Background: Cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers of neurodegenerative diseases are relatively sensitive and specific in highly curated research cohorts, but proper validation for clinical use is mostly missing. Objective: We studied these biomarkers in a novel memory clinic cohort with a variety of different neurodegenerative diseases. Methods: This study consisted of 191 patients with subjective or objective cognitive impairment who underwent neurological, CSF biomarker (A␤ 42 , p-tau, and tau) and T1-weighted MRI examinations at Kuopio University Hospital. We assessed CSF and imaging biomarkers, including structural MRI focused on volumetric and cortical thickness analyses, across groups stratified based on different clinical diagnoses, including Alzheimer's disease (AD), frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease, vascular dementia, and mild cognitive impairment (MCI), and subjects with no evidence of neurodegenerative disease underlying the cognitive symptoms. Imaging biomarkers were also studied by profiling subjects according to the novel amyloid, tau, and, neurodegeneration (AT(N)) classification. Results: Numerous imaging variables differed by clinical diagnosis, including hippocampal, amygdalar and inferior lateral ventricular volumes and entorhinal, lingual, inferior parietal and isthmus cingulate cortical thicknesses, at a false discovery rate (FDR)-corrected threshold for significance (analysis of covariance; p < 0.005). In volumetric comparisons by AT(N) profile, hippocampal volume significantly differed (p < 0.001) between patients with normal AD biomarkers and patients with amyloid pathology. Conclusion: Our analysis suggests that CSF and MRI biomarkers function well also in clinical practice across multiple clinical diagnostic groups in addition to AD, MCI, and cognitively normal groups.

BackgroundIt is demonstrated that the soluble TREM2 in the cerebrospinal fluid (CSF) is associated with Alzheimer disease (AD). Recent studies by our group found that it is the MS4A4A and/or MS4A6A locus that plays a role in modulating sTREM2 and is also associated with AD risk. The goal of this study is to validate and extend findings from previous studies using a larger cohort, identify functional genes, and determine the overlap of the genetic architecture of CSF TREM2 levels with other traits.MethodWe used 3,033 individuals from Knight ADRC, ADNI, DIAN, and PPMI, and 8,499,039 variants (MAF >0.01) to identify protein quantitative trait loci (pQTLs) that modify TREM2 levels via a linear regression including age, sex, first 10 genetic principal components and array/cohort as covariates. TREM2 protein measurements were obtained from SomaScan 7k platform. Colocalization analyses were conducted for AD risk as well as functional genes from eQTLGen. LDSC and GNOVA and Mendelian randomization (MR) is being used to determine the overlap of the genetic architecture of sTREM2 levels with those for AD risk, onset and progression, as well as cardiovascular and lipid traits.ResultThe pQTL analysis identified the previously discovered MS4A gene region on chr11 (rs72918674, P = 7.009e‐58) as well as a peak on chr3 (rs73823326, P = 2.227e‐09). The lead variant resides in the intron of MS4A6A gene. Conditional analysis on this variant revealed rs10897026 as an additional independent signal located in the intron of MS4A4A. Chr11 peak colocalized with AD risk (PP‐H4 = 0.97) and MS4AE and MS4A6A expression QTL in blood (PP‐H4 = 0.97 and 0.96, respectively). Four regulatory region variants are in high linkage disequilibrium (LD) with chr3 index variant. RBMS3 and TGFBR2 are two genes flanking the chr3 peak, both expressed in microglia.ConclusionThis is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. The findings validated discoveries from previous studies and identified a novel signal on chr3 at genome‐wide significance. We propose two new genes, RBMS3 and TGFBR2 on chr3, could be involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD.

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Background:The DnaJ heat shock protein family member C5 (DNAJC5) gene encodes Cysteine String Protein-alpha (CSPα). CSPα is a key endo-lysosomal element of the misfolding-associated protein secretion (MAPS) machinery. MAPS eliminates misfolded cytosolic proteins, including alpha-synuclein, tau, TDP-43, huntingtin. Mutations in the DNAJC5 gene cause rare early-onset dementia called adult-onset Neuronal ceroid lipofuscinosis (ANCL). Data from CSPα-deficient mice and flies suggest that CSPα is critical for preventing age-dependent neurodegeneration. The endolysosome plays an essential role in normal and abnormal Amyloid-beta precursor protein (APP) processing and subsequent β-amyloidogenesis in Alzheimer's disease (AD).However, the role of CSPα in APP processing, trafficking, and amyloidogenesis is not well understood.