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INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α‐synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α‐synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala‐ or olfactory‐predominant LBP, for which CSF α‐synuclein SAA has low sensitivity. Highlights: Cerebrospinal fluid (CSF) real‐time quaking‐induced conversion (RT‐QuIC) detects misfolded α‐synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients.CSF RT‐QuIC does not detect α‐synuclein seeding activity in asymptomatic mutation carriers.Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala‐predominant variants.LBP develops late in the disease course in ADAD.CSF α‐synuclein RT‐QuIC has low sensitivity for focal, low‐burden LBP. [ABSTRACT FROM AUTHOR]

Background: Disease‐modifying therapies for Alzheimer's Disease (AD) are likely most beneficial when initiated in the pre‐symptomatic phase. To track success of such interventions fluid biomarkers became instrumental, with neurofilament light chain (NfL) showing particular promise. We previously reported that serum NfL increases in pre‐symptomatic phases of familial (autosomal‐dominantly inherited) AD (fAD) and that within‐person rate‐of‐change in NfL is an earlier predictor of fAD symptom onset compared to cross‐sectional levels. The aim of the study at hand was to extend these initial findings in a larger cohort. Method: Participants enrolled in the Dominantly Inherited Alzheimer Network (DIAN) with matched cross‐sectional and longitudinal cerebrospinal fluid (CSF; n = 962) as well as plasma (n = 1294) samples were used. NfL measurements have been performed on the SIMOA platform using commercially available assay‐kits. To investigate the influence of physiological factors independent from AD, we first analyzed whether age and body mass index (BMI) could account for observed variation in inter‐individual CSF and plasma NfL levels considering non‐carrier family‐members (NC) as a healthy control group. Next, utilizing estimated years to symptom onset (EYO) and previously published methods (Preische et al., 2019), we determined the point in disease course when baseline and longitudinal CSF and plasma NfL concentrations started to increase in mutation carriers (MC) relative to NC, after adjusting for age and BMI. Result: Our results reveal a tight correlation of CSF and blood NfL values within MC as well as NC (figure 1A‐B). However, within NC, after correction for age and BMI, some unexplained variability remained (figure 1C). Further, a decrease of the NfL plasma/CSF ratio over age was found after correcting for BMI (figure 1D). The discrimination of MC from NC was equally good for plasma compared to CSF, being possible on the group level as early as around ‐15 to almost ‐20 EYO depending on the modelling (figure 2). Conclusion: Our results support plasma equivalently to CSF NfL as a clinically useful biomarker to longitudinally track neurodegeneration in fAD. The systemic factors influencing physiological NfL values in blood should be investigated in future studies to further improve interpretation of this biomarker. [ABSTRACT FROM AUTHOR]

