A Comparative Study of Site-Specific Distribution of Aging-Related Tau Astrogliopathy and Its Risk Factors Between Alzheimer Disease and Cognitive Healthy Brains: The Hisayama Study

Knowledge of aging-related tau astrogliopathy (ARTAG) in healthy elderly individuals remains incomplete and studies to date have not focused on the olfactory nerve, which is a vulnerable site of various neurodegenerative disease pathologies. We performed a semiquantitative evaluation of ARTAG in 110 autopsies in the Japanese general population (Hisayama study). Our analysis focused on Alzheimer disease (AD) and cognitive healthy cases (HC), including primary age-related tauopathy. Among the various diseased and nondiseased brains, ARTAG was frequently observed in the amygdala. The ARTAG of HC was exclusively limited to the amygdala whereas gray matter ARTAG in AD cases was prominent in the putamen and middle frontal gyrus following the amygdala. ARTAG of the olfactory nerve mainly consists of subpial pathology that was milder in the amygdala. A logistic regression analysis revealed that age at death and neurofibrillary tangle Braak stage significantly affected the ARTAG of HC. In AD, age at death and male gender had significant effects on ARTAG. In addition, the Thal phase significantly affected the presence of white matter ARTAG. In conclusion, our research revealed differences in the distribution of ARTAG and affected variables across AD and HC individuals.

Association Between Late-Life Hypertension and Resilience to Alzheimer Dementia Among Older Adults

While midlife hypertension is known as one contributing factor for cognitive impairment and Alzheimer dementia in late-life older adults, less is known about the role of late-life hypertension in resilience to Alzheimer dementia. We examined the relationship between late-life hypertension and Alzheimer dementia resilience among older adults using the National Alzheimer’s Coordinating Center data from 2005-2020 (n=3,170). Hypertension, captured within 5 years prior to death, was defined as blood pressure (BP) ≥ 140/90 mmHg in at least two visits and/or ever treated with anti-hypertensive agents. Resilience was defined as positive Alzheimer disease (AD) pathology (CERAD score moderate or severe and BRAAK stage V or VI) from autopsy and Clinical Dementia Rating (CDR) - Sum of Boxes (SOB): 0.5-2.5 or CDR global (0-0.5) from last data point before autopsy. Student’s t-tests and Chi-square tests were conducted to compare patients with and without resilience. A multivariate logistic regression was conducted to estimate the association between late-life hypertension and resilience, adjusting for covariates of demographics and neuropathological characteristics. We had 55 resilient cases among 1,195 positive AD pathology cases. Those resilient were older (88±6.7) and had higher systolic BP (136 ± 18.2 mmHg) than non-resilient (82±7.9 years old, 130±20 mmHg. Untreated hypertension had a protective effect on resilience (adjusted OR: 3.69 (1.10-13.5, p=0.05). Patients with a systolic BP in the range of 135-145 mmHg and a diastolic BP in the range of 65-75 mmHg had the highest resilience possibility. Unlike midlife hypertension, late-life hypertension may have different effect on dementia, prompting further studies.

Topological Dissection of Proteomic Changes Linked to the Limbic Stage of Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. In AD, neurodegeneration spreads throughout different areas of the central nervous system (CNS) in a gradual and predictable pattern, causing progressive memory decline and cognitive impairment. Deposition of neurofibrillary tangles (NFTs) in specific CNS regions correlates with the severity of AD and constitutes the basis for disease classification into different Braak stages (I-VI). Early clinical symptoms are typically associated with stages III-IV (i.e., limbic stages) when the involvement of the hippocampus begins. Histopathological changes in AD have been linked to brain proteome alterations, including aberrant posttranslational modifications (PTMs) such as the hyperphosphorylation of Tau. Most proteomic studies to date have focused on AD progression across different stages of the disease, by targeting one specific brain area at a time. However, in AD vulnerable regions, stage-specific proteomic alterations, including changes in PTM status occur in parallel and remain poorly characterized. Here, we conducted proteomic, phosphoproteomic, and acetylomic analyses of human postmortem tissue samples from AD (Braak stage III-IV, n=11) and control brains (n=12), covering all anatomical areas affected during the limbic stage of the disease (total hippocampus, CA1, entorhinal and perirhinal cortices). Overall, ~6000 proteins, ~9000 unique phosphopeptides and 221 acetylated peptides were accurately quantified across all tissues. Our results reveal significant proteome changes in AD brains compared to controls. Among others, we have observed the dysregulation of pathways related to the adaptive and innate immune responses, including several altered antimicrobial peptides (AMPs). Notably, some of these changes were restricted to specific anatomical areas, while others altered according to disease progression across the regions studied. Our data highlights the molecular heterogeneity of AD and the relevance of neuroinflammation as a major player in AD pathology. Data are available via ProteomeXchange with identifier PXD027173.

