The complementary role of egocentric and allocentric spatial navigation tasks for the diagnosis of Alzheimer's disease: A diagnostic meta-analysis.

Decreased water exchange rate across the blood-brain barrier throughout the Alzheimer's disease continuum: Evidence from Chinese data.

Spatial navigation performance differentiates Alzheimer´s disease biomarker positive and biomarker negative cognitively impaired older adults

Neuroinflammation, particularly early astrocyte reactivity, is a significant driver of Alzheimer disease (AD) pathogenesis. It is unclear how the levels of astrocyte biomarkers change in patients across the AD continuum and which best reflect AD-related change. We performed a systematic review and meta-analysis of 3 blood astrocyte biomarkers (glial fibrillary acidic protein [GFAP], chitinase-3-like protein 1 [YKL-40], and S100B) in patients clinically diagnosed with AD. MEDLINE and Web of Science were searched on March 23, 2023, without restrictions on language, time, or study design, for studies reporting blood levels of the astrocyte biomarkers GFAP, YKL-40, or S100B in patients on the AD continuum (including those with mild cognitive impairment [MCI] and dementia) and a cognitively unimpaired (CU) control population. AD diagnosis was based on established diagnostic criteria and/or comprehensive multidisciplinary clinical consensus. Studies reporting indirect biomarker measures (e.g., levels of biomarker autoantibodies) were excluded. Risk of bias assessment was performed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. Pooled effect sizes were determined using the Hedge g method with a random-effects model. The review was prospectively registered on PROSPERO (registration number CRD42023458305). The search identified 1,186 studies; 36 met inclusion criteria (AD continuum n = 3,366, CU n = 4,115). No study was assessed to have a high risk of bias. Compared with CU individuals, patients on the AD continuum had higher GFAP and YKL-40 levels (GFAP effect size 1.15, 95% CI 0.94-1.36, p < 0.0001; YKL-40 effect size 0.38, 95% CI 0.28-0.49, p < 0.0001). Both biomarkers were elevated in more advanced clinical stages of the disease (i.e., in AD dementia compared with MCI due to AD: GFAP effect size 0.48, 95% CI 0.19-0.76, p = 0.0009; YKL-40 effect size 0.34, 95% CI 0.10-0.57, p = 0.0048). No significant differences in blood S100B levels were identified. We demonstrated significant elevations in blood GFAP and YKL-40 levels in patients on the AD continuum compared with CU individuals. Furthermore, within the AD clinical spectrum, significant elevation correlated with more advanced disease stage. Our findings suggest that both biomarkers reflect AD-related pathology. Our findings are limited by the lack of cultural and linguistic diversity in the study populations meta-analyzed. Future meta-analyses using a biomarker-defined AD population are warranted.

The ATN framework has been developed to categorize biological processes within the Alzheimer disease (AD) continuum. Because AD pathology often coincides with dementia with Lewy bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN profiles in DLB with prognosis. We included 202 patients with DLB from the Amsterdam Dementia Cohort (68±7 years; 19% female; Mini-Mental State Examination 24 ± 3; abnormal DAT-SPECT 105/119). Patients were classified into 8 profiles according to the ATN framework, using CSF β-amyloid (Aβ)42 (A), CSF p-tau (T), and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2 years for n = 139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on the 8 profiles as well as 3 clustered categories (normal AD biomarkers, non-AD pathologic change, and AD continuum). Fifty (25%) patients with DLB had normal AD biomarkers (A-T-N-), 37 (18%) had non-AD pathologic change (A-T+N- 10%, A-T-N+ 6%, A-T+N+ 3%), and 115 (57%) were classified within the AD continuum (A+T-N- 20%, A+T+N- 16%, A+T-N+ 10%, A+T+N+ 9%). A+T+N+ patients were older and least often had REM sleep behavior disorder symptoms. Parkinsonism was more often present in A+T- compared to A-T+ patients (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers. In our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within patients with DLB aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies (for example, AD-modifying treatment). Expanding the framework by incorporating markers for α-synucleinopathy would improve the use of the framework to characterize patients with dementia with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.

