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IntroductionWe investigated the association between sleep duration and neuropathologic changes 19 to 40 years later in oldest-old (age 90+) participants of The 90+ Study.MethodsParticipants self-reported sleep duration and underwent neuropathologic evaluation. We categorized sleep duration as  8 hours and dichotomized neuropathologic changes as present/absent. We estimated odds ratio (OR) and 95% confidence intervals (CI) using logistic regression.ResultsIn 264 participants, mean age at sleep self-report was 69 years, mean age at autopsy was 98 years, and mean interval between sleep self-report and autopsy was 29 years (range: 19-40). Those reporting > 8 hours of sleep had lower likelihood of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) inclusions (OR = 0.18; CI = 0.04-0.82) and amyloid beta deposits (OR = 0.34; 95% CI = 0.12-0.94).DiscussionLong self-reported sleep is associated with lower odds of neurodegenerative neuropathologic changes 19 to 40 years later in the oldest-old, suggesting a potential role of sleep in accumulation of dementia-related neuropathologies.HighlightsAssociation of self-reported sleep with non-Alzheimer's disease neuropathologic changes has not been explored. Whether sleep duration is related to dementia neuropathologic changes decades later is unclear. Long self-reported sleep is associated with lower odds of Alzheimer's disease neuropathologic change 19 to 40 years later in the oldest-old. Long self-reported sleep is associated with lower odds of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change 19 to 40 years later in the oldest-old.

Background and objectivesThe aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially from those seen in younger-old adults.MethodsAutopsied participants from The 90+ Study and Adult Changes in Thought (ACT) Study community-based cohort studies were evaluated for dementia-associated neuropathologic changes. Associations between neuropathologic variables and dementia were assessed using logistic or linear regression, and the weighted population attributable fraction (PAF) per type of neuropathologic change was estimated.ResultsThe 90+ Study participants (n = 414) were older (mean age at death = 97.7 years) and had higher amyloid/tau burden than ACT

Abstract: Background: In the oldest‐old (those >90 years) cerebrovascular diseases are highly prevalent and independently associated with dementia. Although cardiovascular risk factors like hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM) are thought to be major contributors to the development of cerebrovascular diseases, autopsy studies in the oldest‐old show weak associations with HTN, no association with DM, and HLD remains understudied. We expanded upon existing studies by investigating the associations of cardiovascular risk factors, conditions, interventions, and APOE genotype with the presence of cerebrovascular diseases in participants >90‐years‐old. Methods: Participants are from The 90+ study, a population‐based epidemiology study of dementia and aging whose participants were survivors of the Leisure World cohort (n = 267). The self‐reported cardiovascular risk factors were DM, HLD, and HTN. Cardiovascular conditions were arrhythmia, coronary artery disease, congestive heart failure (CHF), heart valve disease, myocardial infarction, stroke, and transient ischemic attack. Cardiovascular interventions were coronary artery bypass, pacemaker placement, and statin use. Cerebrovascular diseases were arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy (CAA), and microvascular lesions (MVLs) on autopsy. Neuropathologic evaluation followed NIA‐AA guidelines. We investigated the association between individual cardiovascular risk factors, conditions, interventions, and APOE genotype with individual cerebrovascular pathologies using logistic regressions adjusted for age of death, sex, and education. Results: Participants were on average 98.1 years at death and 75% were female (Table 1). None of the cardiovascular features were associated with arteriolosclerosis or atherosclerosis (Figure 1). APOE‐ε4 was positively associated with CAA [OR = 3.62] while DM [OR = 0.23] and statin use [OR = 0.57] were negatively associated (Figure 2). CHF was negatively associated with the likelihood of MVLs [OR = 0.39] (figure 2). Conclusions: Cardiovascular risk factors were not associated with cerebrovascular pathologies in our age group, leading to three potential interpretations: 1) they are not risk factors for cerebrovascular pathologies, 2) they have been mitigated through treatment, or 3) they are not associated due to survival bias, as these conditions reduce life expectancy. Associations of APOE‐ε4, DM, and statin use with CAA may relate to β‐amyloid metabolism while CHF’s negative association with MVLs may relate to decreased blood pressure variability. These initial findings on the limited associations warrant further exploration.