Telephone Interview for Cognitive Status Scores Associate with Cognitive Impairment and Alzheimer’s Disease Pathology at Death

Background: Early diagnosis of Alzheimer’s disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown. Objective: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage). Methods: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants. Results: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found. Conclusion: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, ‘at risk’ individuals could be targeted for early interventions which could attenuate the progression of the disease.

Image-level trajectory inference of tau pathology using variational autoencoder for Flortaucipir PET

PurposeAlzheimer’s disease (AD) studies revealed that abnormal deposition of tau spreads in a specific spatial pattern, namely Braak stage. However, Braak staging is based on post mortem brains, each of which represents the cross-section of the tau trajectory in disease progression, and numerous studies were reported that does not conform to this model. This study aimed to identify the tau trajectory and additionally quantify the tau progress in a data-driven approach using the continuous latent space learned by variational autoencoder (VAE). Methods1080 [18F]Flortaucipir brain PET images were collected from Alzheimer’s Disease Neuroimaging Initiative database. VAE was built to compress the hidden features from tau images in latent space. Hierarchical clustering and minimum spanning tree were applied to organize the features and calibrate them to the tau progression, thus deriving pseudo-time. The image-level tau trajectory was inferred by continuously sampling across the calibrated latent features. We assessed the pseudo-time with regards to tau standardized uptake value ratio (SUVr) in AD-vulnerable regions, amyloid deposit, glucose metabolism, cognitive scores and clinical diagnosis. ResultsWe identified 4 clusters that plausibly capture certain stages of AD and organized the clusters in the latent space. The inferred tau trajectory agreed with the Braak staging. According to the derived pseudo-time, tau first deposits in the parahippocampal and amygdala, and then spreads to fusiform, inferior temporal lobe, and posterior cingulate. Prior to the regional tau deposition, amyloid accumulates first. ConclusionThe spatiotemporal trajectory of tau progression inferred in this study was consistent with Braak staging, and the profile of other biomarkers in disease progression agreed well with previous findings. We addressed that this approach additionally carries a potential to quantify tau progression as a continuous variable taking a whole-brain tau image into account.

Association between Lower Body Temperature and Increased Tau Pathology in Cognitively Normal Older Adults

Background Rodent model and in vitro studies suggest body temperature (Tb), and consequently brain temperature, has the potential to bidirectionally interact with tau pathology in Alzheimer’s Disease (AD). Tau phosphorylation is substantially increased by small (< 1°C) reductions in temperature within the human physiological range, and lower brain thermoregulatory areas may be among those first affected by AD pathology. Here, we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. Methods Tb was measured with ingestible telemetry continuously over 48 hours, including two nights of nocturnal polysomnography to delineate whether tau pathology is differentially associated with Tb during waking vs sleep. Tau pathology was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement, as well as neurofibrillary tangle (NFT) burden in early Braak stage areas, imaged with MR-PET using the [18F]MK-6240 radiotracer on average one month later. Results Plasma and CSF P-tau levels were highly correlated with one another, and with tau tangle radiotracer uptake. Lower Tb, as quantified by lower mean Tb and a greater proportion of time Tb was under 37.0°C, was associated with increased NFT burden and increased plasma and CSF P-tau levels. NFT burden was associated with lower Tb during waking, but not during sleeping intervals. Conclusions Preliminary results suggest that lower Tb in older adults may be associated with increased soluble and aggregated tau pathology.