Background: Accuracy of clinical diagnosis in neurodegenerative diseases is critically important for patient care and study recruitment. We aimed to investigate the precision of clinical diagnosis of various neurodegenerative conditions using neuropathological diagnosis for reference. Method: All 1310 autopsy cases between 1993 and 2017 from the Neurobiobank München (Munich, Germany) were screened for neurodegenerative diagnoses. Neuropathological diagnoses that occurred in at least five cases were included in the study. Real world clinical diagnoses were extracted from medical records of admitting hospitals in Germany and correlated with neuropathological diagnoses. Sensitivity, specificity and accuracy (using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis) of clinical diagnoses were calculated. Result: The study included 455 cases with neuropathologically diagnosed Alzheimer's disease (AD, n = 132), argyrophilic grain disease (AGD, n = 6), corticobasal degeneration (CBD, n = 20), frontotemporal lobar degeneration (FTLD, n = 47), Huntington's disease (HD, n = 22), Lewy body disease (LBD, n = 104), motor neuron disease (MND, n = 10), multiple system atrophy (MSA, n = 37) and progressive supranuclear palsy (PSP, n = 77). Clinical diagnoses in these cases comprised AD (n = 136), CBD (n = 17), Creutzfeldt‐Jakob disease (CJD, n = 6), dementia with Lewy bodies (DLB, n = 11), frontotemporal dementia (FTD, n = 44), HD (n = 23), MND (n = 20), MSA (n = 36), Parkinson's disease (PD, n = 92), PSP (n = 60) and vascular dementia (VD, n = 10). Figure 1 illustrates the relationship between clinical (left) and neuropathological diagnoses (right). Figure 2 shows sensitivity, specificity, ROC curves, AUCs including standard errors (SE) and 95% confidence intervals (CI) and p‐values for testing the null hypothesis AUC = 0.5 for clinical diagnoses. Conclusion: Clinical diagnoses of neurodegenerative diseases exhibited a wide span of sensitivity depending on the particular disease (0‐100%) while specificity was high for all clinical diagnoses (89.5‐100%). Accuracy of clinical diagnoses as determined with AUC analysis was very good (AUC>0.9) for HD, MND and MSA, good (AUC = 0.8‐0.9) for AD, DLB/PD and PSP, moderate (AUC = 0.7‐0.8) for FTD, poor (AUC = 0.51‐0.7) for CBD and bad/no discrimination capacity (AUC = 0.5) for AGD. Based on these findings, an increase of sensitivity of clinical diagnoses may be key to improve correct identification of neurodegenerative diseases. This may be possible through development and clinical implementation of molecular biomarkers that are able to indicate the causal proteinopathies of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Accuracy of clinical diagnosis in neurodegenerative diseases is critically important for patient care and study recruitment. We aimed to investigate the precision of clinical diagnosis of various neurodegenerative conditions using neuropathological diagnosis for reference. Method: All 1310 autopsy cases between 1993 and 2017 from the Neurobiobank München (Munich, Germany) were screened for neurodegenerative diagnoses. Neuropathological diagnoses that occurred in at least five cases were included in the study. Real world clinical diagnoses were extracted from medical records of admitting hospitals in Germany and correlated with neuropathological diagnoses. Sensitivity, specificity and accuracy (using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis) of clinical diagnoses were calculated. Result: The study included 455 cases with neuropathologically diagnosed Alzheimer's disease (AD, n = 132), argyrophilic grain disease (AGD, n = 6), corticobasal degeneration (CBD, n = 20), frontotemporal lobar degeneration (FTLD, n = 47), Huntington's disease (HD, n = 22), Lewy body disease (LBD, n = 104), motor neuron disease (MND, n = 10), multiple system atrophy (MSA, n = 37) and progressive supranuclear palsy (PSP, n = 77). Clinical diagnoses in these cases comprised AD (n = 136), CBD (n = 17), Creutzfeldt‐Jakob disease (CJD, n = 6), dementia with Lewy bodies (DLB, n = 11), frontotemporal dementia (FTD, n = 44), HD (n = 23), MND (n = 20), MSA (n = 36), Parkinson's disease (PD, n = 92), PSP (n = 60) and vascular dementia (VD, n = 10). Figure 1 illustrates the relationship between clinical (left) and neuropathological diagnoses (right). Figure 2 shows sensitivity, specificity, ROC curves, AUCs including standard errors (SE) and 95% confidence intervals (CI) and p‐values for testing the null hypothesis AUC = 0.5 for clinical diagnoses. Conclusion: Clinical diagnoses of neurodegenerative diseases exhibited a wide span of sensitivity depending on the particular disease (0‐100%) while specificity was high for all clinical diagnoses (89.5‐100%). Accuracy of clinical diagnoses as determined with AUC analysis was very good (AUC>0.9) for HD, MND and MSA, good (AUC = 0.8‐0.9) for AD, DLB/PD and PSP, moderate (AUC = 0.7‐0.8) for FTD, poor (AUC = 0.51‐0.7) for CBD and bad/no discrimination capacity (AUC = 0.5) for AGD. Based on these findings, an increase of sensitivity of clinical diagnoses may be key to improve correct identification of neurodegenerative diseases. This may be possible through development and clinical implementation of molecular biomarkers that are able to indicate the causal proteinopathies of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Comparisons of late‐onset Alzheimer's disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age. Methods: We compared biomarkers from cerebrospinal fluid (CSF), magnetic resonance imaging, and amyloid imaging with Pittsburgh Compound‐B (PiB) across four groups of 387 cognitively normal participants, 42 to 65 years of age, in the Dominantly Inherited Alzheimer Network (DIAN) and the Adult Children Study (ACS) of LOAD: DIAN mutation carriers (MCs) and non‐carriers (NON‐MCs), and ACS participants with a positive (FH+) and negative (FH–) family history of LOAD. Results: At baseline, MCs had the lowest age‐adjusted level of CSF Aβ42 and the highest levels of total and phosphorylated tau‐181, and PiB uptake. Longitudinally, MC had similar increase in PiB uptake to FH+, but drastically faster decline in hippocampal volume than others, and was the only group showing cognitive decline. Discussion: Preclinical ADAD and LOAD share many biomarker signatures, but cross‐sectional and longitudinal differences may exist. [ABSTRACT FROM AUTHOR]