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p

IntroductionThe association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear.MethodsWe examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians.ResultsA total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups.DiscussionNeuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health.HighlightsIndividual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.

Background and objectivesLimbic predominant age-related TAR DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is a prevalent degenerative pathology in the oldest-old who are the fastest-growing segment of our population with the highest rates of dementia. We aimed to determine the relationship between LATE-NC and cognitive impairment and to identify its potential risk factors by studying its relationship with common past medical histories in an oldest-old cohort.MethodsParticipants from The 90+ Study with longitudinal evaluations and autopsy data were included. Dementia status and impairment in 5 main cognitive domains were determined at postmortem conferences leveraging all clinical and neuropsychological data blind to neuropathologic diagnosis. Medical history information was obtained from patients and their informants. LATE-NC and Alzheimer disease neuropathologic change (ADNC) were considered present in those with TDP-43 pathology in the hippocampus and/or neocortex and those with high likelihood of ADNC according to NIA-AA guidelines, respectively. We examined the association of degenerative pathologies with cognitive outcomes and multiple comparisons-adjusted relationship of medical history variables with LATE-NC and ADNC using logistic regressions adjusted for age at death, sex, and education.ResultsThree hundred twenty-eight participants were included in this study. LATE-NC was present in 32% of the participants. It had a significant association with the presence of dementia (OR 2.8, 95% CI 1.7-4.6) and impairment in memory (OR 3.0, 95% CI 1.8-5.1), language (OR 2.6, 95% CI 1.6-4.3), and orientation (OR 3.5, 95% CI 2.1-5.9). The association with impaired orientation was unique to LATE-NC, and the strength and significance of the other associations were comparable to ADNC. Furthermore, we found that history of osteoarthritis (OR 0.37, adjusted 95% CI 0.21-0.66) and hypertension (OR 0.52, adjusted 95% CI 0.28-0.98) were associated with a reduced likelihood of LATE-NC, but not ADNC.DiscussionOur results suggest that LATE-NC is a prevalent degenerative pathology in the oldest-old and has significant associations with dementia and impairment in cognitive domains with magnitudes that are comparable to ADNC. We also found that past medical histories of hypertension and osteoarthritis were associated with a lower likelihood of LATE-NC. This might help identify upstream mechanisms leading to this important pathology.

BackgroundDecedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia.ObjectiveAssess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC.MethodsBrains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC).ResultsAmong 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels.ConclusionPolymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

BackgroundLimbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals.ObjectiveOur aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART).MethodsIn 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART.ResultsOf 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups.ConclusionsDespite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

BackgroundAlzheimer's disease (AD) is the most common cause of dementia. AD neuropathologic change (ADNC) likely begins decades before clinical manifestations. One mechanism implicated in AD is oxidative stress. We explored the potential association of ADNC with antioxidant vitamin supplements taken about 30 years before death.MethodsThe 264 brain-autopsied participants were part of The 90+ Study, a longitudinal study of aging among people aged 90+ years, and originally members of the Leisure World Cohort Study, a population-based health study established in the 1980s. Intake of supplemental vitamins A, C, and E was collected by the Leisure World Cohort Study about 30 years before ADNC assessment. Odds ratios of ADNC (intermediate/high vs. none/low) for vitamin intake were estimated using logistic regression.ResultsThe adjusted odds ratio (95% CI) of ADNC was 0.52 (0.29-0.92) for vitamin E supplements and 0.51 (0.27-0.93) for vitamin C supplements. Supplemental vitamin E intake was the first variable, after education, to enter the stepwise model. Intake of vitamin A or C did not improve the model fit.ConclusionsThe observed association of ADNC and supplemental vitamin E intake decades earlier suggests a beneficial effect and supports further investigation into a nutritional approach to preventing AD with vitamin supplementation.

