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Cerebral hypoperfusion and impaired autophagy are two etiological factors that have been identified as being associated with the development of Alzheimer’s disease (AD). Nevertheless, the exact relationships among these pathological processes remain unknown. To elucidate the impact of cerebral hypoperfusion in AD, we created a unilateral common carotid artery occlusion (UCCAO) model by occluding the left common carotid artery in both young and old 3xTg-AD mice. Two months after occlusion, we found that ligation increases phospho-Tau (p-Tau) at Serine 199/202 in the hippocampus of 3-month-old AD mice, compared to sham-operated AD mice; whereas, there is no change in the wild type (WT) mice after ligation. Moreover, cerebral hypoperfusion led to significant increase of p-Tau in both the hippocampus and cortex of 16-month-old AD mice and WT mice. Notably, we did not detect any change in Aβ 42 level in either young or old AD and WT mice after ligation. Interestingly, we observed a downregulation of LC3-II in the cortex of aged AD mice and WT mice after ligation. Our results suggest that elevated p-Tau and reduced autophagy are major cellular changes that are associated with hypoperfusion in AD. Therefore, targeting p-Tau and autophagy pathways may ameliorate hypoperfusion-induced brain damage in AD.

Perivascular spaces (PVS) support metabolic clearance in the brain and are increasingly recognized as key contributors to dementia pathogenesis. Plasma-based biomarkers, such as glial fibrillary acidic protein (GFAP) and the amyloid β42/40 (Aβ42/40) ratio, show promise in dementia diagnosis but remain understudied in vascular cognitive impairment (VCI). VCI, a major global cause of cognitive decline, may be more prevalent in Southeast Asia. Despite its impact, it is underdiagnosed compared to Alzheimer’s, highlighting the need for early, reliable markers. This study aims to examine how these biomarkers relate to PVS burden and domain-specific cognitive outcomes in VCI. VCI was defined as global cognition as assessed by a Montreal Cognitive Assessment Score <26, along with the presence of confluent white matter hyperintensities (deep white matter hyperintensities score >2 or periventricular hyperintensities >3), and >1 lacuna. A total of 108 participants (mean age of 67.3 years, 51.9% female) were included. Multivariate ordinal regression assessed biomarker associations with PVS grade, adjusting for age and diastolic blood pressure. A Aβ42/40 ratio <0.05 and GFAP >54.1 pg/mL were used as biomarker thresholds to subgroup the participants, and the relationship between these thresholds and cognitive performance was analyzed. Elevated GFAP (p = 0.0438) and a reduced Aβ42/40 ratio (p < 0.01) were correlated with a higher PVS grade. In the subgroup with a low Aβ42/40 ratio, a greater PVS burden was associated with poorer executive function (p = 0.045, β = 0.612), while in those with high GFAP levels, it was linked to more pronounced impairments in learning and memory (p = 0.006, β = 0.375). A lower Aβ42/40 ratio and higher GFAP levels track greater PVS burden in VCI. PVS severity may be associated with domain-specific cognitive decline, highlighting the potential utility of these biomarkers in refining clinical assessments and monitoring disease progression.

Background Continuous assessment and remote monitoring of cognitive function in individuals with mild cognitive impairment (MCI) enables tracking therapeutic effects and modifying treatment to achieve better clinical outcomes. While standardized neuropsychological tests are inconvenient for this purpose, wearable sensor technology collecting physiological and behavioral data looks promising to provide proxy measures of cognitive function. The objective of this study was to evaluate the predictive ability of digital physiological features, based on sensor data from wrist-worn wearables, in determining neuropsychological test scores in individuals with MCI. Methods We used the dataset collected from a 10-week single-arm clinical trial in older adults (50–70 years old) diagnosed with amnestic MCI ( N  = 30) who received a digitally delivered multidomain therapeutic intervention. Cognitive performance was assessed before and after the intervention using the Neuropsychological Test Battery (NTB) from which composite scores were calculated (executive function, processing speed, immediate memory, delayed memory and global cognition). The Empatica E4, a wrist-wearable medical-grade device, was used to collect physiological data including blood volume pulse, electrodermal activity, and skin temperature. We processed sensors’ data and extracted a range of physiological features. We used interpolated NTB scores for 10-day intervals to test predictability of scores over short periods and to leverage the maximum of wearable data available. In addition, we used individually centered data which represents deviations from personal baselines. Supervised machine learning was used to train models predicting NTB scores from digital physiological features and demographics. Performance was evaluated using “leave-one-subject-out” and “leave-one-interval-out” cross-validation. Results The final sample included 96 aggregated data intervals from 17 individuals. In total, 106 digital physiological features were extracted. We found that physiological features, especially measures of heart rate variability, correlated most strongly to the executive function compared to other cognitive composites. The model predicted the actual executive function scores with correlation r  = 0.69 and intra-individual changes in executive function scores with r  = 0.61. Conclusions Our findings demonstrated that wearable-based physiological measures, primarily HRV, have potential to be used for the continuous assessments of cognitive function in individuals with MCI.

