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The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.The amyloid hypothesis has been the dominant model for the pathogenesis of Alzheimer disease for several decades. In this Perspective, Giovanni Frisoni and colleagues examine evidence for and against this hypothesis before outlining an alternative model, the probabilistic model of Alzheimer disease.

Spatial navigation is emerging as a critical factor in identifying preclinical Alzheimer’s disease (AD). However, the impact of interindividual navigation ability and demographic risk factors (e.g., APOE, age, and sex) on spatial navigation make it difficult to identify persons “at high risk” of AD in the preclinical stages. In the current study, we use spatial navigation big data (n = 27,108) from the Sea Hero Quest (SHQ) game to overcome these challenges by investigating whether big data can be used to benchmark a highly phenotyped healthy aging laboratory cohort into high- vs. low-risk persons based on their genetic (APOE) and demographic (sex, age, and educational attainment) risk factors. Our results replicate previous findings in APOE ε4 carriers, indicative of grid cell coding errors in the entorhinal cortex, the initial brain region affected by AD pathophysiology. We also show that although baseline navigation ability differs between men and women, sex does not interact with the APOE genotype to influence the manifestation of AD-related spatial disturbance. Most importantly, we demonstrate that such high-risk preclinical cases can be reliably distinguished from low-risk participants using big-data spatial navigation benchmarks. By contrast, participants were undistinguishable on neuropsychological episodic memory tests. Taken together, we present evidence to suggest that, in the future, SHQ normative benchmark data can be used to more accurately classify spatial impairments in at-high-risk of AD healthy participants at a more individual level, therefore providing the steppingstone for individualized diagnostics and outcome measures of cognitive symptoms in preclinical AD.

INTRODUCTION Whether temporal proximity to parental onset of dementia (PPO) can be used to estimate timing of the preclinical stage of sporadic Alzheimer's disease (AD) remains uncertain. METHODS We investigated cross‐sectionally adults aged > 50 without dementia included in the European Prevention of Alzheimer's Dementia (EPAD) study. PPO was tested as a predictor of quantitative levels of cerebrospinal fluid (CSF) β‐amyloid (1‐42) (Aβ1‐42) in those with a parental history of dementia (n = 688) and of phosphorylated tau (p‐tau) and EPAD neuropsychological examination (ENE) subscores in an amyloid positive subgroup (n = 226). Possible interactions were explored. RESULTS Shorter PPO predicted lower CSF Aβ1‐42 level (β = 9.357; T = 4.161; p < 0.001), interacting with apolipoprotein E (APOE) ‐𝜀4 carriage in a dose‐dependent manner. Concomitant APOE‐𝜀2 carriage appeared to provide protection. PPO did not predict p‐tau levels or cognitive performance. DISCUSSION PPO may provide a valid method of stratifying risk of early AD pathologic change in APOE‐𝜀4 carriers, with empirical and clinical applications. Highlights Proximity to age of parental dementia onset can predict amyloid accrual The effect is APOE‐𝜀4 dose‐dependent and APOE‐𝜀2 appears to provide protection PPO does not appear to predict further advancement along the AD continuum In the era of anti‐amyloid treatments, this may inform timing of amyloid screening Used as an empirical metric, PPO could help elucidate the natural history of LOAD

Alzheimer's disease (AD), including its mild cognitive impairment (MCI) phase that may or may not progress into the AD, is the most ordinary form of dementia. It is extremely important to correctly identify patients during the MCI stage because this is the phase where AD may or may not develop. Thus, it is crucial to predict outcomes during this phase. Thus far, many researchers have worked on only using a single modality of a biomarker for the diagnosis of AD or MCI. Although recent studies show that a combination of one or more different biomarkers may provide complementary information for the diagnosis, it also increases the classification accuracy distinguishing between different groups. In this paper, we propose a novel machine learning-based framework to discriminate subjects with AD or MCI utilizing a combination of four different biomarkers: fluorodeoxyglucose positron emission tomography (FDG-PET), structural magnetic resonance imaging (sMRI), cerebrospinal fluid (CSF) protein levels, and Apolipoprotein-E (APOE) genotype. The Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset was used in this study. In total, there were 158 subjects for whom all four modalities of biomarker were available. Of the 158 subjects, 38 subjects were in the AD group, 82 subjects were in MCI groups (including 46 in MCIc [MCI converted; conversion to AD within 24 months of time period], and 36 in MCIs [MCI stable; no conversion to AD within 24 months of time period]), and the remaining 38 subjects were in the healthy control (HC) group. For each image, we extracted 246 regions of interest (as features) using the Brainnetome template image and NiftyReg toolbox, and later we combined these features with three CSF and two APOE genotype features obtained from the ADNI website for each subject using early fusion technique. Here, a different kernel-based multiclass support vector machine (SVM) classifier with a grid-search method was applied. Before passing the obtained features to the classifier, we have used truncated singular value decomposition (Truncated SVD) dimensionality reduction technique to reduce high dimensional features into a lower-dimensional feature. As a result, our combined method achieved an area under the receiver operating characteristic (AU-ROC) curve of 98.33, 93.59, 96.83, 94.64, 96.43, and 95.24% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIc, and HC vs. MCIs subjects which are high relative to single modality results and other state-of-the-art approaches. Moreover, combined multimodal methods have improved the classification performance over the unimodal classification.