<h3>Background and Objectives</h3> The ATN framework has been developed to categorize biological processes within the Alzheimer disease (AD) continuum. Because AD pathology often coincides with dementia with Lewy bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN profiles in DLB with prognosis. <h3>Methods</h3> We included 202 patients with DLB from the Amsterdam Dementia Cohort (68±7 years; 19% female; Mini-Mental State Examination 24 ± 3; abnormal DAT-SPECT 105/119). Patients were classified into 8 profiles according to the ATN framework, using CSF β-amyloid (Aβ)₄₂ (A), CSF p-tau (T), and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2 years for n = 139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on the 8 profiles as well as 3 clustered categories (normal AD biomarkers, non-AD pathologic change, and AD continuum). <h3>Results</h3> Fifty (25%) patients with DLB had normal AD biomarkers (A–T–N–), 37 (18%) had non-AD pathologic change (A−T+N− 10%, A−T−N+ 6%, A−T+N+ 3%), and 115 (57%) were classified within the AD continuum (A+T−N− 20%, A+T+N− 16%, A+T−N+ 10%, A+T+N+ 9%). A+T+N+ patients were older and least often had REM sleep behavior disorder symptoms. Parkinsonism was more often present in A+T− compared to A−T+ patients (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers. <h3>Discussion</h3> In our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within patients with DLB aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies (for example, AD-modifying treatment). Expanding the framework by incorporating markers for α-synucleinopathy would improve the use of the framework to characterize patients with dementia with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.

The Alzheimer's disease (AD) continuum is a unique spectrum of cognitive impairment that typically involves the stages of subjective memory complaints (SMC), mild cognitive impairment (MCI), and AD dementia. Neuropsychiatric symptoms (NPS), such as apathy, anxiety, stress, and depression, are highly common throughout the AD continuum. However, there is a dearth of research on how these NPS vary across the AD continuum, especially SMC. There is also disagreement on the effects of specific NPS on each stage of the AD continuum due to their collinearity with other NPS, cognitive decline, and environmental factors (e.g., stress). In this article, we conduct a novel perspective review of the scientific literature to understand the presence of NPS across the AD continuum. Specifically, we review the effects of apathy, depression, anxiety, and stress in AD, MCI, and SMC. We then build on this knowledge by proposing two theories of NPS' occurrence across the AD continuum. Consequently, we highlight the current landscape, limitations (e.g., differing operationalization), and contentions surrounding the NPS literature. We also outline theories that could clear up contention and inspire future NPS research.

Plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort.

As a part of the glymphatic system, the choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain. We investigated the association between CP volume (CPV), amyloid-β (Aβ) burden, and cognition in patients on the Alzheimer's disease (AD) continuum. We retrospectively reviewed the records of 203 patients on the AD continuum and 82 healthy controls who underwent brain magnetic resonance imaging and 18F-florbetaben positron emission tomography. Automatic segmentation was performed, and the CPV was calculated. Cognitive function was assessed using detailed neuropsychological tests, and patients on the AD continuum were categorized into the non-dementia and dementia groups. The relationships between CPV, Aβ burden, and cognitive function were assessed using multivariate linear regression and linear mixed model. CPV was greater in the AD group than in the healthy control group (1.50 vs. 1.30, P < 0.001), but was comparable between the AD non-dementia and dementia groups (1.50 vs. 1.48, P = 0.585). After adjusting for age and sex, a larger CPV was significantly associated with greater global Aβ deposition (β = 0.20, P = 0.002). Larger CPV was also associated with worse general cognitive function assessed using the sum of boxes of the clinical dementia rating scale (β = 0.85, P = 0.034) and lower composite scores for memory (β = -0.68, P = 0.002) and frontal/executive function domains (β = -0.65, P < 0.001). In addition, a larger CPV was associated with a more rapid decline in Mini-Mental State Examination scores in the AD dementia group (β = -0.58, P = 0.004). The present study demonstrated that CP enlargement was associated with increased Aβ deposition and impaired memory and frontal/executive function in patients on the AD continuum.

