE genotype and β-amyloid (Aβ) burden, as measured by PET in patients with subcortical vascular cognitive impairment (SVCI) and those with Alzheimer disease-related cognitive impairment (ADCI). This was a cross-sectional study of 310 patients with SVCI and 999 with ADCI. To evaluate the effects of APOE genotype or diagnostic group on Aβ positivity, we performed multivariate logistic regression analyses. Further distinctive underlying features of latent subgroups were examined by employing a latent class cluster analysis approach. In comparison with ε3 homozygotes, in the ADCI group, ε2 carriers showed a lower frequency of Aβ positivity (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.23-0.79), while in the SVCI group, ε2 carriers showed a higher frequency of Aβ positivity (OR 2.26, 95% CI 1.02-5.01). In particular, we observed an interaction effect of ε2 carrier status and diagnostic group on Aβ positivity (OR 5.12, 95% CI 1.93-13.56), in that relative to ε3 homozygotes, there were more Aβ-positive ε2 carriers in the SVCI group than in the ADCI group. We also identified latent subgroups of Aβ-positive APOE ε2 carriers with SVCI and Aβ-positive APOE ε4 carriers with ADCI. Our findings suggest that APOE ε2 is distinctly associated with Aβ deposition in patients with SVCI and those with ADCI. Our findings further suggest that there is a distinctive subgroup of Aβ-positive APOE ε2 carriers with SVCI among patients with cognitive impairment.

A new Centiloid method for 18F-florbetaben and 18F-flutemetamol PET without conversion to PiB.

We developed a new method to directly calculate Centiloid (CL) units of 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) without conversion to the PiB standardized uptake value ratio (SUVR). Paired FBB and FMM PET scans were obtained from 20 Alzheimer's disease-related cognitive impairment patients, 16 old controls, and 20 young controls. We investigated the correlations between the FBB and FMM CL units using the direct comparison of FBB-FMM CL (dcCL) method and the standard CL method and compare differences in FBB and FMM CL units between dcCL method and the standard method. Following the conversion of FBB or FMM SUVRs into CL units, a direct relationship was formed between the FBB or FMM SUVRs and the CL units using dcCL method (FBB dcCL = 151.42 × FBB dcSUVR - 142.24 and FMM dcCL = 148.52 × FMM dcSUVR - 137.09). The FBB and FMM CL units were highly correlated in both our method (R2 = 0.97, FMM dcCL = 0.97 × FBB dcCL + 1.64) and the standard method (R2 = 0.97, FMM CLstandard = 0.79 × FBB CLstandard + 1.36). However, the CL variations between FBB and FMM were smaller when calculated by dcCL method (6.15) than when calculated by the previous method (10.22; P = 0.01). Our findings suggest that our direct comparison of FBB-FMM method, rather than the standard method, is a reasonable way to convert FBB or FMM SUVRs into CL units, at least in environments where FBB or FMM ligands are used frequently.

Effects of Alzheimer's disease and Lewy body disease on subcortical atrophy.

Subcortical structures are affected by neurodegeneration in Alzheimer's disease (AD) and Lewy body disease (LBD). Although the co-occurrence of AD and LBD pathologies and their possible interaction have been reported, the effect of AD and LBD on subcortical structures remains unknown. The effects of AD and LBD on subcortical atrophy and their relationship with cognitive dysfunction were investigated. The cross-sectional study recruited 42 patients with pure AD related cognitive impairment (ADCI), 30 patients with pure LBD related cognitive impairment (LBCI), 58 patients with mixed ADCI and LBCI, and 29 normal subjects. A general linear model was used to compare subcortical volume and shape amongst the groups, to investigate the independent and interaction effects of ADCI and LBCI on subcortical shape and volume, and to analyze the relationship between subcortical volume and cognitive dysfunction in each group. Alzheimer's disease related cognitive impairment and LBCI were independently associated with subcortical atrophies in the hippocampus and amygdala and in the hippocampus and putamen respectively, but their interaction effect was not significant. Compared to the control group, the pure LBCI group exhibited additional local atrophies in the amygdala, caudate and thalamus. Subcortical atrophies correlated differently with cognitive dysfunction according to the underlying causes of cognitive dysfunction. The patterns of subcortical atrophies and their correlation with cognitive dysfunction differ according to the underlying AD, LBD or concomitant AD and LBD.

Olfactory dysfunction in Alzheimer's disease– and Lewy body–related cognitive impairment

IntroductionOlfactory dysfunction is common in Alzheimer's disease– and Lewy body–related disorders, but its neural correlates have not been clearly elucidated. MethodsWe retrospectively recruited 237 patients with Alzheimer's disease–related cognitive impairment (ADCI) and 217 with Lewy body–related cognitive impairment (LBCI). They were identically evaluated using the Cross-Cultural Smell Identification Test, neuropsychological tests, and brain magnetic resonance imaging. ResultsLBCI had more severe olfactory dysfunction than ADCI. Patients with more severe cognitive dysfunction had worse olfactory function in both groups. In ADCI, lower Cross-Cultural Smell Identification Test scores correlated with a lower cortical thickness in brain regions typically affected in Alzheimer's disease, most prominently in the right parahippocampal cortex, whereas in LBCI, the scores correlated with white matter abnormalities in regions vulnerable to Lewy body, including subcortical regions of the orbitofrontal and frontoparietal cortices. DiscussionOur results suggest that cortical atrophy in ADCI and white matter abnormalities in LBCI play important roles in olfactory dysfunction.

DIAGONAL EARLOBE CREASE, CEREBRAL SMALL VESSEL DISEASE, AND BETA-AMYLOIDOSIS IN COGNITIVELY IMPAIRED PATIENTS

Diagonal earlobe crease (DELC) has been proposed as a marker of generalized atherosclerosis. In this study, we investigated the frequency and clinical significance of DELC in patients with cognitive impairment using imaging biomarkers measured by white matter hyperintensities (WMH) on MRI and amyloid PET. A total of 471 patients with cognitive impairment (271 patients with Alzheimer disease-related cognitive impairment [ADCI], and 200 patients with subcortical vascular cognitive impairment [SVCI]) and 243 cognitively normal (CN) individuals were included in this study. The ear lobes of study participants were assessed using 3D-reconstructed volumetric brain MRI scans. Multivariate logistic regression analyses were performed to determine whether imaging biomarkers were associated with the presence of DELC. Patients with cognitive impairment (ADCI and SVCI) had more DELC than CN individuals (58.3% vs. 41.7%, p = 0.001). Compared to subjects with none or mild degree of WMH, subjects with moderate to severe degree of WMH had more frequent DELC (OR 2.5, 95% CI 1.8 to 3.4, p < 0.001). In addition, ADCI and SVCI patients with amyloid positive had more frequent DELC than those with amyloid negative (OR 2.5, 95% CI 1.5 to 4.0, p < 0.001).

MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden

Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer's disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer's disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer's disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity ('none/mild', 'moderate' or 'frequent/severe'). Univariable and multivariable regression analyses were performed. Those with Alzheimer's disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E ɛ4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E ɛ3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer's disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66-23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer's disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00-0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provide further evidence that the anatomical distribution of MRI-visible perivascular spaces may reflect the underlying cerebral small vessel disease. Using MRI-visible perivascular space location and severity together with other imaging markers may improve the diagnostic value of neuroimaging in memory clinic populations, in particular in differentiating between clinically diagnosed Alzheimer's and subcortical vascular cognitive impairment.

Cortical superficial siderosis: a marker of vascular amyloid in patients with cognitive impairment.

To investigate the prevalence and associations of cortical superficial siderosis (cSS) utilizing MRI markers of cerebral small vessel disease and amyloid burden assessed through in vivo amyloid imaging in a cognitively impaired population. Gradient-recalled echo, T2*-weighted MRIs from 232 patients (Alzheimer disease-related cognitive impairment [ADCI], n = 90; subcortical vascular cognitive impairment [SVCI], n = 142) were reviewed for cSS. All subjects underwent in vivo amyloid imaging using [(11)C] Pittsburgh compound B (PiB)-PET. A multivariate logistic regression model was constructed to evaluate the predictive factors of cSS. A follow-up MRI was performed in 154 (66.4%) of 232 patients. Twelve patients (5.2%) with cSS were equally distributed in ADCI (n = 6) and SVCI (n = 6) groups, but cSS was not present in any of the patients with a negative PiB scan. cSS was associated with markers of cerebral amyloid angiopathy, including higher global PiB retention ratio, APOE ε2 allele presence, and a strictly lobar distribution of cerebral microbleeds. Of those patients with baseline cSS, 33% showed progression over time; there were 2 cases of symptomatic intracranial hemorrhage. cSS occurred in both ADCI and SVCI groups, but not in patients with amyloid-negative SVCI, supporting the hypothesis that cSS reflects an amyloid rather than ischemic etiology. The associations with strictly lobar cerebral microbleeds and APOE ε2 suggest that cerebral amyloid angiopathy, with increased vascular fragility related to APOE genotype, contributes to cSS in this population, with a high risk of progression over time and future intracranial hemorrhage.

Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment

Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [(11) C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Parietal and occipital lobar CMBs counts were higher in PiB(+) ADCI with moderate WMH than PiB(+) ADCI with minimal WMH, whereas PiB(-) patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs.

P4‐075: Cholesterol ester transfer protein–deficient polymorphisms alter cerebrospinal fluid biomarkers and reduce Alzheimer's disease–related cognitive impairment in apolipoprotein E‐ε4 carriers

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation amyloid-β (Aβ) and tau deposits within the brain. The most significant genetic risk factor for late-onset AD is the e4 allele of apolipoprotein E (apoE), a major lipid and Aβ binding protein. While only 15% of the normal population carries apoE4, up to 60% of AD patients have one or two copies of apoE4. Recent genetic studies suggest that cholesterol ester transfer protein (CETP) deficient polymorphisms may reduce AD incidence in apoE4 carriers. While CETP deficient polymorphisms and CETP inhibitors treatment have been shown to produce larger plasma HDL with increased apoE content, the effect of CETP loss-of-function on CSF apoE and AD biomarkers is unknown. Here we evaluated the impact of CETP deficient polymorphisms and apoE genotype on CSF disease markers and AD status. CSF from 80 probable AD patients and 50 normal controls were characterized for apoE, apoJ, apoAI and cholesterol content in addition to AD biomarkers Aβ 40, Aβ 42, tau and p-tau. Corresponding plasma samples were evaluated for triglycerides, total cholesterol, HDL and LDL cholesterol, CETP, apoE, apoJ and apoAI content. Genotyping for apoE (APOE e 2/e 3/e 4) and the three most common CETP deficient polymorphisms (CETp I405V, TaqIB and -629C>A) was carried out by restriction fragment length polymorphism analysis. We found that 40 of the 80 probable AD patients presented a biochemically confirmed AD CSF profile established by cut-offs for Aβ 42/tau and Aβ 42/40 ratio. Within this AD population, patients carrying both apoE4 and CETP deficient polymorphisms had a less deteriorated CSF tau to Aβ 42 ratio disease profile when compared to patients carrying the non-deficient CETP alleles. CETP deficient polymorphisms also impacted the level of apolipoproteins and cholesterol in the CSF. Furthermore, while CETP deficient polymorphisms did not appear to affect AD incidence, AD patients carrying apoE4 and CETP deficient polymorphisms showed reduced cognitive impairment when compared to the non-deficient CETP alleles. Our results suggest that CETP deficient polymorphisms slow disease progression in apoE4 carriers and reveal the potential for CETP inhibitors to be a therapeutic approach for the prevention and possibly the treatment of AD.