INTRODUCTION Growing evidence suggests a connection between insulin resistance and apolipoprotein E (APOE) genotype in Alzheimer's disease (AD) pathogenesis, but the mechanisms are unclear. We examined effects of insulin resistance and APOE genotype on blood–brain barrier (BBB) integrity in AD. METHODS BBB integrity was measured in 196 biologically‐confirmed non‐diabetic patients with AD evaluating CSF/serum albumin ratio, kappa and lambda free light chains (FLCs). Insulin resistance was assessed using triglyceride–glucose index (TyG). The impact of TyG on BBB integrity, and its interaction with APOE genotypes, was analyzed using multivariate models. RESULTS Sixty‐four percent of patients with AD showed altered TyG, with the 21.8% classified as high TyG. TyG subgroups were associated with BBB abnormalities, with similar AD clinical and biomarkers profile. A significant interaction between TyG and APOE ε4/ε4 genotype on BBB permeability was found in multivariate analyses. DISCUSSION Insulin resistance is a common feature in non‐diabetic AD and correlates with altered BBB permeability, interacting synergistically with APOE genotype. Highlights Insulin resistance and apolipoprotein E (APOE) genotype are well‐recognized risk factors for Alzheimer's disease (AD). Insulin resistance shows high prevalence in patients with AD. Insulin resistance is related to damage in blood–brain barrier (BBB) integrity. The association between the triglyceride–glucose (TyG) index and BBB permeability varies in relation to APOE genotype; patients with the APOE ε4/ε4 displayed higher BBB permeability.

Neuropathological changes that precede or accompany early cognitive decline in Alzheimer's disease (AD) may also impact pain processing; however, the molecular connection between these domains remains unclear. In this study, we investigated whether a shared causal factor underlies both increased pain susceptibility and AD progression. Analysis of two ethnically distinct cohorts revealed a significant association between pain susceptibility and cognitive decline from cognitively normal (CN) status to mild cognitive impairment (MCI), particularly in non‐APOE4 (non‐E4) males, an unexpected finding given that APOE4 females exhibited the highest overall pain susceptibility across sex and genotype groups. To explore potential drivers of this APOE genotype‐ and sex‐specific association, blood transcriptomic analysis identified LPCAT2 expression as correlating with both heightened pain susceptibility and progression from MCI to AD, most notably in non‐E4 males. This relationship was further supported by elevated LPCAT2 protein levels in the hippocampus of postmortem non‐E4 male AD patients. Strengthening this link, our genetic association analysis across four cohorts identified several functional LPCAT2 variants that not only influenced its expression but were also associated with altered pain susceptibility, increased AD risk, and accelerated progression from MCI to AD. To move beyond correlation and assess causality, Mendelian randomization analysis supported a causal role for LPCAT2 in both pain susceptibility and MCI‐to‐AD progression. Collectively, these findings identify LPCAT2 as a key molecular link between altered pain processing and AD progression, highlighting its potential as both a therapeutic target for genotype‐ and sex‐specific subpopulations and a prognostic biomarker for MCI‐to‐AD conversion. We aimed to uncover the molecular mechanisms linking age‐related pain susceptibility with cognitive decline in Alzheimer's disease (AD). By integrating transcriptomic, human AD brain, genomic, and Mendelian randomization analyses, we identified the lipid‐modifying enzyme LPCAT2 as a sex‐ and APOE genotype–dependent causal mediator of both heightened pain vulnerability and AD progression.