Phosphorylated tau fluid biomarker sites recognize earlier neurofibrillary tangle maturity levels in the postmortem Alzheimer’s disease brain

Alzheimer’s disease (AD) biomarkers have become increasingly more reliable in predicting AD pathology. While phosphorylated tau fluid biomarkers have been studied for over 20 years, there is a lack of deep characterization of these sites in the postmortem brain. Neurofibrillary tangle-bearing neurons, one of the major neuropathologic hallmarks of AD, undergo morphologic changes that mature along a continuum as hyperphosphorylated tau aggregates. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, our goal was to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) they recognize. We queried the Florida Autopsied Multi-Ethnic (FLAME) cohort for cases from Braak stages I-VI. We excluded non-AD pathologies and tauopathies. A total of 24 cases, 2 males and 2 females for each Braak stage, were selected. We performed immunohistochemistry on the posterior hippocampus using antibodies directed towards phospho (p) threonine (T) 181, pT205, pT217, and pT231. Slides were digitized to enable quantification of tau burden. To examine differences in regional vulnerability between CA1 and subiculum, we developed a semi-quantitative system to rank the frequency of each neurofibrillary tangle maturity level. We identified all neurofibrillary tangle maturity levels at least once for each phosphorylated tau site. Primarily earlier neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle) were recognized for all phosphorylated tau sites. There was an increase in tau burden in the subiculum compared to CA1; however, this was attenuated compared to thioflavin-S positive tangle counts. On a global scale, tau burden generally increased with each Braak stage. These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during earlier neurofibrillary tangle maturity levels. This may help explain why these phosphorylated tau biomarker sites are observed before symptom onset in fluids.

The Relationship of Anxiety with Alzheimer’s Disease: A Narrative Review

Background: There is an increased effort to better understand neuropsychiatric symptoms of Alzheimer’s disease (AD) as an important feature of symptomatic burden as well as potential modi- fiable factors of the disease process. Anxiety is one of the most common neuropsychiatric symptoms in Alzheimer’s disease (AD). A growing body of work has emerged that addresses the epidemiology and biological correlations of anxiety in AD. Objective and Methods: Here, we review human studies in research and clinical cohorts that examined anxiety in AD. We focused on work related to prevalence across AD stages, correlation with established biomarkers, relationship with AD neuropathology and genetic risk factors, and impact on progression. Results: Anxiety is prominent in the early stages and increases across the spectrum of functional stages. Biomarker relationships are strongest at the level of FDG-PET and amyloid measured via PET or cerebrospinal fluid analysis. Neuropathologically, anxiety emerges with early Braak stage tau pathology. The presence of the apolipoprotein E e4 allele is associated with increased anxiety at all stages, most notably at mild cognitive impairment. Anxiety portended a faster progression at all pre-dementia stages. Conclusion: This body of work suggests a close biological relationship between anxiety and AD that begins in early stages and influences functional decline. As such, we discuss future work that would improve our understanding of this relationship and test the validity of anxiolytic treatment as disease modifying therapy for AD.

Alzheimer’s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort

Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1–42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1–42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals

Background To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. Methods In this longitudinal study, we included 396 cognitively normal to dementia subjects with 18F-Florbetapir/18F-Florbetaben-amyloid-PET, 18F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+)/negative(−) at pre-established cut-offs, classifying subjects as Braak0/BraakI+/BraakI–IV+/BraakI–VI+/Braakatypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. Results Baseline global tau-PET SUVRs explained more variance (partial R2) in future cognitive decline than Centiloid across all cognitive tests (Cohen’s d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. Conclusion Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings.