Polygenic risk associated with Alzheimer's disease and other traits influences genes involved in T cell signaling and activation.

Introduction: T cells, known for their ability to respond to an enormous variety of pathogens and other insults, are increasingly recognized as important mediators of pathology in neurodegeneration and other diseases. T cell gene expression phenotypes can be regulated by disease-associated genetic variants. Many complex diseases are better represented by polygenic risk than by individual variants. Methods: We first compute a polygenic risk score (PRS) for Alzheimer's disease (AD) using genomic sequencing data from a cohort of Alzheimer's disease (AD) patients and age-matched controls, and validate the AD PRS against clinical metrics in our cohort. We then calculate the PRS for several autoimmune disease, neurological disorder, and immune function traits, and correlate these PRSs with T cell gene expression data from our cohort. We compare PRS-associated genes across traits and four T cell subtypes. Results: Several genes and biological pathways associated with the PRS for these traits relate to key T cell functions. The PRS-associated gene signature generally correlates positively for traits within a particular category (autoimmune disease, neurological disease, immune function) with the exception of stroke. The trait-associated gene expression signature for autoimmune disease traits was polarized towards CD4+ T cell subtypes. Discussion: Our findings show that polygenic risk for complex disease and immune function traits can have varying effects on T cell gene expression trends. Several PRS-associated genes are potential candidates for therapeutic modulation in T cells, and could be tested in in vitro applications using cells from patients bearing high or low polygenic risk for AD or other conditions.

Limited but specific engagement of the mature language network during linguistic statistical learning.

Statistical learning (SL) is the ability to detect and learn regularities from input and is foundational to language acquisition. Despite the dominant role of SL as a theoretical construct for language development, there is a lack of direct evidence supporting the shared neural substrates underlying language processing and SL. It is also not clear whether the similarities, if any, are related to linguistic processing, or statistical regularities in general. The current study tests whether the brain regions involved in natural language processing are similarly recruited during auditory, linguistic SL. Twenty-two adults performed an auditory linguistic SL task, an auditory nonlinguistic SL task, and a passive story listening task as their neural activation was monitored. Within the language network, the left posterior temporal gyrus showed sensitivity to embedded speech regularities during auditory, linguistic SL, but not auditory, nonlinguistic SL. Using a multivoxel pattern similarity analysis, we uncovered similarities between the neural representation of auditory, linguistic SL, and language processing within the left posterior temporal gyrus. No other brain regions showed similarities between linguistic SL and language comprehension, suggesting that a shared neurocomputational process for auditory SL and natural language processing within the left posterior temporal gyrus is specific to linguistic stimuli.

The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study.

BACKGROUND: Many studies have reported that impaired gait precedes cognitive impairment in older people. We aimed to characterise the time course of cognitive and motor decline in older individuals and the association of these declines with the pathologies of Alzheimer's disease and related dementias. METHODS: This multicohort study used data from three community-based cohort studies (Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study, all in the USA). The inclusion criteria for all three cohorts were no clinical dementia at the time of enrolment and consent to annual clinical assessments. Eligible participants consented to post-mortem brain donation and had post-mortem pathological assessments and three or more repeated annual measures of cognition and motor functions. Clinical and post-mortem data were analysed using functional mixed-effects models. Global cognition was based on 19 neuropsychological tests, a hand strength score was based on grip and pinch strength, and a gait score was based on the number of steps and time to walk 8 feet and turn 360°. Brain pathologies of Alzheimer's disease and related dementias were assessed at autopsy. FINDINGS: From 1994 to 2022, there were 1570 eligible cohort participants aged 65 years or older, 1303 of whom had cognitive and motor measurements and were included in the analysis. Mean age at death was 90·3 years (SD 6·3), 905 (69%) participants were female, and 398 (31%) were male. Median follow-up time was 9 years (IQR 5-11). On average, cognition was stable from 25 to 15 years before death, when cognition began to decline. By contrast, gait function and hand strength declined during the entire study. The combinations of pathologies of Alzheimer's disease and related dementias associated with cognitive and motor decline and their onsets of associations varied; only tau tangles, Parkinson's disease pathology, and macroinfarcts were associated with decline of all three phenotypes. Tau tangles were significantly associated with cognitive decline, gait function decline, and hand function decline (p<0·0001 for each); however, the association with cognitive decline persisted for more than 11 years before death, but the association with hand strength only began 3·57 years before death and the association with gait began 3·49 years before death. By contrast, the association of macroinfarcts with declining gait function began 9·25 years before death (p<0·0001) compared with 6·65 years before death (p=0·0005) for cognitive decline and 2·66 years before death (p=0·024) for decline in hand strength. INTERPRETATION: Our findings suggest that average motor decline in older adults precedes cognitive decline. Macroinfarcts but not tau tangles are associated with declining gait function that precedes cognitive decline. This suggests the need for further studies to test if gait impairment is a clinical proxy for preclinical vascular cognitive impairment. FUNDING: National Institutes of Health.