Plasma glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker in neurological disorders, but further evidence is required in relation to its usefulness for diagnosis and prediction of Alzheimer disease (AD). Plasma GFAP was measured in participants with AD, non-AD neurodegenerative disorders, and controls. Its diagnostic and predictive value were analyzed alone or combined with other indicators. A total of 818 participants were recruited (210 followed). Plasma GFAP was significantly higher in AD than in non-AD dementia and non-demented individuals. It increased in a stepwise pattern from preclinical AD, through prodromal AD to AD dementia. It effectively distinguished AD from controls [area under the curve (AUC) > 0.97] and non-AD dementia (AUC > 0.80) and distinguished preclinical (AUC > 0.89) and prodromal AD (AUC > 0.85) from Aβ-normal controls. Adjusted or combined with other indicators, higher levels of plasma GFAP displayed predictive value for risk of AD progression (adjusted hazard radio= 4.49, 95%CI, 1.18-16.97, P = 0.027 based on the comparison of those above vs below average at baseline) and cognitive decline (standard-β=0.34, P = 0.002). Additionally, it strongly correlated with AD-related cerebrospinal fluid (CSF)/neuroimaging markers. Plasma GFAP effectively distinguished AD dementia from multiple neurodegenerative diseases, gradually increased across the AD continuum, predicted the individual risk of AD progression, and strongly correlated with AD CSF/neuroimaging biomarkers. Plasma GFAP could serve as both a diagnostic and predictive biomarker for AD.

This study explores the impact of sleep disturbances on gray matter structural covariance networks (SCNs) across the Alzheimer's disease (AD) continuum. Amyloid-negative participants served as controls, whereas amyloid positive (A+) individuals were categorized into six groups based on cognitive status and sleep quality. SCNsfor the default mode network (DMN), salience network (SN), and executive control network (ECN) were derived from T1-weighted magnetic resonance images. In the DMN, increased structural associations were observed in cognitive unimpaired (CU) A+ and mild cognitive impairment (MCI) groups regardless of sleep quality, whereas AD with poor sleep (PS) showed a decrease and AD with normal sleep (NS) an increase. For the ECN, AD-NS showed increased and AD-PS showed reduced associations. In the SN, reduced associations were observed in CU A+ NS and MCI-NS, whereas AD-NS displayed increased associations; only AD-PS had decreased associations. Distinct SCN damage patterns between normal and poor sleepers provide insights into sleep disturbances in AD. We delineated distinct patterns of structural covariance networks (SCN) impairment across the Alzheimer's disease (AD) continuum, uncovering significant disparities between individuals with normal sleep architecture and those afflicted by sleep disturbances.These observations underscore the pivotal importance of addressing sleep disruptions in AD therapeutics, providing a refined understanding of their detrimental impact on brain networks implicated in the disease.Our investigation epitomizes methodological precision by constructing an AD continuum using amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers to minimize diagnostic heterogeneity, further enhanced by a substantial cohort size that bolsters the robustness and generalizability of our findings.

