Association of the ATN Research Framework With Clinical Profile, Ccognitive Decline, and Mortality in Patients With Dementia With Lewy Bodies

Background and Objectives: The ATN framework has been developed to categorize biological processes within the Alzheimer’s disease (AD) continuum. Since AD pathology often coincides with dementia with Lewy Bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN-profiles in DLB to prognosis. / Methods: We included 202 DLB patients from the Amsterdam Dementia Cohort (68±7yrs, 19%F, MMSE: 24±3, DAT-SPECT abnormal: 105/119). Patients were classified into eight profiles according to the ATN framework, using CSF Aβ42 (A), CSF p-tau (T) and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2yrs for n=139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on both the eight profiles, as well as three clustered categories (normal AD biomarkers, non-AD pathologic change, AD continuum). / Results: Fifty (25%) DLB patients had normal AD biomarkers (A-T-N-), 37 (18%) had non-AD pathologic change (A-T+N-: 10%/A-T-N+: 6%/A-T+N+: 3%) and 115 (57%) were classified within the AD continuum (A+T-N-: 20%/A+T+N-: 16%/A+T-N+: 10%/A+T+N+: 9%). A+T+N+ patients were older and least often had RBD symptoms. Parkinsonism was more often present in A+T-, compared to A-T+ (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers. / Discussion: In our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within DLB patients aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies, e.g. AD modifying treatment. Expanding the framework by incorporating markers for alpha-synucleinopathy would improve the use of the framework to characterize dementia patients with mixed pathology, which could enhance proper stratification of patients for therapeutic trials

Plasma‐derived biomarkers of Alzheimer\u27s disease and neuropsychiatric symptoms: A community‐based study

INTRODUCTION: We examined associations between plasma-derived biomarkers of Alzheimer\u27s disease (AD) and neuropsychiatric symptoms (NPS) in community-dwelling older adults. METHODS: Cross-sectional study involving 1005 persons ≥50 years of age (mean 74 years, 564 male, 118 cognitively impaired), who completed plasma-derived biomarker (amyloid beta 42 [Aβ42]/Aβ40, phosphorylated tau 181 [p-tau181], p-tau217, total tau [t-tau], neurofilament light [NfL]), and NPS assessment. RESULTS: P-tau181 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.41–3.00, p < 0.001), p-tau217 (OR 1.70, 95% CI 1.10–2.61, p = 0.016), and t-tau (OR 1.44, 95% CI 1.08–1.92, p = 0.012) were associated with appetite change. We also found that p-tau181 and p-tau217 were associated with increased symptoms of agitation (OR 1.93, 95% CI 1.20–3.11, p = 0.007 and OR 2.04, 95% CI 1.21–3.42, p = 0.007, respectively), and disinhibition (OR 2.39, 95% CI 1.45–3.93, p = 0.001 and OR 2.30, 95% CI 1.33–3.98, p = 0.003, respectively). Aβ42/Aβ40 and NfL were not associated with NPS. CONCLUSION: Higher plasma-derived p-tau181 and p-tau217 levels are associated with increased symptoms of appetite change, agitation, and disinhibition. These findings may support the validity of plasma tau biomarkers for predicting behavioral symptoms that often accompany cognitive impairment. HIGHLIGHTS - We studied 1005 community-dwelling persons aged ≥ 50 years - Higher plasma tau levels are associated with increased neuropsychiatric symptoms - Aβ42/Aβ40 and NfL are not associated with neuropsychiatric symptoms - Clinicians should treat neuropsychiatric symptoms in persons with high plasma-derived ta

Alzheimers Dement

INTRODUCTION: Inferring the timeline from mild cognitive impairment (MCI) to severe dementia is pivotal for patients, clinicians, and researchers. Literature is sparse and often contains few patients. We aim to determine the time spent in MCI, mild-, moderate-, severe dementia, and institutionalization until death. METHODS: Multistate modeling with Cox regression was used to obtain the sojourn time. Covariates were age at baseline, sex, amyloid status, and Alzheimer's disease (AD) or other dementia diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Cohort and Memento). RESULTS: Using 80,543 patients, the sojourn time from clinically identified MCI to death across all patient groups ranged from 6.20 (95% confidence interval [CI]: 5.57-6.98) to 10.08 (8.94-12.18) years. DISCUSSION: Generally, sojourn time was inversely associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis

Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects

In a large multicentre study, Toledo et al. examine core Alzheimer's disease CSF biomarkers in 1233 cognitively normal subjects aged 40-85 years. Alzheimer disease-like changes in Aβ1-42 are seen as early as middle age, while APOE genotype strongly modifies age-related effects on both Aβ1-42 and phosphorylated/total ta