Lower GLUT1 and unchanged MCT1 in Alzheimer's disease cerebrovasculature.

The brain is a highly demanding organ, utilizing mainly glucose but also ketone bodies as sources of energy. Glucose transporter-1 (GLUT1) and monocarboxylates transporter-1 (MCT1) respectively transport glucose and ketone bodies across the blood-brain barrier. While reduced glucose uptake by the brain is one of the earliest signs of Alzheimer's disease (AD), no change in the uptake of ketone bodies has been evidenced yet. To probe for changes in GLUT1 and MCT1, we performed Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders Study. Participants clinically diagnosed with AD had lower cerebrovascular levels of GLUT1, whereas MCT1 remained unchanged. GLUT1 reduction was associated with lower cognitive scores. No such association was found for MCT1. GLUT1 was inversely correlated with neuritic plaques and cerebrovascular ß-secretase-derived fragment levels. No other significant associations were found between both transporters, markers of Aß and tau pathologies, sex, age at death or apolipoprotein-ε4 genotype. These results suggest that, while a deficit of GLUT1 may underlie the reduced transport of glucose to the brain in AD, no such impairment occurs for MCT1. This study thus supports the exploration of ketone bodies as an alternative energy source for the aging brain.

Association between hippocampal microglia, AD and LATE-NC, and cognitive decline in older adults.

INTRODUCTION: This study investigates the relationship between microglia inflammation in the hippocampus, brain pathologies, and cognitive decline. METHODS: Participants underwent annual clinical evaluations and agreed to brain donation. Neuropathologic evaluations quantified microglial burden in the hippocampus, amyloid beta (Aß), tau tangles, and limbic age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and other common brain pathologies. Mixed-effect and linear regression models examined the association of microglia with a decline in global and domain-specific cognitive measures, and separately with brain pathologies. Path analyses estimated direct and indirect effects of microglia on global cognition. RESULT: Hippocampal microglia were associated with a faster decline in global cognition, specifically in episodic memory, semantic memory, and perceptual speed. Tau tangles and LATE-NC were independently associated with microglia. Other pathologies, including Aß, were not related. Regional hippocampal burden of tau tangles and TDP-43 accounted for half of the association of microglia with cognitive decline. DISCUSSION: Microglia inflammation in the hippocampus contributes to cognitive decline. Tau tangles and LATE-NC partially mediate this association.

Delineating cognitive resilience using fractal regulation: Cross-sectional and longitudinal evidence from the Rush Memory and Aging Project.

INTRODUCTION: Degradation of fractal patterns in actigraphy independently predicts dementia risk. Such observations motivated the study to understand the role of fractal regulation in the context of neuropathologies. METHODS: We examined associations of fractal regulation with neuropathologies and longitudinal cognitive changes in 533 older participants who were followed annually with actigraphy and cognitive assessments until death with brain autopsy performed. Two measures for fractal patterns were extracted from actigraphy, namely, α1 (representing the fractal regulation at time scales of <90 min) and α2 (for time scales 2 to 10 h). RESULTS: We found that larger α1 was associated with lower burdens of Lewy body disease or cerebrovascular disease pathologies; both α1 and α2 were associated with cognitive decline. They explained an additional significant portion of the variance in the rate of cognitive decline above and beyond neuropathologies. DISCUSSION: Fractal patterns may be used as a biomarker for cognitive resilience against dementia-related neuropathologies.

Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.

Genetic associations with dementia-related proteinopathy: Application of item response theory.

INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aß, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aß/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. HIGHLIGHTS: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Association of Age-Related Neuropathologic Findings at Autopsy With a Claims-Based Epilepsy Diagnosis in Older Adults.

BACKGROUND AND OBJECTIVES: Epilepsy is 1 of the 3 most common neurologic diseases of older adults, but few studies have examined its underlying pathologies in older age. We examined the associations of age-related brain pathologies with epilepsy in older persons. METHODS: Clinical and pathologic data came from 2 ongoing clinical pathologic cohort studies of community-dwelling older adults. Epilepsy was ascertained using Medicare fee-for-service Parts A and B claims data that were linked to data from the cohort studies. The postmortem pathologic assessment collected indices of 9 pathologies including Alzheimer disease, hippocampal sclerosis, macroinfarcts, and cerebral amyloid angiopathy. The fixed brain hemisphere was imaged using 3T MRI scanners before the pathologic assessments in a subgroup of participants. RESULTS: The participants (n = 1,369) were on average 89.3 (6.6) years at death, and 67.0% were women. Epilepsy was identified in 58 (4.2%) participants. Cerebral amyloid angiopathy (odds ratio [OR] = 2.21, 95% CI 1.24-3.95, p = 0.007) and cortical macroinfarcts (OR = 2.74, 95% CI 1.42-5.28, p = 0.003) were associated with a higher odds of epilepsy. Of note, hippocampal sclerosis and Alzheimer disease pathology were not associated with epilepsy (both p's > 0.25), although hippocampal sclerosis was not common and thus hard to examine with the modest number of epilepsy cases here. In 673 participants with MRI data, the association of cerebral amyloid angiopathy and cortical macroinfarcts with epilepsy did not change after controlling for cortical gray matter atrophy, which was independently associated with a higher odds of epilepsy (OR = 1.06, 95% CI 1.02-1.10, p = 0.003). By contrast, hippocampal volume was not associated with epilepsy. DISCUSSION: Cerebrovascular pathologies and cortical atrophy were associated with epilepsy in older persons.

Distinctive retinal peri-arteriolar versus peri-venular amyloid plaque distribution correlates with the cognitive performance.

Introduction: The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition. Methods: Using scanning laser ophthalmoscopy, we quantified retinal peri-arteriolar and peri-venular curcumin-positive APs in the first, secondary and tertiary branches in twenty-eight subjects. Perivascular AP burden among cognitive states was correlated with neuroimaging and cognitive measures. Results: Peri-arteriolar exceeded peri-venular AP count (p<0.0001). Secondary branch AP count was significantly higher in cognitively impaired (p<0.01). Secondary small and tertiary peri-venular AP count strongly correlated with clinical dementia rating, hippocampal volumes, and white matter hyperintensity count. Discussion: Our topographic analysis indicates greater retinal amyloid accumulation in the retinal peri-arteriolar regions overall, and distal peri-venular regions in cognitively impaired individuals. Larger longitudinal studies are warranted to understand the temporal-spatial relationship between vascular dysfunction and perivascular amyloid deposition in AD. Highlights: Retinal peri-arteriolar region exhibits more amyloid compared with peri-venular regions.Secondary retinal vascular branches have significantly higher perivascular amyloid burden in subjects with impaired cognition, consistent across sexes.Cognitively impaired individuals have significantly greater retinal peri-venular amyloid deposits in the distal small branches, that correlate with CDR and hippocampal volumes.

Chronic traumatic encephalopathy and aging-related tau astrogliopathy in community-dwelling older persons with and without moderate-to-severe traumatic brain injury.