&lt;p dir="ltr"&gt;Alzheimer disease (AD), with accumulation of typical deposits of amyloid-beta (AB) and phosphorylated tau, starts to develop in the CNS many years before the onset of early clinical symptoms. The perception of AD has evolved and it is in- creasingly recognized as a biological entity, not just a distinct clinical phenotype. It has been proposed that the presence of a deterministic mutation or the pres- ence of pathological levels of biomarkers that are surrogate measures to detect AD neuropathological change (AB plaques and tau neurofibrillary tangles), will de- fine whether an individual is on the AD continuum. Concordantly, the AD contin- uum spans over both asymptomatic and symptomatic phases. Autosomal domi- nant AD (ADAD) is caused by deterministic genetic variants in the APP, PSEN1 and PSEN2 genes. Such mutations elicit early-onset disease, with the first symptoms observed before the age of 65 years. Studies of ADAD families provide a unique and important model for investigation of the natural progression of AD patho- physiology and symptoms. In Sweden, the Familial Alzheimer Disease (FAD) study has been ongoing at Karolinska Institutet since the 1990's. This longitudinal obser- vational study enrolls relatives with 50% risk of developing AD and the research protocol includes sampling of biofluids, brain MRI, electroencephalography and neurocognitive testing. The objective of this thesis was to continue profiling of ADAD and investigate novel clinical, biofluid and genetic biomarkers for AD in or- der to explore preclinical and clinical phases of AD pathophysiology, monitor dis- ease severity and improve the diagnostic work-up.&lt;/p&gt;&lt;p dir="ltr"&gt;In Study I, we found that plasma concentrations of glial fibrillary acidic protein (GFAP), tau phosphorylated at position 181 (p-tau181) and neurofilament light chain (NfL) all started to increase in the presymptomatic phase and, thus, are potential biomarkers for monitoring asymptomatic individuals on the AD continuum. Eleva- tions of plasma GFAP concentrations were the earliest to be detected, supporting that this is a sensitive marker in presymptomatic AD.&lt;/p&gt;&lt;p dir="ltr"&gt;In Study Il we investigated plasma AB concentrations over the AD continuum by mutation type, due to strong variant-specific effects. In the Swedish double mu- tation (APP p.KM670/671NL), AB peptides were more than 3-fold increased in both presymptomatic and symptomatic mutation carriers compared to non-carrier controls at baseline. Thus, measurement in clinical routine would indirectly confer the risk of disclosing mutation status. Plasma Aß did not correlate to CSF AB levels, nor did longitudinal results suggest any mutation-specific effects on AB42/40 ratio with increasing age. Thus, the results did not support the utility of plasma AB measurement in ADAD.