BackgroundSome oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers.ObjectiveOur objective was to examine the associations between Alzheimer's disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals.MethodsWe analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study. Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score ≥28 in the last visit 12 to 2 months before death. To examine the associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education.ResultsAlzheimer's disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR = 8.37; 95% CI: 1.48-47.44) and neocortical (OR = 10.80;95% CI: 1.03-113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR = 5.28; 95% CI: 1.10-25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP.ConclusionOldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age.

Background and objectivesAge is the largest risk factor for dementia. However, dementia is not universal, even among the oldest-old age groups. Following contemporary neuropathologic guidelines, our objectives were to describe the key neuropathologic lesions and their associations with antemortem cognition in oldest-old individuals.MethodsParticipants were those enrolled in The 90+ Study, a longitudinal, population-based study of aging/dementia in the oldest old, who agreed to postmortem brain examination. All autopsied brains as of December 2020 were evaluated for the prevalence of Alzheimer disease neuropathologic change (ADNC) and non-ADNC neuropathologic comorbidities. Associations between neuropathologic lesions or the total neuropathologic burden score (sum of the individual scores) and cognition were assessed using multinomial logistic regression and multiple linear regression. Separate regression analyses evaluated relationships between limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and hippocampal sclerosis (HS) or ADNC/primary age-related tauopathy (PART). Resistance, or failure to develop ADNC/PART, and resilience, inferred from higher-than-expected cognitive functioning, were evaluated in the presence or absence of non-ADNC neuropathologic features.ResultsThe most common neuropathologic features in the sample (n = 367) were ADNC/PART related. Increased dementia odds were associated with elevated total neuropathologic burden (odds ratio [OR] 1.5, 95% CI 1.3-1.7, p < 0.0001), β-amyloid (OR 1.6, 95% CI 1.2-2.0, p < 0.0001), neurofibrillary tangles (OR 2.6, 95% CI 1.7-4.1, p < 0.0001), and LATE-NC (OR 2.3, 95% CI 1.7-3.1, p < 0.0001), correcting for multiple comparisons. LATE-NC was associated with dementia with (OR 6.1, 95% CI 2.0-18.7, p = 0.002) and without (OR 5.0, 95% CI 2.6-9.7, p < 0.0001) co-occurring HS and increased the odds of dementia among participants with ADNC (OR 5.0, 95% CI 2.7-9.2, p < 0.0001). Resistance to moderate/severe ADNC/PART was rare (3%), but resilience to ADNC/PART was not (55%). Resilience was rarer in the presence of non-ADNC comorbid lesions, particularly LATE-NC. Among those with moderate/severe ADNC/PART, dementia odds increased with each non-ADNC comorbid lesion (e.g., 1 lesion: OR 2.4, 95% CI 1.3-4.5, p < 0.005; 2 lesions: OR 5.9, 95% CI 2.8-12.3, p < 0.0001).DiscussionThese results highlight the importance of non-ADNC neuropathologic comorbidity, predominantly LATE-NC, to cognition in the oldest old. Given the cumulative effects of non-ADNC comorbid neuropathologic abnormalities, reducing their prevalence, especially LATE-NC, will be vital to the ultimate goal of reducing dementia burden in the oldest-old individuals.

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p

Cognitive resilience provides insights into maintaining good cognition despite dementia-related neuropathologic changes. It is of special interest in the oldest-old (age 90+) because age is the strongest risk factor for dementia. We describe the only participant of The 90+ Study, among 367 autopsies, who maintained normal cognition despite intermediate-high levels of 3 dementia-related neuropathologic changes, advanced age, and comorbidities associated with cognitive impairment. This man remained cognitively normal throughout 13 semi-annual study visits, last one being 4 months before his death at 96. His cognitive test scores remained around the 90th percentile for non-timed tests and declined from 90th to 50th percentile (significant for semantic fluency) for timed tests. He remained physically and cognitively active until death, despite extrapyramidal signs in the last year of life. Neuropathological examination revealed intermediate level of Alzheimer's disease neuropathologic change (Thal phase 5, Braak NFT stage IV, CERAD score 3), Lewy bodies and neurites in the olfactory bulb, brainstem and limbic areas (Braak PD stage 4), TDP-43 inclusions in the amygdala and hippocampus (LATE stage 2), and a microvascular lesion in putamen. This case demonstrates that cognitive impairment is not inevitable even in the oldest-old with mutltiple dementia-related neuropathologic changes.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples. To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains. This study illustrates that DIA data may contain unforeseen results of interest and may be particularly useful for pilot studies investigating new research directions. In this case, a promising target for future investigations into the therapy and prevention of AD has been identified.

