National Institute On Aging-Alzheimer's Association Research Articles

The neuropathological landscape of small vessel disease and Lewy pathology in a cohort of Hispanic and non-Hispanic White decedents with Alzheimer disease

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer’s Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging– Alzheimer’s Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon’s test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

The prevalence of mild cognitive impairment in breast cancer patients receiving chemotherapy according to the criteria of the National Institute on Aging-Alzheimer's Association (NIA-AA).

Breast cancer patients receiving chemotherapy can develop cognitive impairment. There is no gold standard for defining cognitive impairment. We applied the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) to determine its prevalence in breast cancer patients receiving adjuvant chemotherapy and examine differences between patients with and without MCI. We used pre-existing cognitive data on 5 neuropsychological test outcomes (verbal memory, processing speed, executive functioning, and verbal fluency) gathered from 240 breast cancer patients who received adjuvant conventional (n = 154) or high-dose chemotherapy (n = 86). Assessments occurred 6 or 12months post-chemotherapy and results were compared with data from 66 women without cancer. MCI was defined by the following: (i) presence of concern regarding a change in cognition, (ii) impairment in one or more cognitive tests (1.5 standard deviation below a normative mean), (iii) preservation of independence in functional abilities, and (iv) the absence of dementia. Twenty percent (n = 49) of breast cancer patients who received chemotherapy (conventional therapy n = 29 (12%), high-dose therapy = 20 (8.3%)) met the criteria for MCI, compared with 7.6% (n = 5) of controls. Prevalence was significantly different between patients and controls (P = 0.020, and corrected for IQ P < 0.001). Patients with MCI had significant lower education levels (P < 0.002) and premorbid IQ (P = 0.001) compared with patients without MCI. Twenty percent of breast cancer patients treated with chemotherapy met NIA-AA criteria for MCI, compared with 7.6% of the controls. These criteria, which include formal test performance as well as a person's symptoms and functional status, can be useful in clinical practice and scientific research.

Prevalence of Mild cognitive impairment (MCI) in a rural Indian population and its association with hypertension, diabetes and depression

AbstractBackgroundMild cognitive impairment (MCI) is a transitional phase between normal cognitive ageing and dementia. The prevalence of MCI in rural populations is an understudied area. Risk factors such as hypertension, diabetes, and depression are more prevalent in rural areas, which can contribute to the development of MCI (Longfei et al, 2020). The purpose of this study is to find out the prevalence of MCI amongst a rural cohort and to study the relationship between MCI and hypertension, diabetes and depression.MethodCross sectional analysis on the subset of data taken from ongoing longitudinal study on dementia named Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) (Sundarakumar et al, 2020), which has a target of 10000 participants. MCI was diagnosed in the subject whose Clinical Dementia Rating (CDR) score was 0.5, as per the NIA‐AA (National Institute on Aging‐Alzheimer’s Association) criteria, 2011. Presence of hypertension and diabetes were collected through a structured clinical questionnaire. Depression was assessed using the Geriatric Depression Scale 30 (GDS‐30) and a score above 9 was considered as depression. Chi‐square analysis(χ2) was used to study the association between MCI and hypertension, diabetes and depression.ResultA total of 3789 participants were examined amongst which 293 had a CDR score of 0.5, indicating presence of MCI in 7.7% of the study group. Prevalence of depression in non‐MCI and MCI subjects was 14.91% and 30.73% respectively and depression was found to be significantly associated with MCI(χ2 =24.522, p&lt; 0.001). Hypertension was seen in 13.83% of non‐MCI subjects and in 17.76% of subjects with MCI. Diabetes was seen in 16.93% of non‐MCI subjects and in 18.25% of subjects with MCI. Both hypertension (χ2 =2.086, p = 0.149) and diabetes (χ2=0.195, p = 0.659) were not significantly associated with MCI.ConclusionDepression was significantly associated with MCI. It is known that late onset depression, which is diagnosed above the age of 50, may be a predisposing factor for dementia in later life. Our results may indicate this relationship between depression and cognitive impairment. However, further longitudinal studies are necessary to evaluate causal relationship.