INTRODUCTION Understanding the interplay between genetic factors and lifestyle choices in cognitive health is crucial for enhancing late‐life quality. This study examines the effects of Apolipoprotein E (APOE) genotypes and healthy lifestyles on life expectancy with and without cognitive impairment (CI) in Chinese older adults. METHODS Data from 6488 participants aged at least 65 in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) were analyzed using continuous‐time three‐state Markov models. Cognitive function was assessed with the Mini‐Mental State Examination (MMSE). RESULTS APOE ε4 allele carriers had a higher risk of transitioning from cognitively healthy (CH) to impaired, while ε2 carriers had a reduced risk of transitioning from healthy to death. Participants with 4 or 5 healthy lifestyle factors experienced significant protective effects, extending the cognitively healthy life expectancy. DISCUSSION These findings underscore the importance of promoting healthy lifestyles to delay cognitive decline, regardless of genetic predispositions, particularly in the Asian context. Highlights Compared with ε3 homozygotes, APOE ε4 carriers in China have a higher risk of transitioning from CH to CI, and APOE ε2 carriers with CH have a lower risk of transitioning to death. Healthy lifestyles can extend life expectancy, primarily extending CH life expectancy. Healthy lifestyles reduce the risk of CI and delay its onset in later life, regardless of APOE genetic risk.

Data on 2,045 non-demented individuals with memory complaints were drawn from the Memento cohort study to examine the association between Apolipoprotein E ε4 allele (APOE4) and regional brain gray matter volumes. Linear regression was used to examine the association of APOE4 and measures of regional gray matter volumes in cross-sectional analysis and change therein using longitudinal analyses based on two brain MRI performed at baseline and at two-year follow-up. Overall, in analyses adjusted for age, sex, and intracranial volume, the presence of APOE4 was associated with lower total gray matter volume at baseline and with a higher atrophy rate over the follow-up. The hippocampus and entorhinal cortex were the two gray matter regions most associated with APOE4. Further adjustment for cardiovascular risk factors had little impact on these associations. There was an interaction between age, APOE4 status and total brain volume atrophy rate, with evidence of an earlier age at onset of atrophy in hippocampal volume in APOE4 carriers compared to non-carriers. Those results are in accordance with the role of medial temporal structures in the greater risk of dementia observed in people carrying the APOE4 allele.

Objective Little is known about amyotrophic lateral sclerosis (ALS)‐nonspecific cognitive deficits – most notably memory disturbance – and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS. Methods APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T‐tau), and phosphorylated tau (P‐tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype. Results APOE‐E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non‐carriers) and lower CSF Aβ42 (−0.8 vs. 0.1, log‐transformed values) and Aβ42/40 ratio (−0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS‐specific (β = 0.24) and ALS‐nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T‐tau (β = −0.29) and P‐tau181 (β = −0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22). Conclusions APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD‐like pathophysiological processes, but additional ALS‐specific mechanisms could be involved.

The association between APOE genotypes and cardiovascular disease (CVD) is partially mediated by LDL-cholesterol concentration but persists after adjusting for lipid levels and other cardiovascular risk factors. Data from the Aragon Workers Health Study (AWHS) (n = 4159) and the Lipid Unit at the Hospital Universitario Miguel Servet (HUMS) (n = 3705) were used to investigate the relationship between C-reactive protein (CRP) levels and APOE genotype. Lipoprotein particle and GlycA concentrations were analyzed in a subsample from AWHS. APOE genotyping was carried out by the Sanger method in both cohorts. APOE4 carriers had significantly lower levels of CRP than APOE3 carriers. Furthermore, APOE4 carriers had cholesterol-enriched LDL particles compared to APOE2 carriers. APOE4 carriers also had higher concentrations of small, medium, and large LDL particles. CRP levels were not associated with lipoprotein particle number, size, or composition. GlycA levels were not associated with APOE genotypes. However, GlycA levels were significantly associated with the size and the amount of cholesterol contained in HDL, VLDL, and LDL particles. APOE genotype influences CRP concentration regardless of lipid profile. APOE2 carriers showed the highest CRP levels, followed by APOE3 and APOE4. A more atherogenic lipid profile, but not inflammatory markers could partly explain the higher CVD risk observed in APOE4 carriers.