Alzheimer's disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (> 90 years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90 years (n = 47) from The 90+ Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell-type-specific (CTS) signals using computational methods. CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. In neurons of the dentate gyrus, DNA methylation significantly differed with increased burden of amyloid beta (Aβ) plaques at 5897 promoter regions of protein-coding genes. Amongst these, higher Aβ plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of gamma-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into Aβ peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases.

In recent years, metabolomics has been used as a powerful tool to better understand the physiology of neurodegenerative diseases and identify potential biomarkers for progression. We used targeted and untargeted aqueous, and lipidomic profiles of the metabolome from human cerebrospinal fluid to build multivariate predictive models distinguishing patients with Alzheimer's disease (AD), Parkinson's disease (PD), and healthy age-matched controls. We emphasize several statistical challenges associated with metabolomic studies where the number of measured metabolites far exceeds sample size. We found strong separation in the metabolome between PD and controls, as well as between PD and AD, with weaker separation between AD and controls. Consistent with existing literature, we found alanine, kynurenine, tryptophan, and serine to be associated with PD classification against controls, while alanine, creatine, and long chain ceramides were associated with AD classification against controls. We conducted a univariate pathway analysis of untargeted and targeted metabolite profiles and find that vitamin E and urea cycle metabolism pathways are associated with PD, while the aspartate/asparagine and c21-steroid hormone biosynthesis pathways are associated with AD. We also found that the amount of metabolite missingness varied by phenotype, highlighting the importance of examining missing data in future metabolomic studies.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

AbstractPrimary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer's and Parkinson's diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson's disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.

Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.

A primary goal of research in cognitive impairment and dementia is to understand how some individuals retain sufficient cognitive function for a fulfilling life while many others are robbed of their independence, sometimes their essence, in the last years and decades of life. In this commentary, we propose operational definitions of the types of factors that may help individuals retain cognitive function with aging. We propose operational definitions of resistance, resilience, reserve, with an eye toward how these may be measured and interpreted, and how they may enable research aimed at prevention. With operational definitions and quantification of resistance, resilience, and reserve, a focused analytic search for their determinants and correlates can be undertaken. This approach, essentially a search to identify protective risk factors and their mechanisms, represents a relatively unexplored pathway toward the identification of candidate preventive interventions.

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values  0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Objective: To determine whether plasma phosphorylated‐Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). Methods: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid‐β PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. Results: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR‐SB, as well as accelerated decline in CDR‐SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR‐SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. Interpretation: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526–538 [ABSTRACT FROM AUTHOR]

ImportanceThe strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner.ObjectiveTo evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy.Design, setting, and participantsThis multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017.Main outcomes and measuresBiomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer's Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles.ResultsOf the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55; P

INTRODUCTION:Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. METHODS:Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. RESULTS:Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. CONCLUSIONS:This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD.