Impact of White Matter Hyperintensities on domain‐specific cognition in Southeast Asians

AbstractBackgroundDementia affects 55 million people worldwide, with 60% of the burden in Asia. White Matter Hyperintensities (WMH) is a key marker of small vessel disease, with high prevalence in Asian populations with prodromal and clinical dementia. WMH is described as: Deep White Matter Hyperintensities (DWMH), Periventricular Hyperintensities (PVH) or Fazekas‐Total (DWMH and PVH).However, association between WMH topography and performance in specific cognitive domains remains unexplored. Thus, this study aims to characterise the impact of Fazekas‐Total, DWMH and PVH on different cognitive domains.Method304 participants (mean age 60.6, mean education years 14.2, mean Montreal Cognitive Assessment 25.99, 43.8% males) from Biomarkers and Cognition Study, Singapore (Dementia Research Centre (Singapore)) met the inclusion criteria.Eight domains of cognition were tested: global cognition, learning and memory, language, executive function, complex‐attention, perceptual‐motor, social‐cognition, and processing speed.Normality tests, correlation analysis and stepwise regression (with Benjamini and Hochberg False Discovery Rate correction) were performed to understand association between Fazekas‐Total, DWMH, PVH on domains of cognition tested, accounting for age, education, and gender.Two approaches were used for data analysis: (1) by grouping participants as Mild Cognitive Impairment (MCI), Subjective Cognitive Decline (SCD) and Cognitively Normal (CN) as per the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) criteria and (2) by grouping participants’ WMH as confluent (DWMH ≥2 and PVH ≥3) and non‐confluent.ResultHigher Fazekas‐Total was associated with slower processing speed (p = 0.0255, R = ‐0.039) in prodromal participants (MCI and SCD). Higher PVH was associated with slower processing speed in MCI (p = 0.017, R = ‐0.32) and CN (p = 0.017, R = ‐0.663) participants. Higher PVH was significantly associated with poorer learning and memory (p = 0.045, R = ‐0.043) in SCD participants. Higher DWMH was significantly associated with poorer learning and memory (p = 0.017, R = ‐0.765) in CN participants.ConclusionThese results demonstrate differential association between PVH, DWMH and cognitive domains, thus the location of WMH determines the affected cognitive domains. Therefore, it is worthwhile to assess PVH and DWMH in clinical cognitive outcomes separately and to understand the upstream pathobiology of DWMH and PVH.Furthermore, higher Fazekas‐Total was strongly associated with slower processing speed in prodromal participants and could be a marker of cognitive decline.

ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium.

The National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. We observed a significant difference in Aβ42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage. This suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity. Some A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

Alzheimer's disease: a mini-review for the clinician.

Alzheimer's disease (AD), the most common form of dementia, is a striking example of the connection between neurophysiological abnormalities and higher-order cognitive deficiencies. Since its initial description in 1906, research into the pathophysiology and etiology of AD has led to the illumination of an incredibly complex set of genetic and molecular mechanisms for the disease's progression, characterized by much more than the neuropathological hallmarks of beta-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs). In this review, findings relating the neurodegeneration present in AD to its clinical presentation and treatment are summarized, with an emphasis on the interconnectedness of disease pathophysiology. Further, diagnostic guidelines are provided based on the National Institute on Aging-Alzheimer's Association (NIA-AA) workgroup's clinical recommendations. Through the dissemination of detailed but digestible open access resources such as this one, we can move towards an increase in the equity and accessibility of education for the modern clinician.

Amyloid on autopsy in the oldest‐old may be associated with sleep duration thirty years earlier: The 90+ Study