This study examined the frequency of chronic traumatic encephalopathy-neuropathologic change (CTE-NC) and aging-related tau astrogliopathy (ARTAG) in community-dwelling older adults and tested the hypothesis that these tau pathologies are associated with a history of moderate-to-severe traumatic brain injury (msTBI), defined as a TBI with loss of consciousness >30 minutes. We evaluated CTE-NC, ARTAG, and Alzheimer disease pathologies in 94 participants with msTBI and 94 participants without TBI matched by age, sex, education, and dementia status TBI from the Rush community-based cohorts. Six (3%) of brains showed the pathognomonic lesion of CTE-NC; only 3 of these had a history of msTBI. In contrast, ARTAG was common in older brains (gray matter ARTAG = 77%; white matter ARTAG = 54%; subpial ARTAG = 51%); there were no differences in severity, type, or distribution of ARTAG pathology with respect to history of msTBI. Furthermore, those with msTBI did not have higher levels of PHF-tau tangles density but had higher levels of amyloid-ß load (Estimate = 0.339, SE = 0.164, p = 0.040). These findings suggest that CTE-NC is infrequent while ARTAG is common in the community and that both pathologies are unrelated to msTBI. The association of msTBI with amyloid-ß, rather than with tauopathies suggests differential mechanisms of neurodegeneration in msTBI.

Identification of retinal tau oligomers, citrullinated tau, and other tau isoforms in early and advanced AD and relations to disease status.

Importance: This study identifies and quantifies diverse pathological tau isoforms in the retina of both early and advanced-stage Alzheimer's disease (AD) and determines their relationship with disease status. Objective: A case-control study was conducted to investigate the accumulation of retinal neurofibrillary tangles (NFTs), paired helical filament (PHF)-tau, oligomeric tau (oligo-tau), hyperphosphorylated tau (p-tau), and citrullinated tau (Cit-tau) in relation to the respective brain pathology and cognitive dysfunction in mild cognitively impaired (MCI) and AD dementia patients versus normal cognition (NC) controls. Design setting and participants: Eyes and brains from donors diagnosed with AD, MCI (due to AD), and NC were collected (n=75 in total), along with clinical and neuropathological data. Brain and retinal cross-sections-in predefined superior-temporal and inferior-temporal (ST/IT) subregions-were subjected to histopathology analysis or Nanostring GeoMx digital spatial profiling. Main outcomes and measure: Retinal burden of NFTs (pretangles and mature tangles), PHF-tau, p-tau, oligo-tau, and Cit-tau was assessed in MCI and AD versus NC retinas. Pairwise correlations revealed associations between retinal and brain parameters and cognitive status. Results: Increased retinal NFTs (1.8-fold, p=0.0494), PHF-tau (2.3-fold, p<0.0001), oligo-tau (9.1-fold, p<0.0001), CitR 209 -tau (4.3-fold, p<0.0001), pSer202/Thr205-tau (AT8; 4.1-fold, p<0.0001), and pSer396-tau (2.8-fold, p=0.0015) were detected in AD patients. Retinas from MCI patients showed significant increases in NFTs (2.0-fold, p=0.0444), CitR 209 -tau (3.5-fold, p=0.0201), pSer396-tau (2.6-fold, p=0.0409), and, moreover, oligo-tau (5.8-fold, p=0.0045). Nanostring GeoMx quantification demonstrated upregulated retinal p-tau levels in MCI patients at phosphorylation sites of Ser214 (2.3-fold, p=0.0060), Ser396 (1.8-fold, p=0.0052), Ser404 (2.4-fold, p=0.0018), and Thr231 (3.3-fold, p=0.0028). Strong correlations were found between retinal tau forms to paired-brain pathology and cognitive status: a) retinal oligo-tau vs. Braak stage (r=0.60, P=0.0002), b) retinal PHF-tau vs. ABC average score (r=0.64, P=0.0043), c) retinal pSer396-tau vs. brain NFTs (r=0.68, P<0.0001), and d) retinal pSer202/Thr205-tau vs. MMSE scores (r= -0.77, P=0.0089). Conclusions and Relevance: This study reveals increases in immature and mature retinal tau isoforms in MCI and AD patients, highlighting their relationship with brain pathology and cognition. The data provide strong incentive to further explore retinal tauopathy markers that may be useful for early detection and monitoring of AD staging through noninvasive retinal imaging.

Associations of brain morphology with cortical proteins of cognitive resilience.