Traumatic brain injury (TBI) commonly occurs in civilian and military populations. Some epidemiologic studies previously have associated TBI with an increased risk of Alzheimer disease (AD). Recent clinicopathologic and biomarker studies have failed to confirm the relationship of TBI to the development of AD dementia or pathologic changes, and suggest that other neurodegenerative processes might be linked to TBI. Additional studies are required to determine the long-term consequences of TBI.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P

We characterized the relationship between late life cholesterol exposure and neuropathological outcomes in a community-based, older adult cohort. Adult Changes in Thought (ACT) is a cohort study that enrolls consenting, randomly selected, non-demented people aged ≥65 from a healthcare delivery system. We used late life HDL and total cholesterol lab values from Group Health computerized records, and calculated HDL and non-HDL levels. We evaluated neuropathological outcomes of Alzheimer's disease, cerebral amyloid angiopathy, vascular brain injury, and Lewy body disease. Using linear mixed models with age and antilipemic medication as predictors, we obtained predicted cholesterol values at age 70 and 10 years prior to death for individuals with available cholesterol data in 10-year exposure windows. We used logistic regression to determine whether predicted late life cholesterol levels were associated with neuropathological outcomes controlling for age at death, APOE genotype, sex, and their interactions with cholesterol levels. 525 decedents came to autopsy by 08/2014. Of these, plasma cholesterol concentration was available for 318 (age 70, model 1) and 396 (10 years prior to death, model 2) participants. We did not find associations between late life cholesterol and Alzheimer's disease neuropathological changes, and there were no associations between cholesterol levels and amyloid angiopathy or vascular brain injury. We observed an association between predicted non-HDL cholesterol at age 70 and Lewy body disease. Our study suggests an association between late life non-HDL cholesterol exposure and Lewy body disease. We did not observe associations between late life cholesterol levels and Braak stage or CERAD score.

BackgroundLong acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.ObjectiveThe present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.MethodsThis randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.ResultsThe regular insulin treated group had better memory after two and four months compared with placebo (p

IntroductionAlzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood.MethodsTau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects.ResultsThe efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau.ConclusionsTau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

Objective: More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α‐synuclein seed amplification assay (αSyn‐SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co‐pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. Methods: Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn‐SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. Results: Following a decade‐long follow‐up, the clinically or autopsy‐defined diagnosis changed for nine participants. αSyn‐SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non‐LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co‐pathology, amyloidosis was present in 18%, 48%, and 71% (χ2(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2(2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co‐occurring biomarkers for αSyn‐SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2(3) = 13.87, p = 0.003). Interpretation: Our study shows that using a combination of αSyn‐SAA and AD biomarkers can identify people with αSyn, ADNC, and co‐pathology better and earlier than traditional clinical diagnostic criteria alone. [ABSTRACT FROM AUTHOR]

IntroductionNeuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used.MethodsFifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change.ResultsCurrent practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable.DiscussionAD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

Cognitive impairment, including dementia, is common in Parkinson's disease (PD). The Mini-Mental State Examination (MMSE) has been recommended as a screening tool for Parkinson's disease dementia (PDD), with values below 26 indicative of possible dementia. Using a detailed neuropsychological battery, we examined the range of cognitive impairment in PD patients with an MMSE score of 26 or higher. In this multicenter, cross-sectional, observational study, we performed neuropsychological testing in a sample of 788 PD patients with MMSE scores of 26 or higher. Evaluation included tests of global cognition, executive function, language, memory, and visuospatial skills. A consensus panel reviewed results for 342 subjects and assigned a diagnosis of no cognitive impairment, mild cognitive impairment, or dementia. Sixty-seven percent of the 788 subjects performed 1.5 standard deviations below the normative mean on at least one test. On eight of the 15 tests, more than 20% of subjects scored 1.5 standard deviations or more below the normative mean. Greatest impairments were found on Hopkins Verbal Learning and Digit Symbol Coding tests. The sensitivity of the MMSE to detect dementia was 45% in a subset of participants who underwent clinical diagnostic procedures. A remarkably wide range of cognitive impairment can be found in PD patients with a relatively high score on the MMSE, including a level of cognitive impairment consistent with dementia. Given these findings, clinicians must be aware of the limitations of the MMSE in detecting cognitive impairment, including dementia, in PD.