AbstractBackgroundAmyloid production and clearance from the brain are thought to be related to sleep duration. The association between brain amyloid accumulation and self‐reported sleep duration has been mostly established in cross‐sectional studies using PET. Our aim is to examine the longitudinal association between amyloid in the oldest‐old (90+ years), measured on autopsy and PET, with sleep duration self‐reported ∼30 years earlier.MethodWe analyzed data on 289 individuals with one‐time report of their usual nocturnal sleep duration as part of Leisure World Cohort Study (LWCS) in the early 1980s, and brain autopsy or 18F‐florbetapir (amyloid) PET between 2004 and 2021 with The 90+ Study. Sleep duration was analyzed as continuous and categorical variables (&lt;7(short), 7‐8(optimal, reference) and &gt;8 hours(long)). National Institute on Aging Alzheimer Association (NIA‐AA) amyloid (A) and neuritic (C) plaque scores were dichotomized as negative (0‐1, reference) and positive (2‐3). Standardized uptake value ratio (SUVr) for the posterior cingulate/precuneuswas analyzed as continuous and binary (SUVr &lt;0.76 vs. ≥0.76) variables. We analyzed sleep duration, as predictor, in relation to amyloid on autopsy (A and C scores) and PET (SUVr), as outcomes, using multiple logistic and multiple linear regressions, controlling for age, sex, education, positive items from the Zung depression scale, and time between sleep report and PET or autopsy.ResultSleep was reported on average at 68 years, autopsy was done ∼29 years and PET was done ∼32 years later (Table 1). Long sleep, compared to optimal sleep, was associated with 67% decrease in the odds of being NIA‐AA A positive (Table 2). Although PET amyloid results were not significant, they suggest that every hour increase in sleep duration may be associated with 0.01 unit decrese in SUVr and with 11% lower odds of being PET amyloid positive (Table 3). PET amyloid by sleep group analysis was underpowered and not done.ConclusionIn this group of oldest‐old individuals, long, compared to optimal, sleep duration self‐reported 29 years earlier is associated with lower odds of amyloid deposition on autopsy. One of the plausible mechanisms is that longer sleep duration may support greater amyloid clearance and decreased production.

Tau, β-Amyloid, and Glucose Metabolism Following Service-Related Traumatic Brain Injury in Vietnam War Veterans: The Australian Imaging Biomarkers and Lifestyle Study of Aging-Veterans Study (AIBL-VETS).

Traumatic brain injury (TBI) is common among military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimer's disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 National Institute on Aging - Alzheimer's Association (NIA-AA) research framework, by measuring tau, β-amyloid, and glucose metabolism using positron emission tomography (PET) in veterans with service-related TBI. Seventy male Vietnam war veterans-40 with TBI (age 68.0 ± 2.5 years) and 30 controls (age 70.1 ± 5.3 years)-with no prior diagnosis of dementia or mild cognitive impairment underwent β-amyloid (18F-Florbetaben), tau (18F-Flortaucipir), and fluorodeoxyglucose (18F-FDG) PET. The TBI cohort included 15 participants with mild, 16 with moderate, and nine with severe injury. β-Amyloid level was calculated using the Centiloid (CL) method and tau was measured by standardized uptake value ratios (SUVRs) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE-e4. The findings were validated in an independent cohort from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD ADNI) study. There were no significant nor trending differences in β-amyloid or tau levels or 18F-FDG uptake between the TBI and control groups before and after controlling for covariates. The β-amyloid and tau findings were replicated in the DOD ADNI validation cohort and persisted when the Australian Imaging Biomarkers and Lifestyle study of aging-Veterans study (AIBL-VETS) and DOD ADNI cohorts were combined (114 TBI vs. 87 controls in total). In conclusion, no increase in the later life accumulation of the neuropathological markers of AD in veterans with a remote history of TBI was identified.

Dynamic changes of CSF clusterin levels across the Alzheimer’s disease continuum

BackgroundClusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer’s disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD.MethodsFollowing the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria, we employed on the levels of CSF Aβ42(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aβ42 and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aβ42 and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aβ42 and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aβ42 and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups.ResultsCompared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P < 0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aβ42 (β = 0.040, P < 0. 001), CSF p-tau (β = 0.325, P < 0.001) and CSF t-tau (β = 0.346, P < 0.001).ConclusionsOur results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aβ pathology; and the increased levels are associated with tau pathology and neurodegeneration.