Introduction: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. Methods: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. Results: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross‐sectionally, mutation carriers with AD neurological examination findings showed a more than two‐fold faster cognitive decline and had greater parieto‐temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. Discussion: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs. [ABSTRACT FROM AUTHOR]

Objective: The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia. Background: An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease‐modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits. Updated Hypothesis: It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid‐only and pre‐amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti‐Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease‐modifying Aβ therapies. Major Challenges for the Hypothesis: Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common "sporadic" late‐onset AD. Linkage to Other Major Theories: The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co‐pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about effects of physical activity (PA) in genetically driven early‐onset autosomal dominant Alzheimer's disease (AD). Methods: A total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross‐sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations. Results: Mutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD‐like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers. Discussion: These results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD. [ABSTRACT FROM AUTHOR]

Introduction The objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers. Methods In 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self-reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ 42, and CSF tau levels was evaluated using linear regression. Results No differences in brain amyloid load, CSF Aβ 42 , or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels. Discussion Our findings indicate a relationship exists between self-reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers. [ABSTRACT FROM AUTHOR]

Background: Lewy body pathology (LBP) occurs in a substantial portion of individuals with autosomal dominant (ADAD) and sporadic Alzheimer disease (sAD) (Ringman, 2016; Cairns, 2015; Leverenz, 2007; Lippa, 1998). Whereas other non‐AD pathologies are frequent in sAD, LBP seems to be the most common co‐pathology in the relatively young ADAD population (Cairns, 2015). Knowledge of clinical and genetic characteristics of LBP in both ADAD and sAD is incomplete. Method: Data from the National Alzheimer's Coordinating Center, the Dominantly Inherited Alzheimer Network, the Queen Square Brain Bank at University College London and the Neurobiobank Munich were leveraged to compare individuals with ADAD and neuropathologically diagnosed sAD with and without LBP. Chi‐squared and Student's t‐test were used for comparison of categorical and continuous variables respectively. Result: The study included 139 ADAD and 4661 sAD autopsy cases. LBP occurred in 59% of ADAD and 38% of sAD cases. LBP was associated with a longer survival in both ADAD (10.1 vs. 8.6 years, p=0.024) and sAD (10.5 vs. 10.2 years, p=0.016). Memory disturbance occurred more frequently as the first clinical AD symptom in both AD variants when LBP was present (ADAD: 90 vs. 65%, p=0.005; sAD: 78 vs. 71%, p<0.001). In both ADAD and sAD, the presence of at least one APOE e4 allele was more common in individuals with LBP (ADAD: 40 vs. 21%, p=0.047; sAD: 57 vs. 46%, p<0.001). In ADAD, frequency of LBP did not differ between individuals with PSEN1 and APP mutations. Conclusion: In this investigation of 139 ADAD and 4661 sAD autopsy cases, LBP occurred in about 60% with ADAD and 40% with sAD. In both ADAD and sAD, the presence of LBP was associated with longer survival, higher frequency of memory disturbance as the first AD symptom and positive APOE e4 status. Further study of these associations may increase our understanding of the role of LBP in AD. [ABSTRACT FROM AUTHOR]