The development of in vivo biomarkers of Alzheimer’s disease (AD) has advanced the diagnosis of AD from a clinical syndrome to a biological construct. The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals. While neuropsychiatric symptoms (NPS) are non-cognitive symptoms that are increasingly recognized as early manifestations of AD, the associations of NPS with AD pathophysiology in preclinical AD remain unclear. Here, we review the associations between NPS and AD biomarkers amyloid-β (Aβ), tau and neurodegeneration in preclinical AD and cognitively-unimpaired individuals in 19 eligible English-language publications (8 cross-sectional studies, 10 longitudinal, 1 both cross-sectional and longitudinal). The cross-sectional studies have consistently shown that NPS, particularly depressive and anxiety symptoms, are associated with higher Aβ. The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time. However, most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology. For the association of NPS and neurodegeneration, two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD, respectively. However, evidence for the association between atrophy and NPS in preclinical AD is less consistent. Therefore, future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N) biomarkers, NPS and cognitive decline, but also to elucidate the contribution of comorbid pathology to preclinical AD.

Large-scale neuronal network breakdown underlies memory impairment in Alzheimer's disease (AD). However, the differential trajectories of the relationships between network organisation and memory across pathology and cognitive stages in AD remain elusive. We determined whether and how the influences of individual-level structural and metabolic covariance network integrity on memory varied with amyloid pathology across clinical stages without assuming a constant relationship. Seven hundred and eight participants from the Alzheimer's Disease Neuroimaging Initiative were studied. Individual-level structural and metabolic covariance scores in higher-level cognitive and hippocampal networks were derived from magnetic resonance imaging and [ F] fluorodeoxyglucose positron emission tomography using seed-based partial least square analyses. The non-linear associations between network scores and memory across cognitive stages in each pathology group were examined using sparse varying coefficient modelling. We showed that the associations of memory with structural and metabolic networks in the hippocampal and default mode regions exhibited pathology-dependent differential trajectories across cognitive stages using sparse varying coefficient modelling. In amyloid pathology group, there was an early influence of hippocampal structural network deterioration on memory impairment in the preclinical stage, and a biphasic influence of the angular gyrus-seeded default mode metabolic network on memory in both preclinical and dementia stages. In non-amyloid pathology groups, in contrast, the trajectory of the hippocampus-memory association was opposite and weaker overall, while no metabolism covariance networks were related to memory. Key findings were replicated in a larger cohort of 1280 participants. Our findings highlight potential windows of early intervention targeting network breakdown at the preclinical AD stage. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). We also acknowledge the funding support from the Duke NUS/Khoo Bridge Funding Award (KBrFA/2019-0020) and NMRC Open Fund Large Collaborative Grant (OFLCG09May0035).

INTRODUCTIONThere is a lack of studies on the association between specific physical activity (PA) types and dementia. We examined the association of leisure time physical activity (LTPA), occupational physical activity (OPA), and sedentary lifestyle with dementia risk and cognitive decline using the UK-Biobank study.METHODSBaseline PA was collected using questionnaires. A total of 502,481 dementia-free participants were recruited in 2006–2010 and followed for 10 years until the end of 2020 for the ascertainment of dementia. Associations of PA with incident dementia and cognitive decline were examined.RESULTSHigher levels of LTPA and OPA and lower levels of sedentary hours were associated with lower dementia risk. The fifth quintiles of LTPA (hazard ratio [HR] = 0.53, 95% confidence interval [CI]: 0.43-0.67) and OPA (HR = 0.68, 95% CI:0.51-0.90) had lower dementia risk, whereas the fifth quintile of sedentary lifestyle had higher dementia risk (HR = 1.23, 95% CI:1.08-1.41).DISCUSSIONOur findings suggest the promotion of an active lifestyle suggested to be preventive of dementia risk. This research has been conducted using the UK Biobank Resource under Application Number 71022.