Different criteria modify Alzheimer’s disease diagnosis and prognosis

AbstractBackgroundAlzheimer’s disease (AD) has recently been reconceptualized into a dual entity, a biological disease, and a clinical syndrome. Following these advances, the National Institute on Aging – Alzheimer’s Association (NIA‐AA) and the International Working Group (IWG) released four updated diagnostic guidelines for AD diagnosis: NIA‐AA 2011, IWG 2016, NIA‐AA 2018, and IWG 2021. Although many studies still rely solely on a clinical diagnosis of AD, and a consensus on diagnostic criteria is still lacking. Here, we aim to elucidate how the aforementioned AD guidelines affect the individuals’ diagnostic label.MethodClinical, demographic and biomarker data were extracted from ADNI (n = 1215), and used to build classification algorithms according to diagnostic criteria from NIA‐AA 2011, IWG 2016, NIA‐AA 2018, and IWG 2021. Subjects then were labeled as Not AD (NA), At Risk of Developing AD (AR), or AD. Results were compared according to cognitive stage, cognitively unimpaired (CU) or cognitively impaired (CI), and to AD biomarkers profile. Kaplan‐Meier curves were used to evaluate conversion to CI in CU individuals using each diagnostic guideline. All analyses were performed in R (v 4.0.3).ResultIndividuals were diagnosed using criteria from the NIA‐AA 2011 [NA = 36.8%, AR = 23.2%, AD = 40%], IWG 2016 [NA = 37.9%, AR = 28.8%, AD = 33.3%], NIA‐AA 2018 [NA = 40.5%, AR = 11.1%, AD = 48.4%], and the IWG 2021 [NA = 51.3%, AR = 8.7%, AD = 40%] (Figure 1). Diagnoses were discordant between criteria in 39.8% of the individuals, with 69.4% of those being in the A+T‐ or A‐T+ biomarker groups. Conversion to CI of CU individuals AR compared to NA were calculated for the NIA‐AA 2011 [log‐rank 0,001], IWG 2016 [log‐rank 0,000], NIA‐AA 2018 [log‐rank 0,24], and IWG 2021 [log‐rank 0,000].ConclusionOur findings indicated that almost 40% of the studied population presented discordant diagnoses using different AD criteria. Most of these had only one positive biomarker (amyloid or tau). All guidelines except for the NIA‐AA 2018 managed to differentiate asymptomatic individuals at risk of developing cognitive impairment. Our findings have important implications in clinical practice and the design of future clinical trials.

Plasma β-amyloid, tau, neurodegeneration biomarkers and inflammatory factors of probable Alzheimer's disease dementia in Chinese individuals.

BackgroundPlasma-derived β-amyloid, tau, and neurodegeneration (ATN) biomarkers can accurately diagnose Alzheimer’s disease (AD) and predict its progression. Few studies have investigated the relationship between plasma biomarkers and changes in plasma inflammatory markers in clinically diagnosed AD.MethodsSeventy-four participants were recruited, including 30 mild-to-moderate AD dementia patients and 44 normal controls (NC). All participants underwent neuropsychological testing and blood sampling for biomarker testing. AD was clinically diagnosed according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) core criteria and required age-mismatched hippocampal atrophy. We performed Single Molecule Array (Simoa), an ultra-sensitive enzyme-linked immunosorbent assay (ELISA), to examine plasma ATN markers, including β-amyloid (Aβ) 40, Aβ42, p-tau181, total (t)-tau, neurofilament protein light chain (NfL), and inflammatory factors (TNF-α, IL-1β, IL-6, and IL-8).ResultsThe level of the plasma Aβ42/Aβ40 ratio was significantly declined and the levels of the plasma p-tau181, NfL and TNF-α were significantly higher in the AD group than the NC group, but there was no significant difference in the levels of plasma t-tau, IL-1β, IL-6, and IL-8 between the AD and NC groups. The levels of plasma p-tau181, NfL, Aβ42/Aβ40 ratio, and TNF-α were all associated with impairments in multiple cognitive domains. Among them, the plasma Aβ42/Aβ40 ratio, and the p-tau181 and TNF-α levels were associated with impairments in global cognition, memory, and visuospatial abilities, but not with executive function, only plasma NfL level was associated with executive function. Plasma NfL showed higher diagnostic performance in AD than in NC individuals (AUC = 0.833). A combined diagnostic prediction model of plasma Aβ42/Aβ40 ratio, p-tau 181, and NfL had the highest value than each factor alone (AUC = 0.902),with a sensitivity and specificity of 0.867 and 0.886, respectively.ConclusionThe levels of plasma ATN biomarkers (Aβ42/Aβ40 ratio, p-tua181, and NfL) were significantly changed in clinically diagnosed AD patients and they all associated with different domains of cognitive impairment. Plasma ATN biomarkers better differentiate mild-to-moderate AD dementia from NC when they are incorporated into diagnostic models together rather than individually. Plasma ATN biomarkers have the potential to be a screening tool for AD. However, the expression of inflammatory factors in AD patients requires further research.

Isolated Amyloid-β Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer's Disease Patients.

Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer's disease (AD) patients. In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer's Association (NIA-AA) classification and APOE genotype. 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of amyloid-β (Aβ) deposition (A) and fibrillar tau (T), in four groups: A+/T-E4 (n = 9), A+/T-E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation protocol over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination (MMSE) scores respect to the baseline. A+/T-E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T-E3 and to A+/T+ patients independently from genotype (p < 0.001). In addition, A+/T-E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (delta MMSE -0.5±2.12 versus -6.05±4.95; post-hocp = 0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p = 0.028). No differences were found for SAI protocol (p > 0.05). Our results suggest that APOE4 in patients with isolated Aβ pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

Forecasting the prevalence of dementia

Forecasting the prevalence of dementia

Alzheimer's disease biomarkers in Black and non-Hispanic White cohorts: A contextualized review of the evidence.

Black Americans are disproportionately affected by dementia. To expand our understanding of mechanisms of this disparity, we look to Alzheimer's disease (AD) biomarkers. In this review, we summarize current data, comparing the few studies presenting these findings. Further, we contextualize the data using two influential frameworks: the National Institute on Aging–Alzheimer's Association (NIA‐AA) Research Framework and NIA's Health Disparities Research Framework. The NIA‐AA Research Framework provides a biological definition of AD that can be measured in vivo. However, current cut‐points for determining pathological versus non‐pathological status were developed using predominantly White cohorts—a serious limitation. The NIA's Health Disparities Research Framework is used to contextualize findings from studies identifying racial differences in biomarker levels, because studying biomakers in isolation cannot explain or reduce inequities. We offer recommendations to expand study beyond initial reports of racial differences. Specifically, life course experiences associated with racialization and commonly used study enrollment practices may better account for observations than exclusively biological explanations.

Effects of vitamin B12 on cognitive function in elderly patients

AbstractBackgroundEstablishing preventive and therapeutic methods for Alzheimer's disease (AD) is an urgent issue. Because Vitamin B12(VB12) has a neuroprotective effect on the central nervous system, it has begun to receive attention. Recently, we found that VB12 can suppress β‐amyloid toxicity in vitro. Besides, it has been reported that VB12 might be useful for keeping memory in Mild Cognitive Impairment (MCI). To clarify the effects of VB12 in AD and MCI patients, we examined the effects of the VB12 on cognitive function and regional cerebral blood flow (rCBF).MethodWe examined 46 participants who consulted to our memory clinic. They were divided into three groups: Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy controls (HC) based on the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) diagnostic criteria. We used Wechsler Memory Scale‐Revised(WMS‐R) to assess the cognitive function and evaluate what kind of function is degraded. Three‐dimensional stereotactic surface projection(3D‐SSP)was used to quantify the rCBF of hippocampus, thalamus, and callosomarginal regions, which had a well‐established connection with AD. Multiple regression analysis was conducted to examine the correlations among serum VB12, WMS‐R, and rCBF in each group.ResultRegarding the correlations between VB12 and memory function, we found that the VB12 was significantly correlated with the WMS‐R scores of visual paired association I/II in the MCI group and the verbal paired associates I in the AD group (all, p&lt;0.05). Besides, there were significant correlations between VB12 and WMS‐R scores of the visual reproduction I, logical memory I, and visual memory span in the HC group (all, p&lt;0.05). Regarding the correlations between VB12 and rCBF, VB12 concentration was significantly correlated with the rCBF of the left hippocampal in the MCI group (all, p&lt;0.05). Neither AD nor HC groups showed significant correlations between rCBF and VB12. Finally, the rCBF of the left hippocampus was positively correlated with visual paired association I/II(all, p&lt;0.05).ConclusionThese results suggested that VB12 affects memory function and rCBF, especially in the MCI. Considering the relationship between WMS‐R and rCBF, VB12 may affect the progression of dementia. The early intervention with VB12 can be more effective in AD treatment strategies.

Neuropathology of late life depression: Clinical predictors of amyloid and tau neuropathology in non-demented older adults with depression.