CSF ApoE predicts clinical progression in nondemented APOEε4 carriers

Possible associations between cerebrospinal fluid (CSF) and plasma apolipoprotein E (ApoE) concentration and early clinical and pathophysiological manifestation of Alzheimer's disease were studied in a large and well-defined population of nondemented patients. CSF and plasma ApoE concentrations were related to CSF Aβ42, Tau and pTau levels and clinical characteristics in patients with subjective cognitive decline (n = 207) or mild cognitive impairment (n = 213) aged 64.2 ± 9.0 years, with a 2.5 ± 1.5 years follow-up. A 1 standard deviation increase in log-transformed CSF ApoE concentrations increased the risk of clinical progression in APOEε4 carriers 1.5 times (hazard ratio [95% confidence interval] 1.5 [1.1–2.0]), while this was not the case in APOEε4 noncarriers (hazard ratio [95% confidence interval] 1.0 [0.8–1.2]). Plasma ApoE did not predict clinical progression. Using linear regression models, strong associations between CSF ApoE levels and CSF Tau (β 0.51 [0.38–0.65]) and pTau (β 0.53 [0.40–0.60]) values were observed in APOEε4 carriers. We hypothesize CSF ApoE4 increases risk of clinical progression through its association with CSF Tau in APOEε4 carriers. Development of Alzheimer's disease in APOEε4 noncarriers may be unrelated to ApoE concentration

Pre-amyloid stage of Alzheimer's disease in cognitively normal individuals

Objective: To study risk factors for decreasing aβ1–42 concentrations in cerebrospinal fluid (CSF) in cognitively unimpaired individuals with initially normal amyloid and tau markers, and to investigate whether such aβ1–42 decreases are associated with subsequent decline in cognition and other biomarkers of Alzheimer's disease. Methods: Cognitively normal subjects (n = 83, 75 ± 5 years, 35(42%) female) with normal CSF aβ1–42 and tau and repeated CSF sampling were selected from ADNI. Subject level slopes of aβ1–42 decreases were estimated with mixed models. We tested associations of baseline APP processing markers (BACE1 activity, aβ1–40, aβ1–38 and sAPPβ) and decreasing aβ1–42 levels by including an interaction term between time and APP marker. Associations between decreasing aβ1–42 levels and clinical decline (i.e., progression to mild cognitive impairment or dementia, MMSE, memory functioning) and biological decline (tau, hippocampal volume, glucose processing and amyloid PET) over a time period of 8–10 years were assessed. Results: Aβ1–42 levels decreased annually with −4.6 ± 1 pg/mL. Higher baseline BACE1 activity (β(se) = −0.06(0.03), P < 0.05), aβ1–40 (β(se)= −0.11(.03), P < 0.001), and aβ1–38 levels (β(se) = −0.11(0.03), P < 0.001) predicted faster decreasing aβ1–42. The fastest tertile of decreasing aβ1–42 rates was associated with subsequent pathophysiological processes: 11(14%) subjects developed abnormal amyloid levels after 3 ± 1.7 years, showed increased risk for clinical progression (Hazard Ratio[95CI] = 4.8[1.1–21.0]), decreases in MMSE, glucose metabolism and hippocampal volume, and increased CSF tau and amyloid aggregation on PET (all P < 0.05). Interpretation: Higher APP processing and fast decreasing aβ1–42 could be among the earliest, pre-amyloid, pathological changes in Alzheimer's disease

ApoE and clusterin CSF levels influence associations between APOE genotype and changes in CSF tau, but not CSF Aβ42, levels in non-demented elderly

Apolipoprotein E (APOE) ε4 genotype is associated with increased cerebral amyloid beta (Aβ) deposition in nondemented elderly and suggested to influence ApoE as well as ApoJ (clusterin [Clu]) and ApoA1 expression. We aimed to assess whether APOE affects early Alzheimer's disease pathophysiology via these apolipoproteins. Cerebrospinal fluid (CSF) ApoE, Clu, ApoA1, and CSF amyloid beta1-42 (Aβ42) and tau levels were assessed in 403 individuals with subjective cognitive decline and mild cognitive impairment using enzyme-linked immunosorbent assay. Whether CSF apolipoprotein levels mediated APOEε4 allele frequency effects on CSF Aβ42 and tau in nondemented elderly was investigated using mediation analysis, with age- and gender-adjusted linear regression analyses. CSF ApoE mediated 48% of the association between APOEε4 and CSF tau, whereas Clu and ApoA1 did not. In addition, CSF Clu partially mediated the relation between CSF ApoE and tau (12%). CSF apolipoproteins did not mediate the inverse relation between APOEε4 and CSF Aβ42, despite a strong association between the latter 2 biomarkers. In summary, our findings suggest that ApoE and Clu are involved in Aβ-independent pathways as part of the cascade leading to Alzheimer pathology