In a recent proteome-wide study, we identified several candidate proteins for drug discovery whose cortical abundance was associated with cognitive resilience to late-life brain pathologies. This study examines the extent to which these proteins are associated with the brain structures of cognitive resilience in decedents from the Religious Orders Study and Memory and Aging Project. Six proteins were associated with brain morphometric characteristics related to higher resilience (i.e., larger anterior and medial temporal lobe volumes), and five were associated with morphometric characteristics related to lower resilience (i.e., enlarged ventricles). Two synaptic proteins, RPH3A and CPLX1, remained inversely associated with the lower resilience signature, after further controlling for 10 neuropathologic indices. These findings suggest preserved brain structure in periventricular regions as a potential mechanism by which RPH3A and CPLX1 are associated with cognitive resilience. Further work is needed to elucidate other mechanisms by which targeting these proteins can circumvent the effects of pathology on individuals at risk for cognitive decline.

CHRNA5 links chandelier cells to severity of amyloid pathology in aging and Alzheimer's disease.

Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to neuropathology in Alzheimer's Disease (AD). Protective and cognitive-enhancing roles for the nicotinic α5 subunit have been identified, but this gene has not been closely examined in the context of human aging and dementia. Therefore, we investigate the nicotinic α5 gene CHRNA5 and the impact of relevant single nucleotide polymorphisms (SNPs) in prefrontal cortex from 922 individuals with matched genotypic and post-mortem RNA sequencing in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We find that a genotype robustly linked to increased expression of CHRNA5 (rs1979905A2) predicts significantly reduced cortical ß-amyloid load. Intriguingly, co-expression analysis suggests CHRNA5 has a distinct cellular expression profile compared to other nicotinic receptor genes. Consistent with this prediction, single nucleus RNA sequencing from 22 individuals reveals CHRNA5 expression is disproportionately elevated in chandelier neurons, a distinct subtype of inhibitory neuron known for its role in excitatory/inhibitory (E/I) balance. We show that chandelier neurons are enriched in amyloid-binding proteins compared to basket cells, the other major subtype of PVALB-positive interneurons. Consistent with the hypothesis that nicotinic receptors in chandelier cells normally protect against ß-amyloid, cell-type proportion analysis from 549 individuals reveals these neurons show amyloid-associated vulnerability only in individuals with impaired function/trafficking of nicotinic α5-containing receptors due to homozygosity of the missense CHRNA5 SNP (rs16969968A2). Taken together, these findings suggest that CHRNA5 and its nicotinic α5 subunit exert a neuroprotective role in aging and Alzheimer's disease centered on chandelier interneurons.

Healthy Lifestyle and Cognition in Older Adults With Common Neuropathologies of Dementia.

Importance: A healthy lifestyle is associated with better cognitive functioning in older adults, but whether this association is independent of the accumulation of dementia-related pathologies in the brain is uncertain. Objective: To determine the role of postmortem brain pathology, including ß-amyloid load, phosphorylated tau tangles, cerebrovascular pathology, and other brain pathologies, in the association between lifestyle and cognition proximate to death. Design, Setting, and Participants: This cohort study used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study with autopsy data from 1997 to 2022 and up to 24 years of follow-up. Participants included 754 deceased individuals with data on lifestyle factors, cognitive testing proximate to death, and a complete neuropathologic evaluation at the time of these analyses. Data were analyzed from January 2023 to June 2023. Exposures: A healthy lifestyle score was developed based on self-reported factors, including noncurrent smoking, at least 150 minutes of physical activity per week, limiting alcohol consumption, a Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet score higher than 7.5, and a late-life cognitive activity score higher than 3.2. The lifestyle score ranges from 0 to 5, with higher scores reflecting a healthier lifestyle. Main Outcomes and Measures: The global cognitive score was derived from a battery of nineteen standardized tests. Brain pathology measures included ß-amyloid load, phosphorylated tau tangles, global Alzheimer disease pathology, vascular brain pathologies, Lewy body, hippocampal sclerosis, and TAR DNA-binding protein 43. Results: Of 586 included decedents, 415 (70.8%) were female, 171 (29.2%) were male, and the mean (SD) age at death was 90.9 (6.0) years. Higher lifestyle score was associated with better global cognitive functioning proximate to death. In the multivariable-adjusted model, a 1-point increase in lifestyle score was associated with 0.216 (SE = 0.036, P < .001) units higher in global cognitive scores. Neither the strength nor the significance of the association changed substantially when common dementia-related brain pathologies were included in the multivariable-adjusted models. The ß estimate after controlling for the ß-amyloid load was 0.191 (SE = 0.035; P < .001). A higher lifestyle score was associated with lower ß-amyloid load in the brain (ß = -0.120; SE = 0.041; P = .003), and 11.6% of the lifestyle-cognition association was estimated through ß-amyloid load. Conclusions and Relevance: This study found that in older adults, a healthy lifestyle may provide a cognitive reserve to maintain cognitive abilities independently of common neuropathologies of dementia.