Previous studies regarding the relationship between depression and amyloid and tau neuropathology have reported conflicting findings. We examined whether depression is associated with higher Alzheimer's disease neuropathologic changes and whether sex moderates their relationships. Using the National Alzheimer's Coordinating Center database (2005-2020), we conducted a cross-sectional study of non-demented older adults (age 50+; CDR ≤ 0.5) who had autopsy within 1 year of their last clinic visit. Multivariable cumulative logit models were fitted to determine if recent and/or remote depression were associated with Thal phase score (a measure of spread of amyloid plaques) modified according to National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines, modified Braak stage for neurofibrillary degeneration according to NIA-AA guidelines, density of neuritic plaques [CERAD score] and if any of their associations were moderated by sex. All regression models were adjusted for covariates associated with both depression and Alzheimer's disease, including selective serotonin or serotonin norepinephrine reuptake inhibitor use, sex, age, years of education, the presence of apolipoprotein E e4 allele, and history of diabetes, hypertension, hypercholesteremia, and traumatic brain injury. We included 395 participants (94 Thal, 393 Braak, and 394 CERAD). Those who had recent (within previous 2 years) but not remote depression were more likely to have higher Thal phase compared to those without a history of depression (Odds Ratio = 13.3; 95% CI, 1.5-116.3, p = 0.019). Sex did not moderate the association between recent depression and Thal phase. No significant associations between depression and Braak or CERAD scores were observed. Our findings suggest that recently active late-life depression is associated with spread of amyloid pathology beyond cortical regions to include subcortical regions but not with density of neuritic plaques or neurofibrillary tangles.

Genome‐wide association study of mild cognitive impairment in diverse Hispanic/Latinos identifies novel loci and reveals heterogeneous associations across genetic backgrounds

AbstractBackgroundMild cognitive impairment (MCI) is considered a prodromal phase to Alzheimer’s disease and related dementias (ADRD) that appear to disproportionally affect Hispanics/Latinos, the largest ethnic minority in the US. The genetic architecture of MCI is poorly understood especially among Hispanics/Latinos. We performed a genome‐wide association analyses in Hispanincs/Latinos to identify genetic loci associated with MCI with consideration of genetic background.MethodGenome‐wide association studies of MCI were performed in 4,981 participants in the Hispanic Community Health Study/Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA), distributed among six genetic background groups (backgrounds; Central American, Cuban, Dominican, Mexican, Puerto Rican and South American). MCI was defined according to the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) criteria. Participants with severe CI were also included (n=68). Genetic associations were estimated using mixed effects models adjusted for age, sex, recruitment center, sampling weight, top 5 principal components, and background as fixed effects, and for kinship, household, and block group as random effects. A subgroup analysis in subjects aged 60 and above was also performed. To account for heterogeneity among Latino backgrounds, stratified analyses by background were performed and results were combined using fixed‐ and a random‐effect based methods.ResultWe identified a novel genome‐wide significant association for MCI at rs141694916 in SLC25A21 (p=2.17x10‐8). In analyses excluding cases with severe CI, its association was less significant (p=1.22x10‐6) but two novel loci were identified: rs75090804 in DAB1 (p=1.10x10‐9) and rs112528434 in APOC1 (p=3.66x10‐8). In the aged group, we identified an association for MCI in CADM2 (rs148903011, p=1.41x10‐9). Fixed‐effect meta‐analysis of background‐stratified GWAS identified two additional loci, rs144595178 near GCNT3 (p=1.37x10‐8) and rs16974577 near KC6 (p=3.51x10‐8), while random effect meta‐analysis identified 8 additional loci showing evidence of heterogeneity (heterogeneity p&lt;0.05) by background. These included rs543428512 in STARD13 (p=5.07x10 ‐9) and rs962088 near CDH10 (p=4.14x10‐8). The identified loci showed gene expression enrichment in the hippocampus and amygdala and were enriched in gene sets implicated in the regulation of plasma amyloid beta levels.ConclusionGWAS of MCI in diverse Hispanics/Latinos identified several novel loci with functional relevance to ADRD. Examining heterogeneity by background allowed us to detect additional loci.

Neuropsychological Impairments and Their Cognitive Architecture in Mild Cognitive Impairment (MCI) with Lewy Bodies and MCI-Alzheimer's Disease.

The present study aimed to clarify the neuropsychological profile of the emergent diagnostic category of Mild Cognitive Impairment with Lewy bodies (MCI-LB) and determine whether domain-specific impairments such as in memory were related to deficits in domain-general cognitive processes (executive function or processing speed). Patients (n = 83) and healthy age- and sex-matched controls (n = 34) underwent clinical and imaging assessments. Probable MCI-LB (n = 44) and MCI-Alzheimer's disease (AD) (n = 39) were diagnosed following National Institute on Aging-Alzheimer's Association (NIA-AA) and dementia with Lewy bodies (DLB) consortium criteria. Neuropsychological measures included cognitive and psychomotor speed, executive function, working memory, and verbal and visuospatial recall. MCI-LB scored significantly lower than MCI-AD on processing speed [Trail Making Test B: p = .03, g = .45; Digit Symbol Substitution Test (DSST): p = .04, g = .47; DSST Error Check: p < .001, g = .68] and executive function [Trail Making Test Ratio (A/B): p = .04, g = .52] tasks. MCI-AD performed worse than MCI-LB on memory tasks, specifically visuospatial (Modified Taylor Complex Figure: p = .01, g = .46) and verbal (Rey Auditory Verbal Learning Test: p = .04, g = .42) delayed recall measures. Stepwise discriminant analysis correctly classified the subtype in 65.1% of MCI patients (72.7% specificity, 56.4% sensitivity). Processing speed accounted for more group-associated variance in visuospatial and verbal memory in both MCI subtypes than executive function, while no significant relationships between measures were observed in controls (all ps > .05). MCI-LB was characterized by executive dysfunction and slowed processing speed but did not show the visuospatial dysfunction expected, while MCI-AD displayed an amnestic profile. However, there was considerable neuropsychological profile overlap and processing speed mediated performance in both MCI subtypes.

Optimal Combinations of AT(N) Biomarkers to Determine Longitudinal Cognition in the Alzheimer's Disease.

Background: National Institute on Aging—Alzheimer's Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer's disease (AD) as a biological construct. However, the associations between different AT(N) combinations and cognitive progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants were classified into cognitively unimpaired (CU; n = 200) and cognitively impaired (CI; n = 141) groups according to the clinical manifestations and neuropsychological tests. Cerebrospinal fluid (CSF) Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), hippocampal volume, temporal cortical thickness, [18F]fluorodeoxyglucose (FDG) PET, and plasma neurofilament light (NfL) were used as biomarkers for (N). Binary biomarkers were obtained from the Youden index and publicly available cutoffs. Prevalence of AT(N) categories was compared between different biomarkers within the group using related independent sample non-parametric test. The relationship between AT(N) combinations and 12-year longitudinal cognition was assessed using linear mixed-effects modeling.Results: Among the CU participants, A–T–(N)– was most common. More T+ were detected using p-tau than tau PET (p < 0.05), and more (N)+ were observed using fluid biomarkers (p < 0.001). A+T+(N)+ was more common in the CI group. Tau PET combined with cortical thickness best predicted cognitive changes in the CI group and MRI predicted changes in the CU group.Conclusions: These findings suggest that optimal AT(N) combinations to determine longitudinal cognition differ by cognitive status. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for future studies.

Meta-analysis of ICU Delirium Biomarkers and Their Alignment With the NIA-AA Research Framework.

Between 30% and 80% of survivors of critical illness experience cognitive impairment, but the underlying mechanisms remain unknown. To determine whether intensive care unit (ICU) delirium biomarkers align with the National Institute on Aging-Alzheimer's Association (NIA-AA) research framework for diagnostic biomarkers for Alzheimer disease and other related dementias (ADRD). Ovid MEDLINE, PsycInfo, Embase, and the Cochrane Library were systematically searched for articles published between January 1, 2000, and February 20, 2020, on the relationship between delirium and biomarkers listed in the NIA-AA framework. Only studies that addressed delirium in the ICU setting and fluid biomarkers were included in these analyses. Of 61 256 records screened, 38 studies met inclusion criteria, 8 of which were suitable for meta-analysis. In pooled analysis, significant associations were found between ICU delirium and amyloid β-peptide 1-40 (standard mean difference [SMD], 0.42; 95% CI, 0.09-0.75), interleukin (IL)-1 receptor antagonist (SMD, 0.58; 95% CI, 0.21-0.94), and IL-6 (SMD, 0.31; 95% CI, 0.06-0.56). No significant association was observed in pooled analyses between ICU delirium and the other biomarkers. Few studies have examined ICU delirium and pathologic tau or neurodegeneration biomarkers. Inflammatory biomarkers and amyloid β are associated with ICU delirium and point to potential overlapping mechanisms between delirium and ADRD. Critical care providers should consider integrating diagnostic approaches used in ADRD in their assessment of post-ICU cognitive dysfunction.