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Background The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN, n  = 221) to mild cognitive impairment (MCI, n  = 414) and AD dementia ( n  = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive ( p  = 0.001, Cohen’s f 2  = 0.137) and memory decline ( p  = 0.006, Cohen’s f 2  = 0.104) as well as longitudinally assessed hippocampal atrophy ( p  = 0.046, Cohen’s f 2  = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ 1–42 , p-tau 181 ). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.

Women carry a higher burden of Alzheimer’s disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler’s logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology. Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

BackgroundHigher docosahexaenoic acid (DHA) intake is inversely correlated with relative risk of Alzheimer’s disease. The potential benefits of DHA supplementation in people with mild cognitive impairment (MCI) have not been fully examined.ObjectiveOur study aimed to assess the effect of a 24-month DHA supplementation on cognitive function and amyloid beta (Aβ)-mediated autophagy in elderly subjects with MCI.MethodsThis was a randomised, double-blind, placebo-controlled trial in Tianjin, China. A total of 240 individuals with MCI were identified and randomly divided into intervention (DHA 2 g/day, n=120) and control (corn oil as placebo, n=120) groups. Cognitive function and blood Aβ-related biomarkers were measured at baseline, 6, 12, 18 and 24 months. Data were analysed using generalised estimating equation.ResultsA total of 217 participants (DHA: 109, placebo: 108) completed the trial. During the follow-up, scores of full-scale IQ, verbal IQ and subdomains of information and digit span were significantly higher in the intervention group than the convention group (p<0.05). In the intervention group, blood Aβ-42 level and expression of Aβ protein precursor mRNA were decreased (p<0.05), while Beclin-1 and LC3-II levels and expression of LC3-II mRNA were increased (p<0.05).ConclusionDaily oral DHA supplementation (2 g/day) for 24 months may improve cognitive function and change blood biomarker-related Aβ-mediated autophagy in people with MCI. Larger longer-term confirmatory studies are warranted.Trial registration numberChiCTR-IOR-15006058.

INTRODUCTION We investigated the efficacy of a multidomain intervention (MI) via face‐to‐face and video communication platforms using a tablet personal computer application in patients with mild cognitive impairment (MCI). METHODS Three hundred participants with MCI and ≥ 1 modifiable dementia risk factor, aged 60‐85 years, were randomly assigned to either the MI group, who underwent a 24‐week intervention, or the control group, who received usual care. RESULTS The overall adherence rate to MI was 84.7%. The adjusted mean change from baseline at 24 weeks in the total scale index score of the repeatable battery for the assessment of neuropsychological status was 8.43 in the MI group and 4.26 in the control group (difference, 4.17; 95% confidence interval, 1.92‐6.43; p < 0.001). MI showed significant beneficial effects on cognition in both apolipoprotein E (APOE) ε4 carriers and noncarriers. DISCUSSION MI can exert beneficial effects on the cognition of patients with MCI. Trial Registration: ClinicalTrials.gov identifier: NCT05023057 Highlights Although the controls also demonstrated improved performance in cognition, multidomain interventions showed significantly greater benefits for cognition in MCI compared to the controls in a randomized controlled trial. Multidomain interventions improved depression and quality of life. Multidomain interventions significantly positively impacted cognition in both APOE ε4 carriers and noncarriers. Multidomain interventions may be more effective for amnestic than nonamnestic MCI.