Background: In the neurodegenerative conditions Alzheimer disease (AD), Lewy body disease (LBD) including the neuropathologically indistinguishable Parkinson disease and dementia with Lewy bodies, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) figures for seizure risk are inconsistent, rare or lacking. This is particular true if neuropathologically confirmed diagnoses are stipulated. Therefore, our goal was to determine the lifetime risk for epileptic seizures and to investigate associated clinical parameters in neuropathologically diagnosed neurodegenerative diseases. Method: Cases from the Neurobiobank Munich, Germany, were matched with information from clinical files regarding the occurrence of epileptic seizures. The aforementioned diseases were compared for lifetime seizure risk. The predictive value of the first clinical symptom regarding lifetime risk for seizures was analyzed and associations between the occurrence of seizures and survival was investigated. Result: We analyzed 454 neuropathologically diagnosed cases with sufficient clinical data available. 144 had AD, 103 LBD, 93 PSP, 53 FTLD, 36 MSA, and 25 CBD. Lifetime risk for epileptic seizures was 31.3% in AD, 20.0% in CBD, 12.6% in LBD, 11.3% in FTLD, 8.3% in MSA and 7.5% in PSP. Patients with AD had a statistically significantly higher lifetime risk for seizures compared to patients with FTLD (p=0.005), LBD (p=0.001), MSA (p=0.005) and PSP (p<0.001). An increased lifetime seizure risk was found in patients with cognitive first symptoms when compared to those with non‐cognitive first symptoms (21.1% vs. 11.0%). A decreases lifetime risk for seizures was observed in cases with motor first symptoms when compared to those with non‐motor first symptoms (10.3% vs. 20.5%). MSA patients with seizures survived longer when compared to those without (12.3 vs. 7.0 years; p = 0.017). Conclusion: In this clinical neuropathological correlation study, nearly every third AD patient and approximately every fifth patient with a neurodegenerative disease experienced epileptic seizures in the disease course. Therefore, epileptic seizures are an important comorbidity in neurodegenerative conditions, in particular in AD. Assessment of the first clinical symptom may improve early estimation of the lifetime seizure risk in the studied neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: The novel PSEN1single amino acid deletion mutation F175del causes autosomal dominant Alzheimer disease (ADAD) in the late thirties. In vitroF175del features an unusual pattern of APP fragments including an increased production of Aβ39. This Aβ species was found particularly in brain vessels and therefore may contribute to the development of cerebral amyloid angiopathy (CAA). Method: Neuropathological examination was performed in a patient with ADAD caused by PSEN1F175del who died at the age of 45 years. Clinical, neuropsychological, genetic and biomarker findings in this patient as well effects of the PSEN1deletion mutation on Aβ processing were described before (Vöglein et al, Neurobiology of Aging, 2019). Result: Copious cored/compact and diffuse Aβ plaques were found in the cerebral cortex. Interestingly, there were plentiful streaky and several cored/compact and diffuse Aβ plaques also in the cerebellum. A large number of cortical neuropil threads and neurons with fibrillary cytoplasmatic tau aggregates as well as several neuritic plaques were detected (ABC score: A3/B3/C3). CAA with Aβ depositions in the leptomeningeal and cortical vessel walls was detected (Thal phase 2). Furthermore, several Lewy bodies and Lewy neurites were found in the cerebral cortex (Braak stage 6). Conclusion: The neuropathological hallmarks of AD, Aβ plaques and neurofibrillary degeneration, were present in PSEN1 F175del associated ADAD. CAA was found that could be in causal connection with the enhanced Aβ 39 generation caused by the mutation as shown in cell culture. Further, an unusually high cerebellar Aβ burden was detected. In summary, we provide neuropathological characteristics of ADAD caused by PSEN1 F175del and potentially unveiled an effect of an altered Aβ processing that was shown in vitro on brain pathology. [ABSTRACT FROM AUTHOR]