Vascular dementia is the second most common form of dementia. Yet, the mechanisms by which cerebrovascular damage progresses are insufficiently understood. Here, we create bilateral common carotid artery stenosis in mice, which effectively impairs blood flow to the brain, a major cause of the disease. Through imaging and single-cell transcriptomics of the mouse cortex, we uncover that blood vessel venous cells undergo maladaptive structural changes associated with increased Epas1 expression and activation of developmental angiogenic pathways. In a human cell model comparing arterial and venous cells, we observe that low-oxygen condition leads to sustained EPAS1 signaling specifically in venous cells. EPAS1 inhibition reduces cerebrovascular abnormalities, microglial activation, and improves markers of cerebral perfusion in vivo. In human subjects, levels of damaged endothelial cells from venous vessels are correlated with white matter injury in the brain and poorer cognitive functions. Together, these findings indicate EPAS1 as a potential therapeutic target to restore cerebrovascular integrity and mitigate neuroinflammation. How changes in brain blood vessels lead to a chronic reduction in blood flow and, consequently, to vascular dementia is poorly understood. Here, the authors show that venous endothelial dysfunction driven by EPAS1 promotes abnormal vascular remodeling and contributes to cognitive decline.

Age-related white matter lesion (WML) is considered a manifestation of sporadic cerebral small vessel disease and an important pathological substrate for dementia. Asia is notable for its large population with a looming dementia epidemic. Yet, the burden of WML and its associated risk factors across different Asian societies are unknown. Subjects from 9 Asian cities (Bangkok, Bandung, Beijing, Bengaluru, Hong Kong, Kaohsiung, Manila, Seoul, and Singapore) were recruited ( n  = 5701) and classified into (i) stroke/transient ischemic attack (TIA), (ii) Alzheimer’s disease (AD)/mild cognitive impairment (MCI), or (iii) control groups. Data on vascular risk factors and cognitive performance were collected. The severity of WML was visually rated on MRI or CT. The prevalence of moderate-to-severe WML was the highest in subjects with stroke/TIA (43.3%). Bandung Indonesia showed the highest prevalence of WML, adjusted for age, sex, education, disease groups, and imaging modality. Hypertension and hyperlipidemia were significant risk factors for WML, and WML was negatively associated with MMSE in all groups. WML is highly prevalent in Asia and is associated with increasing age, hypertension, hyperlipidemia, and worse cognitive performance. Concerted efforts to prevent WML will alleviate the huge dementia burden in the rapidly aging Asian societies.

Background Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social–emotional functional deficits. Methods In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. Results Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. Conclusions Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

Background White matter hyperintensities, a neuroimaging marker of small-vessel cerebrovascular disease and apolipoprotein ε4 (APOE4) allele, are important dementia risk factors. However, APOE4 as a key effect modifier in the relationship between white matter hyperintensities and grey matter volume needs further exploration. Methods One hundred ninety-two early-stage dementia (including mild cognitive impairment and mild dementia) and 259 cognitively unimpaired participants from a neurocognitive research cohort with neuroimaging data, APOE genotyping, and neuropsychological assessments were studied. We investigated independent and interactive effects of white matter hyperintensities and APOE4 on whole-brain voxel-wise grey matter volume using voxel-based morphometry (uncorrected p  < 0.001; minimum cluster size = 100 voxels). We further assessed interactive effects between APOE4 and white matter hyperintensities on global cognition, memory, and executive function in early-stage dementia and cognitively unimpaired participants. Results Independent of APOE4 status, higher white matter hyperintensity load was associated with greater grey matter atrophy across frontal, parietal, temporal, and occipital lobes in cognitively unimpaired and early-stage dementia subjects. However, interaction analyses and independent sample analyses revealed that APOE4 non-carriers demonstrated greater white matter hyperintensity-associated grey matter atrophy compared to APOE4 carriers in both cognitively unimpaired and early-stage dementia groups. Additional confirmatory analyses among APOE4 non-carriers demonstrated that white matter hyperintensities resulted in widespread grey matter loss. Analyses of cognitive function demonstrated that higher white matter hyperintensity load was associated with worse global (Mini-Mental State Examination, Montreal Cognitive Assessment) and executive function (Color Trails 2) in APOE4 non-carriers compared to APOE4 carriers in early-stage dementia but not cognitively unimpaired participants. Conclusions The association between white matter hyperintensities and grey matter loss is more pronounced in APOE4 non-carriers than APOE4 carriers in the cognitively unimpaired and early-stage dementia stages. Furthermore, white matter hyperintensity presence results in poorer executive function in APOE4 non-carriers compared to APOE4 carriers. This finding may have significant impact on the design of clinical trials with disease modifying therapies.