Abstract Objective Regression-based normative approaches are widely used in neuropsychology but often rely on score transformations to satisfy model assumptions. We compared previously published linear regression (LR)-based norms with norms derived using Generalized Additive Models for Location, Scale and Shape (GAMLSS) for the brief cognitive battery used in the Norwegian Dementia Disease Initiation (DDI) cohort. Method GAMLSS norms were developed using the same normative samples as the original LR norms for the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) word list test, Trail Making Test (TMT) A and B, FAS phonemic fluency, and Visual Object and Space Perception Battery (VOSP) Silhouettes. Expected low-score frequencies and empirical base rates were assessed in a normative subsample (n = 131). Clinical implications were evaluated in the DDI clinical cohort (n = 643) using Mild Cognitive Impairment (MCI) classification, two-year diagnostic stability and change, and cerebrospinal fluid (CSF) biomarkers. Results Compared with LR norms, GAMLSS yielded lower frequencies of low scores, primarily driven by CERAD delayed recall. Nevertheless, concordance between approaches was high (κ = 0.91), with only 4.2% discordant classifications. Two-year diagnostic stability and change were broadly similar across approaches, and CSF biomarker profiles did not clearly favor either normative method. Conclusions GAMLSS provided a more faithful representation of neuropsychological score distributions, particularly for bounded and non-normal outcomes. However, downstream clinical differences were modest in this setting, suggesting that well-calibrated LR norms may remain robust for clinical classification.

INTRODUCTION:Alzheimer's disease (AD) is a neurodegenerative disorder influenced by genetic factors, particularly related to immune activation. This study examines genotype-phenotype interactions affecting immune responses in AD as a reaction to neurodegeneration. METHODS:We computed AD polygenic risk scores (PRSs) informed by shared AD-autoimmunity genetics (AD PRSINFL), AD-independent immune activation score from 10 autoimmune diseases (sum PRSIMMUNE), and standard AD PRSs for 294 individuals. Cerebrospinal fluid (CSF) immune markers (sTREM2, clusterin, fractalkine, and chitinase 3 like protein (YKL-40)) were regressed on PRSs, and their interaction with neurodegeneration markers (total tau [t-tau] or neurofilament light chain [NfL]). RESULTS:High AD PRSINFL scores correlated with lower sTREM2 (β = -0.18, p < 0.01), clusterin (β = -0.12, p < 0.05), and fractalkine (β = -0.13, p < 0.05) levels in cases with elevated t-tau. High sum PRSIMMUNE score correlated with lower clusterin in cases with elevated NfL (β = -0.12, p < 0.05). DISCUSSION:Genetic predisposition for immune activation might cause unfavorable immune response in early AD. HIGHLIGHTS:High genetic risk relates to cerebrospinal fluid (CSF) immune markers amid evident neurodegeneration Immune polygenic risk scores (PRSs) capture genotype-phenotype associations in Alzheimer's disease (AD) immune activation AD PRSs and immune phenotype had an opposite relationship of the phenotype PRSs Importance of specific genetic predispositions in early AD immune phenotypes.

BACKGROUND AND OBJECTIVES:Aligning biomarker evidence with clinical presentation in early Alzheimer disease (AD) is essential for improving diagnosis, prognosis, and interventions. This study evaluates the relationship between cognitive impairment, future decline, and phosphorylated tau levels in plasma and CSF in predementia AD. METHODS:This longitudinal observational study included predementia cases and controls from 2 independent cohorts: the Norwegian Dementia Disease Initiation (DDI) and Canadian Pre-Symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD). In DDI, cognitively normal (CN) and mild cognitive impairment (MCI) cases were classified using CSF Aβ42/40 ratio (A) and p-tau181 (T), whereas classification in PREVENT-AD (A) was based on amyloid PET scans. In DDI, we assessed CSF-plasma correlations for p-tau181, p-tau217, and p-tau231. Diagnostic accuracies were evaluated through receiver operating characteristic analyses. Linear mixed models evaluated p-tau associations with future memory decline. Between-group differences in plasma p-tau217 were assessed in both cohorts. RESULTS:In DDI (n = 431), participants were classified as CN A-/T- (n = 169), A+/T- (CN = 26, MCI = 24), A+/T+ (CN = 40, MCI = 105), and A-/T+ (CN = 34, MCI = 33), with a mean age of 64.1 years and 55.9% female. In PREVENT-AD (n = 190), participants were categorized as CN A- (n = 118), CN A+ (n = 49), and MCI A+ (n = 21), with a mean age of 67.8 years and 72.6% female. In DDI, plasma p-tau217 showed high accuracy in identifying A+ participants (areas under the curve [AUC]: 0.85) and a moderate correlation with CSF p-tau217 (rho = 0.65, p < 0.001). Diagnostic accuracy of plasma p-tau217 was greater in MCI A+ (AUC: 0.89) than in CN A+ (AUC: 0.79, p < 0.05) and in A+/T+ (AUC: 0.88) vs A+/T- (AUC: 0.78, p < 0.05). p-Tau181 and p-tau231 had weaker CSF-plasma correlations (rho = 0.47 and rho = 0.32, p < 0.001) and were less associated with cognitive status in A+ individuals. Higher plasma p-tau217 in A+ MCI vs A+ CN individuals (p < 0.001) was confirmed in PREVENT-AD. All CSF p-tau markers, but only plasma p-tau217, were associated with future memory decline (β = 0.05, p < 0.05). DISCUSSION:Our findings suggest that, unlike p-tau181 and p-tau231, plasma p-tau217 consistently aligns with cognitive status in A+ individuals and better reflects CSF biomarker abnormalities, reducing discrepancies between clinical and biochemical findings. Its association with baseline and future memory decline highlights its diagnostic and prognostic value, particularly when CSF analysis or PET is unavailable.

INTRODUCTION:Heterogeneity of clinical progression in Alzheimer's disease (AD) complicates the assessment of disease progression and treatment effects in trials. This study evaluates the potential of plasma phosphorylated tau-217 (p-tau217) to capture this heterogeneity. METHODS:We used k-means clustering to analyze cognitive trajectories in amyloid beta -positive (Aβ+) cognitively normal (CN) and mild cognitive impairment (MCI) participants from two independent cohorts. Cohort 1 included 186 participants (71 CN, 115 MCI; 507 observations) and Cohort 2 included 207 participants (64 CN, 144 MCI; 781 observations), both with up to 10 years of follow-up. RESULTS:Three progression clusters emerged in both cohorts: stable cognition, slow decline, and rapid decline-each including cases initially classified as CN or MCI. Baseline plasma p-tau217 was linked to progression risk in both cohorts, whereas longitudinal increases in Cohort 1 were steepest in rapid decliners. DISCUSSION:Plasma p-tau217 may aid in capturing clinical heterogeneity and support stratification and monitoring of disease progression in clinical trials. HIGHLIGHTS:k-Means found stable, slow, and rapid cognitive decline clusters in amyloid beta-positive (Aβ+) cases. Higher baseline plasma phosphorylated tau-217 (p-tau217) levels predicted faster cognitive decline. Longitudinal increases in plasma p-tau217 were steepest in rapid decliners. Plasma p-tau217 tracks clinical progression heterogeneity in Aβ+ cases. Cognitive stage and amyloid alone may miss severity and risk in early-stage Alzheimer's disease.

Females have an increased risk of developing Alzheimer’s disease (AD). The innate immune system plays a key role in AD pathology, and sex differences in innate immune responses may contribute to differences in disease risk and progression. This study investigated sex differences in innate immune responses among participants without cerebrospinal fluid (CSF) determined amyloid pathology [A–; cognitively normal (CN), n = 83] and those with amyloid pathology (A+, n = 202), further stratified into preclinical (CN with A+, n = 72) and mild cognitive impairment (MCI with A+, n = 130). Participants were drawn from the Norwegian Dementia Disease Initiation cohort (n = 285). We measured plasma glial fibrillary acidic protein (GFAP) and CSF concentrations of nine innate immune markers: soluble triggering receptor expressed on myeloid cells 2 (sTREM2), monocyte chemoattractant protein 1 (MCP-1), fractalkine, chitinase 3-like 1 (YKL-40), clusterin, interferon gamma (IFN-γ), interleukin-6 (IL-6), IL-10, and IL-18. Linear regression was used, adjusted for multiple comparisons using the false discovery rate. In A+ cases (n = 202, females = 105), females had lower MCP-1 (P < 0.01), IL-6 and IL-18 (both P < 0.05) than males, while no sex differences were observed in A– cases (n = 83, females = 39). Among A+ participants, no sex differences were observed in CN cases (n = 72, females = 37), but females (n = 68) with MCI had lower MCP-1 and IL-6 (both P < 0.05) than males (n = 62) with MCI. Moreover, A+ females exhibited stronger positive associations between sTREM2 and clusterin with CSF total tau (P < 0.001; P < 0.05) and Neurofilament light chain (P < 0.01; P < 0.01) than males. These findings suggest sex-specific differences in innate immune responses, which may contribute to disease progression in amyloid-positive individuals.