Pathology-based brain arterial disease phenotypes and their radiographic correlates.

INTRODUCTION: Brain arterial diseases, including atherosclerosis, vasculitis, and dissections, are major contributors to cerebrovascular morbidity and mortality worldwide. These diseases not only increase the risk of stroke but also play a significant role in neurodegeneration and dementia. Clear and unambiguous terminology and classification of brain arterial disease phenotypes is crucial for research and clinical practice. MATERIAL AND METHODS: This review aims to summarize and harmonize the terminology used for brain large and small arterial phenotypes based on pathology studies and relate them to imaging phenotypes used in medical research and clinical practice. CONCLUSIONS AND RESULTS: Arteriosclerosis refers to hardening of the arteries but does not specify the underlying etiology. Specific terms such as atherosclerosis, calcification, or non-atherosclerotic fibroplasia are preferred. Atherosclerosis is defined pathologically by an atheroma. Other brain arterial pathologies occur and should be distinguished from atherosclerosis given therapeutic implications. On brain imaging, intracranial arterial luminal stenosis is usually attributed to atherosclerosis in the presence of atherosclerotic risk factors but advanced high-resolution arterial wall imaging has the potential to more accurately identify the underlying pathology. Regarding small vessel disease, arteriosclerosis is ambiguous and arteriolosclerosis is often used to denote the involvement of arterioles rather than arteries. Lipohyalinosis is sometimes used synonymously with arteriolosclerosis, but less accurately describes this common small vessel thickening which uncommonly shows lipid. Specific measures of small vessel wall thickness, the relationship to the lumen as well as changes in the layer composition might convey objective, measurable data regarding the status of brain small vessels.

Novel avenues of tau research.

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.

Atherosclerosis and Hippocampal Volumes in Older Adults: The Role of Age and Blood Pressure.

BACKGROUND: Lower hippocampal volume is associated with late-life cognitive decline and is an important, but nonspecific marker for clinical Alzheimer's dementia. Cerebrovascular disease may also be associated with hippocampal volume. Here we study the role of intracranial large vessel disease (atherosclerosis) in association with hippocampal volume and the potential role of age, average late-life blood pressure across all visits, and other factors (sex, apolipoprotein ε4 [APOE ε4], and diabetes). METHODS AND RESULTS: Data came from 765 community-based older people (91 years old on average at death; 72% women), from 2 ongoing clinical-pathologic cohort studies. Participants completed baseline assessment, annual standardized blood pressure measurements, vascular risk assessment for diabetes, and blood draws to determine APOE genotype, and at death, brains were removed and underwent ex vivo magnetic resonance imaging and neuropathologic evaluation for atherosclerosis pathology and other cerebrovascular and neurodegenerative pathologies. Linear regression models examined the association of atherosclerosis and hippocampal to hemisphere volume ratio and whether age at death, blood pressure, and other factors modified associations. In linear regression models adjusted for demographics and neurodegenerative and other cerebrovascular pathologies, atherosclerosis severity was associated with a lower hippocampal to hemisphere volume ratio. In separate models, we found the effect of atherosclerosis on the ratio of hippocampal to hemisphere volume was attenuated among advanced age at death or having higher systolic blood pressure (interaction terms P≤0.03). We did not find confounding or interactions with sex, diabetes, or APOE ε4. CONCLUSIONS: Atherosclerosis severity is associated with lower hippocampal volume, independent of neurodegenerative and other cerebrovascular pathologies. Higher systolic blood pressures and advanced age attenuate associations.