Valiltramiprosate (ALZ-801) is an oral inhibitor of amyloid oligomer formation. Tramiprosate (active agent in ALZ-801) had shown promising efficacy signals with favorable safety in ∼1300 APOE4 carriers with AD, with no observed ARIA-E. This trial evaluated Valiltramiprosate in APOE4/4 homozygotes with Early AD. This 78-week double-blind, placebo-controlled, two-arm trial that randomized 325 homozygotes (162 to placebo, 163 to 265 mg BID), stratified by MCI (MMSE 27-30) or Mild AD (MMSE 22-26). MRI (1.5/3 Tesla) were conducted every 26 weeks and analyzed by Clario Inc. The clinical outcomes were ADAS-Cog13 (primary), CDR-SB (key secondary) and DAD (disability assessment for dementia, secondary). Hippocampal volume (HV) was the main imaging outcome. MMRM was the primary analysis model. Safety population (N =325) was 51% females, 90% Caucasian, mean age 68 years, MMSE 25.6, 39% with MCI (MMSE 27-30) and 30% with baseline microhemorrhages and/or siderosis. In the full analysis set (N =320), the placebo-adjusted least-square mean (LSM) difference in change from baseline (CBL) on ADAS-Cog13 favored drug non-significantly (delta=-0.50; p =0.61, 11% vs placebo CBL); CDR-SB and DAD numerically favored drug by 23% and 29%, but HV favored drug significantly (74 mm , nominal p =0.017, 18% less atrophy). Prespecified Mild AD showed small nonsignificant clinical effects favoring placebo, but showed numerical benefit on HV (51mm , 12% p = 0.115). In prespecified MCI, all outcomes favored drug (nominal p -values): ADAS-Cog13= -2.14 (p =0.041; 52%); CDR-SB= -0.65 (p =0.053, 104%); DAD= 6.09 (p =0.016, 96%); and HV= 108 mm (p = 0.004, 26% less atrophy). Nausea (mostly mild) was the most common adverse event; incidence of ARIA-E was the same as placebo. In the overall population, ADAS-Cog13 did not achieve significance, but the hippocampus showed significant 18% slowing of atrophy. The pre-specified Mild group showed trends to HV atrophy slowing that did not translate to clinical benefits. The pre-specified MCI group showed significant 28% HV atrophy slowing with meaningful cognitive and functional benefits and positive trends on several secondary clinical outcomes. Overall safety was favorable with no increased ARIA. In the high-risk APOE4/4 population, this positive benefit-risk profile supports valiltramiprosate's potential as an oral disease-modifying treatment for APOE4/4 homozygotes with MCI.

Bulk brain tissue studies of gene expression have discovered novel biological pathways associated with Alzheimer's disease (AD) neuropathology and pre-morbid cognitive decline. These findings are primarily tuned to much older adults and are focused on end-of-life changes. The objective of this study was to ascertain transcriptomic signals from whole blood associated with cognitive decline in clinically unimpaired older adults from the A4 and LEARN studies. Identifying genes in whole blood that are associated with in vivo AD phenotypes can elucidate biological pathways implicated in the earliest disease processes. 1,737 participants were included from the A4 clinical trial of solanazumab. Both placebo and treatment arms were included (and participants who screen failed at baseline to inform our model intercepts), and the adjoining LEARN observational study (Aβ-). All participants had whole blood gene expression data from the autosome and X chromosome (20,621 genes), and 770 participants (71.3±4.7 years; 62% Female; 45% APOEε4+; 59% Aβ+) had at least two cognitive assessments measured using the PACC. Linear mixed-effects models determined the association between gene expression alone and interactions with sex, APOEε4, continuous Aβ-PET burden, and p-tau on longitudinal PACC. All analyses included random intercepts/slopes, and adjusted for age, education, cohort, PACC version, and cumulative dose. All analyses were FDR corrected. No individual transcript was associated with longitudinal cognition after FDR correction. 167 genes were associated with longitudinal cognition when modified through different markers. One gene (TRBV4-2; Figure 2C) was moderated by APOEε4 x sex, 6 genes by Aβ-PET, 118 genes by Aβ-PET x sex, and 17 genes weakly by p-tau (Figure 1). Of note, lower ETF1P2 expression, a noncoding pseudogene that resembles ETF1 and plays a role in protein synthesis, was associated with faster cognitive decline among participants with high baseline Aβ-PET burden (Figure 2A; b =2.33(0.456), p  = 0.011). Similarly, greater ZSCAN2 expression, implicated in regulating inflammation, was associated with faster cognitive decline particularly among males with higher baseline Aβ-PET burden (Figure 2D; b =-6.92(1.33), p  = 0.004). Whole blood transcriptomic signals were primarily associated with cognitive decline via interactions with Aβ-PET, Aβ-PET x sex, and p-tau . Further work, such as enrichment analysis and validation in external cohorts, will elucidate relevant biological pathways.