&lt;/p&gt;&lt;p dir="ltr"&gt;Study III included analyses of transient global topographies or maps of summated neuronal potentials, i.e microstates, as recorded by electroencephalography (EEG). The EEG microstate methodology was employed for the first time in ADAD, and the results pointed out selective changes associated with either clinical symptoms or mutation status. Albeit exploratory, the findings shed light on the activity of intrinsic global neuronal networks over the AD continuum and may be hypothesis-generating for future work in the field.&lt;/p&gt;&lt;p dir="ltr"&gt;Lastly, Study IV reported biomarker results and clinical characteristics from a novel C-terminally located APP (p.I718M) mutation, not previously described, po- tentially causative of both AD and mixed AD-DLB phenotypes.&lt;/p&gt;&lt;p dir="ltr"&gt;In summary, this thesis integrated studies of fluid and novel EEG biomarkers over the AD continuum. Also, biomarker profiles and clinical characteristics of a novel APP mutation were systematically described. The findings may be crucial for psy- chosocial support and genetic counselling to specific families, advance the gen- eral understanding of pathogenic variants and, thus, may be of importance for the ADAD community worldwide.&lt;/p&gt;&lt;h3&gt;List of scientific papers&lt;/h3&gt;&lt;p dir="ltr"&gt;I. &lt;b&gt;Johansson C,&lt;/b&gt; Thordardottir S, Laffita-Mesa J, Rodriguez-Vieitez E, Zetterberg H, Blennow K, Graff C. Plasma biomarker profiles in autosomal dominant Alzheimer's disease. Brain. 2023 Mar 1;146(3):1132- 1140. &lt;a href="https://doi.org/10.1093/brain/awac399" rel="noreferrer" target="_blank"&gt;https://doi.org/10.1093/brain/awac399&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;II. &lt;b&gt;Johansson C,&lt;/b&gt; Thordardottir S, Laffita-Mesa J, Pannee J, Rodriguez- Vieitez E, Zetterberg H, Blennow K, Graff C. Gene-variant specific effects of plasma amyloid-beta levels in Swedish autosomal dominant Alzheimer disease. Alzheimers Res Ther. 2024;16(1):207. &lt;a href="https://doi.org/10.1186/s13195-024-01574-w" rel="noreferrer" target="_blank"&gt;https://doi.org/10.1186/s13195-024-01574-w&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;III. &lt;b&gt;Johansson C,&lt;/b&gt; Koenig T, Smailovic U, Hallstrom V, Jelic V*, Graff C *. Selective association of EEG microstates with clinical symptoms and mutation status in monogenic Alzheimer disease. *Shared last authors. [Submitted]&lt;/p&gt;&lt;p dir="ltr"&gt;IV. &lt;b&gt;Johansson C,&lt;/b&gt; Rodriguez-Vieitez E, Bluma M, Nennesmo I, Thonberg H, Ullgren A, Jelic V, Zetterberg H, Blennow K, Nordberg A, Graff C. Phenotypic variability in early-onset dementia segregating with the novel APP p.I718M variant. [Submitted]&lt;/p&gt;