The National Alzheimer's Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimer's Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease-related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

Mild cognitive impairment in Parkinson's disease (PD-MCI) is common and increases the risk for dementia. Establishing distinct PD-MCI cognitive subtypes could be valuable for eventually predicting those most likely to convert to dementia. However, the study of PD-MCI subtypes has not yielded consistent results among cohorts. To determine whether there are distinct cognitive subtypes among participants diagnosed with PD-MCI in the Pacific Northwest Udall Center Clinical Consortium, we cognitively subtyped 95 patients with PD-MCI, using the Movement Disorders Society Task Force diagnostic guidelines. Psychometric test scores were then subjected to principle components factor analysis to determine whether similar cognitive subgroups could be identified using statistical methodology. Multiple-domain PD-MCI was diagnosed in 95% of the sample, and a range of cognitive impairments were noted. Factor analysis yielded seven factors and demonstrated overlap of phonemic verbal fluency on two factors, as well as the loading of verbal fluency on the same factor as a visuospatial measure; however, these factors did not partition the sample into distinct cognitive subtypes. Separation of cognitive subtypes based on the current PD-MCI criteria, or via statistical methods, may not provide sufficient information to describe distinct PD groups. Future efforts to validate the PD-MCI criteria and identify combinations of genetic or other risk factors for cognitive impairment are warranted.

Resilience in executive functioning (EF) is characterized by high EF measured by neuropsychological test performance despite structural brain damage from neurodegenerative conditions. We previously reported single nucleotide polymorphism (SNP) genome-wide association study (GWAS) results for EF resilience. Here, we report gene- and pathway-based analyses of the same resilience phenotype, using an optimal SNP-set (Sequence) Kernel Association Test (SKAT) for gene-based analyses (conservative threshold for genome-wide significance = 0.05/18,123 = 2.8 × 10(-6)) and the gene-set enrichment package GSA-SNP for biological pathway analyses (False discovery rate (FDR) < 0.05). Gene-based analyses found a genome-wide significant association between RNASE13 and EF resilience (p = 1.33 × 10(-7)). Genetic pathways involved with dendritic/neuron spine, presynaptic membrane, postsynaptic density, etc., were enriched with association to EF resilience. Although replication of these results is necessary, our findings indicate the potential value of gene- and pathway-based analyses in research on determinants of cognitive resilience.

Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the "right" control population, and the blood-brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.

The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD diseases. Complete data were available for 750 ADNI participants of European descent. Executive functioning resilience was highly heritable (H² = 0.76; S.E. = 0.44). rs3748348 on chromosome 14 in the region of RNASE13 was associated with executive functioning resilience (p-value = 4.31 × 10⁻⁷). rs3748348 is in strong linkage disequilibrium (D' of 1.00 and 0.96) with SNPs that map to TPPP2, a member of the α-synuclein family of proteins. We identified nominally significant associations between rs3748348 and expression levels of three genes (FLJ10357, RNASE2, and NDRG2). The strongest association was for FLJ10357 in cortex, which also had the most significant difference in expression between AD and non-AD brains, with greater expression in cortex of decedents with AD (p-value = 7 × 10⁻⁷). Further research is warranted to determine whether this signal can be replicated and whether other loci may be associated with cognitive resilience.

Studying proteomics data of the human brain could offer numerous insights into unraveling the signature of resilience to Alzheimer's disease. In our previous study with rigorous cohort selection criteria that excluded 4 common comorbidities, we harnessed multiple brain regions from 43 research participants with 12 of them displaying cognitive resilience to Alzheimer's disease. Based on the previous findings, this work focuses on 6 proteins out of the 33 differentially expressed proteins associated with resilience to Alzheimer's disease. These proteins are used to construct a decision tree classifier, enabling the differentiation of 3 groups: (i) healthy control, (ii) resilience to Alzheimer's disease, and (iii) Alzheimer's disease with dementia. Our analysis unveiled 2 important regional proteomic markers: Aβ peptides in the hippocampus and PA1B3 in the inferior parietal lobule. These findings underscore the potential of using distinct regional proteomic markers as signatures in characterizing the resilience to Alzheimer's disease. [ABSTRACT FROM AUTHOR]