Cognitive training (CT) programs aim to improve cognitive performance and impede its decline. Thus, defining the characteristics of individuals who can benefit from these interventions is essential. Our objectives were to assess if the cognitive reserve (CR), APOE genotype (e4 carriers/non-carriers) and/or hippocampal volume might predict the effectiveness of a CT program. Participants were older adults without dementia (n = 226), randomized into parallel experimental and control groups. The assessment consisted of a neuropsychological protocol and additional data regarding total intracranial, gray matter, left/right hippocampus volume; APOE genotype; and Cognitive Reserve (CR). The intervention involved multifactorial CT (30 sessions, 90 min each), with an evaluation pre- and post-training (at six months); the control group simply following the center’s routine activities. The primary outcome measures were the change in cognitive performance and the predictors of change. The results show that APOE-e4 non-carriers (79.1%) with a larger left hippocampal volume achieved better gains in semantic verbal fluency (R 2  = .19). Subjects with a larger CR and a greater gray matter volume better improved their processing speed (R 2  = .18). Age was correlated with the improvement in executive functions, such that older age predicts less improvement (R 2  = .07). Subjects with a larger left hippocampal volume achieved more significant gains in general cognitive performance (R 2  = .087). In conclusion, besides the program itself, the effectiveness of CT depends on age, biological factors like genotype and brain volume, and CR. Thus, to achieve better results through a CT, it is essential to consider the different characteristics of the participants, including genetic factors. Trial registration : Trial retrospectively registered on January 29th, 2020—( ClinicalTrials.gov -NCT04245579).

A polygenic risk score (PRS) estimates an individual's genetic liability for diseases based on accumulated genetic variations. While the PRS has been shown to contribute to the prediction of dementia risk, its utility in predicting the effectiveness of multifactorial interventions to reduce the risk of dementia remains unclear. A genome-wide association study (GWAS) was conducted to identify dementia-related traits in the Japanese population. Subsequently, PRSs were constructed based on GWAS results using PRSice-2 software. The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is an RCT to assess the effect of multi-domain interventions for subjects with mild cognitive impairment. The J-MINT samples were classified into high-risk and low-risk groups using the Japanese PRS. Within each risk group, cognitive function improvement due to the intervention was assessed using Fisher's exact test. We conducted a GWAS with 3962 AD cases and 4074 controls for 4,578,811 genetic markers that passed stringent quality control filters. The optimal PRS, composed of 12,818 SNPs and APOE status, was developed at a p-value threshold of 0.090, selected for its highest model fit with an R score of 0.023. Subsequently, the PRS classified 289 J-MINT samples into 99 high-risk and 190 low-risk groups. Individuals in the young-old group (aged <75 years) showed significant cognitive improvement through the intervention in the high-risk group; however, those in the old-old group (aged 75 years) did not demonstrate such potential in either risk group. While we have successfully developed a Japanese PRS with high predictive ability, it is important to note that our dataset is limited and relatively small. To achieve an accurate AD PRS for the Japanese population, further validation studies are necessary, involving a larger dataset or conducting a meta-analysis with another Japanese cohort. Additionally, our study highlights the potential utility of the PRS in screening subjects for cognitive improvement, especially for individuals with high PRS in the young-old group.

Background Multidomain lifestyle interventions have shown effectiveness in preventing dementia, but identifying high-risk groups most likely to benefit remains unclear. Methods We re-evaluated the SUPERBRAIN-MEET multidomain intervention study in mild cognitive impairment (MCI) patients, incorporating polygenic risk scores (PRS) for Alzheimer’s disease and APOE ε4 status using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total index as the primary outcome. Results Both intervention and control groups showed cognitive improvement over 24 weeks, with greater gains in the intervention arm. Relative intervention efficacy (RIE) increased with higher genetic risk, being most pronounced among APOE ε4 carriers and individuals with high PRS. When both factors were considered jointly, APOE ε4 carriers with high PRS exhibited the largest RIE (β = 7.54, SE = 2.59, p  = 0.005), driven by markedly greater improvement in the intervention group. The secondary outcomes did not show as consistent results as RBANS total index. Discussion These findings suggest that MCI individuals who are APOE ε4 carriers with high PRS may benefit most from multidomain interventions. These results support the complementary use of PRS and APOE status for identifying high-risk subgroups most likely to benefit from multidomain interventions. Trial registration ClinicalTrials.gov identifier: NCT05023057. Registered on 26 August 2021.