&lt;p dir="ltr"&gt;Alzheimer disease (AD), with accumulation of typical deposits of amyloid-beta (AB) and phosphorylated tau, starts to develop in the CNS many years before the onset of early clinical symptoms. The perception of AD has evolved and it is in- creasingly recognized as a biological entity, not just a distinct clinical phenotype. It has been proposed that the presence of a deterministic mutation or the pres- ence of pathological levels of biomarkers that are surrogate measures to detect AD neuropathological change (AB plaques and tau neurofibrillary tangles), will de- fine whether an individual is on the AD continuum. Concordantly, the AD contin- uum spans over both asymptomatic and symptomatic phases. Autosomal domi- nant AD (ADAD) is caused by deterministic genetic variants in the APP, PSEN1 and PSEN2 genes. Such mutations elicit early-onset disease, with the first symptoms observed before the age of 65 years. Studies of ADAD families provide a unique and important model for investigation of the natural progression of AD patho- physiology and symptoms. In Sweden, the Familial Alzheimer Disease (FAD) study has been ongoing at Karolinska Institutet since the 1990's. This longitudinal obser- vational study enrolls relatives with 50% risk of developing AD and the research protocol includes sampling of biofluids, brain MRI, electroencephalography and neurocognitive testing. The objective of this thesis was to continue profiling of ADAD and investigate novel clinical, biofluid and genetic biomarkers for AD in or- der to explore preclinical and clinical phases of AD pathophysiology, monitor dis- ease severity and improve the diagnostic work-up.&lt;/p&gt;&lt;p dir="ltr"&gt;In Study I, we found that plasma concentrations of glial fibrillary acidic protein (GFAP), tau phosphorylated at position 181 (p-tau181) and neurofilament light chain (NfL) all started to increase in the presymptomatic phase and, thus, are potential biomarkers for monitoring asymptomatic individuals on the AD continuum. Eleva- tions of plasma GFAP concentrations were the earliest to be detected, supporting that this is a sensitive marker in presymptomatic AD.&lt;/p&gt;&lt;p dir="ltr"&gt;In Study Il we investigated plasma AB concentrations over the AD continuum by mutation type, due to strong variant-specific effects. In the Swedish double mu- tation (APP p.KM670/671NL), AB peptides were more than 3-fold increased in both presymptomatic and symptomatic mutation carriers compared to non-carrier controls at baseline. Thus, measurement in clinical routine would indirectly confer the risk of disclosing mutation status. Plasma Aß did not correlate to CSF AB levels, nor did longitudinal results suggest any mutation-specific effects on AB42/40 ratio with increasing age. Thus, the results did not support the utility of plasma AB measurement in ADAD.&lt;/p&gt;&lt;p dir="ltr"&gt;Study III included analyses of transient global topographies or maps of summated neuronal potentials, i.e microstates, as recorded by electroencephalography (EEG). The EEG microstate methodology was employed for the first time in ADAD, and the results pointed out selective changes associated with either clinical symptoms or mutation status. Albeit exploratory, the findings shed light on the activity of intrinsic global neuronal networks over the AD continuum and may be hypothesis-generating for future work in the field.&lt;/p&gt;&lt;p dir="ltr"&gt;Lastly, Study IV reported biomarker results and clinical characteristics from a novel C-terminally located APP (p.I718M) mutation, not previously described, po- tentially causative of both AD and mixed AD-DLB phenotypes.&lt;/p&gt;&lt;p dir="ltr"&gt;In summary, this thesis integrated studies of fluid and novel EEG biomarkers over the AD continuum. Also, biomarker profiles and clinical characteristics of a novel APP mutation were systematically described. The findings may be crucial for psy- chosocial support and genetic counselling to specific families, advance the gen- eral understanding of pathogenic variants and, thus, may be of importance for the ADAD community worldwide.&lt;/p&gt;&lt;h3&gt;List of scientific papers&lt;/h3&gt;&lt;p dir="ltr"&gt;I. &lt;b&gt;Johansson C,&lt;/b&gt; Thordardottir S, Laffita-Mesa J, Rodriguez-Vieitez E, Zetterberg H, Blennow K, Graff C. Plasma biomarker profiles in autosomal dominant Alzheimer's disease. Brain. 2023 Mar 1;146(3):1132- 1140. &lt;a href="https://doi.org/10.1093/brain/awac399" rel="noreferrer" target="_blank"&gt;https://doi.org/10.1093/brain/awac399&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;II. &lt;b&gt;Johansson C,&lt;/b&gt; Thordardottir S, Laffita-Mesa J, Pannee J, Rodriguez- Vieitez E, Zetterberg H, Blennow K, Graff C. Gene-variant specific effects of plasma amyloid-beta levels in Swedish autosomal dominant Alzheimer disease. Alzheimers Res Ther. 2024;16(1):207. &lt;a href="https://doi.org/10.1186/s13195-024-01574-w" rel="noreferrer" target="_blank"&gt;https://doi.org/10.1186/s13195-024-01574-w&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;III. &lt;b&gt;Johansson C,&lt;/b&gt; Koenig T, Smailovic U, Hallstrom V, Jelic V*, Graff C *. Selective association of EEG microstates with clinical symptoms and mutation status in monogenic Alzheimer disease. *Shared last authors. [Submitted]&lt;/p&gt;&lt;p dir="ltr"&gt;IV. &lt;b&gt;Johansson C,&lt;/b&gt; Rodriguez-Vieitez E, Bluma M, Nennesmo I, Thonberg H, Ullgren A, Jelic V, Zetterberg H, Blennow K, Nordberg A, Graff C. Phenotypic variability in early-onset dementia segregating with the novel APP p.I718M variant. [Submitted]&lt;/p&gt;