The Delis Kaplan Executive Functions system (D-KEFS) Color-Word Interference Test (CWIT) is a neuropsychological test of executive function. The CWIT, an expanded version of the Stroop test, includes contrast measures created by subtracting lower-level conditions from higher-level conditions. These measures do not have available Norwegian norms and have been criticized for their low reliability. For this reason, we present normative data for regression-based derived measures based on a large sample of healthy Norwegians aged 20-85 years and compare the regression measures to conventional contrast measures. The study sample comprised 1011 healthy participants between ages 20 and 85, pooled from three cohorts: the Dementia Disease Initiation cohort (DDI), the Oslo MCI cohort, and the Lifespan Changes in Brain and Cognition cohort (LCBC). Multiple regression analyses were used to model the effects of the lower-level reading or naming conditions on higher-level inhibition or inhibition/switching conditions. Conventional contrasts and regression-based derived measures were assessed for residual effects of demographics and lower-level CWIT conditions. Stability over time was examined in a sub-sample with available follow-up data. Conventional contrasts showed residual effects of demographics and basic functions. Analyses of stability over time showed ICCs in the poor to moderate range (range = 0.39-0.56) for conventional contrasts and somewhat higher estimates for the regression measures (range = 0.50-0.65). As such, the regression-based derived measures adequately adjust for demographics and lower-level conditions and show better stability over time compared to conventional D-KEFS contrast measures. To fully understand the clinical applicability of regression-based derived measures, future work should include clinical samples.

Synapse loss is linked to cognitive symptoms in Alzheimer’s Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets. We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) (n = 346) and Amsterdam Dementia Cohort (n = 397), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins. In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p < 0.001) were found between 14-3-3 protein genes (YWHAZ, YWHAE) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway (p < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts. Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.

Clinically, Alzheimer's disease (AD) is characterized by progressive cognitive decline due to neuronal and synaptic degeneration. Neurofilament light chain (NfL) and total tau (T-tau) reflect neurodegeneration, NfL putatively more related to white and T-tau to grey matter. This study examines how cerebrospinal fluid (CSF) neurodegeneration markers (T-tau, NfL or both) are correlated with synaptic markers and clinical progression. We included 331 individuals with (n = 212) and without (n = 119) pathological CSF Aβ42/40 ratios. Associations between CSF NfL, T-tau, and the synaptic biomarkers neurogranin and BACE1 were assessed using Pearson's correlation. Group differences in synaptic marker levels were evaluated using linear regression comparing individuals with isolated pathological T-tau, NfL, or both, versus biomarker-negative individuals. Clinical progression to MCI or dementia was assessed using a Cox proportional hazards model (n = 257; mean follow-up = 3.75 years). Linear regression and Cox proportional hazards models included age, sex, and dichotomized APOE-ε4 carriership as covariates. T-tau had a stronger correlation with neurogranin(r = 0.84) and BACE1(r = 0.73) than NfL(r = 0.51 and 0.48; p < 0.001). Group-wise comparisons confirmed this, showing that only individuals with pathological T-tau-alone or with NfL-had significantly higher synaptic marker levels (p < 0.001). Only the combination of pathological T-tau and NfL was associated with a significantly increased risk of clinical progression(HR=6.79; p < 0.001). These findings suggest that T-tau is more closely related to early synaptic dysfunction in AD than NfL. The combined elevation of both biomarkers, linked to greater clinical decline, supports a dual contribution of grey- and white matter degeneration to disease progression.