The structural covariance network (SCN) has provided a perspective on the large‐scale brain organization impairment in the Alzheimer's Disease (AD) continuum. However, the successive structural impairment across brain regions, which may underlie the disrupted SCN in the AD continuum, is not well understood. In the current study, we enrolled 446 subjects with AD, mild cognitive impairment (MCI) or normal aging (NA) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The SCN as well as a casual SCN (CaSCN) based on Granger causality analysis were applied to the T1‐weighted structural magnetic resonance images of the subjects. Compared with that of the NAs, the SCN was disrupted in the MCI and AD subjects, with the hippocampus and left middle temporal lobe being the most impaired nodes, which is in line with previous studies. In contrast, according to the 194 subjects with records on CSF amyloid and Tau, the CaSCN revealed that during AD progression, the CaSCN was enhanced. Specifically, the hippocampus, thalamus, and precuneus/posterior cingulate cortex (PCC) were identified as the core regions in which atrophy originated and could predict atrophy in other brain regions. Taken together, these findings provide a comprehensive view of brain atrophy in the AD continuum and the relationships among the brain atrophy in different regions, which may provide novel insight into the progression of AD.

The retina is the "window" of the central nervous system. Previous studies discovered that retinal thickness degenerates through the pathological process of the Alzheimer's disease (AD) continuum. Hippocampal atrophy is one of the typical clinical features and diagnostic criteria of AD. Former studies have described retinal thinning in normal aging subjects and AD patients, yet the association between retinal thickness and hippocampal atrophy in AD is unclear. The optical coherence tomography (OCT) technique has access the non-invasive to retinal images and magnetic resonance imaging can outline the volume of the hippocampus. Thus, we aim to quantify the correlation between these two parameters to identify whether the retina can be a new biomarker for early AD detection. We systematically searched the PubMed, Embase, and Web of Science databases from inception to May 2023 for studies investigating the correlation between retinal thickness and hippocampal volume. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the study quality. Pooled correlation coefficient r values were combined after Fisher's Z transformation. Moderator effects were detected through subgroup analysis and the meta-regression method. Of the 1,596 citations initially identified, we excluded 1,062 studies after screening the titles and abstract (animal models, n = 99; irrelevant literature, n = 963). Twelve studies met the inclusion criteria, among which three studies were excluded due to unextractable data. Nine studies were eligible for this meta-analysis. A positive moderate correlation between the retinal thickness was discovered in all participants of with AD, mild cognitive impairment (MCI), and normal controls (NC) (r = 0.3469, 95% CI: 0.2490-0.4377, I2 = 5.0%), which was significantly higher than that of the AD group (r = 0.1209, 95% CI:0.0905-0.1510, I2 = 0.0%) (p < 0.05). Among different layers, the peripapillary retinal nerve fiber layer (pRNFL) indicated a moderate positive correlation with hippocampal volume (r = 0.1209, 95% CI:0.0905-0.1510, I2 = 0.0%). The retinal pigmented epithelium (RPE) was also positively correlated [r = 0.1421, 95% CI:(-0.0447-0.3192), I2 = 84.1%]. The retinal layers and participants were the main overall heterogeneity sources. Correlation in the bilateral hemisphere did not show a significant difference. The correlation between RNFL thickness and hippocampal volume is more predominant in both NC and AD groups than other layers. Whole retinal thickness is positively correlated to hippocampal volume not only in AD continuum, especially in MCI, but also in NC. https://www.crd.york.ac.uk/PROSPERO/, CRD42022328088.

BackgroundSpatial navigation deficits are early symptoms of Alzheimer’s disease (AD). The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for AD. This study investigated effects of APOE genotype on spatial navigation in biomarker-defined individuals with amnestic mild cognitive impairment (aMCI) and associations of AD biomarkers and atrophy of AD-related brain regions with spatial navigation.Methods107 participants, cognitively normal older adults (CN, n = 48) and aMCI individuals stratified into AD aMCI (n = 28) and non-AD aMCI (n = 31) groups, underwent cognitive assessment, brain MRI, and spatial navigation assessment using the Virtual Supermarket Test with egocentric and allocentric tasks and a self-report questionnaire. Cerebrospinal fluid (CSF) biomarkers (amyloid-β1–42, phosphorylated tau181 and total tau) and amyloid PET imaging were assessed in aMCI participants.ResultsAD aMCI participants had the highest prevalence of APOE ε4 carriers and worst allocentric navigation. CSF levels of AD biomarkers and atrophy in AD-related brain regions were associated with worse allocentric navigation. Between-group differences in spatial navigation and associations with AD biomarkers and regional brain atrophy were not influenced by APOE genotype. Self-reported navigation ability was similar across groups and unrelated to spatial navigation performance.ConclusionsThese findings suggest that allocentric navigation deficits in aMCI individuals are predominantly driven by AD pathology, independent of APOE genotype. This highlights the role of AD pathology as measured by biomarkers, rather than genetic status, as a major factor in navigational impairment in aMCI, and emphasizes the assessment of spatial navigation as a valuable tool for early detection of AD.