BACKGROUND:Alzheimer's disease (AD) pathology may be present in cognitively unimpaired individuals, but the clinical implications of this are unclear. Subtle cognitive decline is a potential marker of preclinical AD. OBJECTIVE:To investigate whether two-year cognitive change scores are influenced by AD-linked cerebrospinal fluid (Aβ42/40, p-tau, t-tau, NfL) or plasma (p217, BD-tau, NfL) biomarker pathology in individuals who are cognitively unimpaired at baseline. METHODS:Participants were 148 cognitively unimpaired older adults (mean age = 68.11). Mean cognitive change over two years was compared between participants with normal and pathological biomarker status, for each biomarker separately. RESULTS:We found no significant difference between mean change scores in people with abnormal biomarker values compared to normal biomarker groups. CONCLUSION:Regardless of baseline CSF biomarker positivity, no significant cognitive change was observed in this group.

ABSTRACT INTRODUCTION: Depressive symptoms are associated with Alzheimer’s disease (AD), but their neurobiological and neuropsychological correlates remain poorly understood. We investigate if depressive symptoms are associated with amyloid (Aβ) pathology and cognition in predementia AD. METHODS: We included Subjective Cognitive Decline (SCD, n= 160) and Mild Cognitive Impairment (MCI, n=192) from the Dementia Disease Initiation cohort. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS-15). Aβ pathology was determined using cerebrospinal fluid (CSF) Aβ42/40 ratio. Associations between depressive symptoms and cognition were assessed with logistic regression. RESULTS: Only the Aβ negative MCI group (MCI-Aβ-) was associated with depressive symptoms (OR=2.65, p=.005). Depressive symptoms were associated with worse memory in MCI-Aβ- (OR=0.94, p=.039), but with better performance in MCI-Aβ+ (OR=1.103, p=.001). DISCUSSION: Our results suggest that depressive symptoms in MCI are neither associated with Aβ pathology, nor AD-associated memory impairment. However, memory impairment in non-AD MCI may relate to depressive symptoms.

Importance: Detecting early Alzheimers disease (AD) biological and clinical changes is crucial for early diagnostic and therapeutic interventions. Objective: To explore the associations between plasma p-tau biomarkers, cognitive- and biological profiles in predementia AD. Design, Setting, and Participants: In this study (n=619), we examined two independent cohorts consisting of preclinical and prodromal AD. Cohort-1 included 431 participants classified as either cognitively normal (CN) or mild cognitive impaired (MCI) with normal or abnormal cerebrospinal fluid (CSF) AB42/40 ratio (A) and p-tau181 (T) [CN A-/T-, n=169; A+/T-, CN=26; MCI=24; A+/T+, CN=40; MCI=105; CN=34; MCI=33]. A total of n=418 of the participants had longitudinal assessments of verbal memory up to 9.67 years from baseline. Cohort-2 included 190 participants in whom amyloid status was determined using AB positron emission tomography (PET) [AB- CN= 118; AB+ CN= 49; AB+ MCI= 21]. Exposure: CSF and plasma p-tau181, p-tau217 and p-tau231. Main Outcomes and Results: In cohort-1, plasma p-tau217 showed a moderate correlation with its corresponding CSF biomarker (rho=0.65, p<.001) and high accuracy identifying AB+ participants (AUC: 0.85). Diagnostic accuracy of plasma p-tau217 was significantly greater for MCI AB+ (AUC: 0.89) versus CN AB+ (AUC: 0.79, p<.05) and for A+/T+ (AUC: 0.88) versus A+/T- (AUC: 0.78, p<.05). P-tau181 and p-tau231 showed significantly weaker CSF-plasma correlations (rho= 0.47, and rho=0.32, p<.001, respectively) and levels were not as tightly associated with cognitive status in the AB+ group. Moreover, p-tau217 was the only plasma marker that associated with future memory decline (B=0.05, p<0.05). Additionally, plasma p-tau217 had the weakest correlation with glomerular filtration rate (rho=-14, p<.05), followed by p-tau181 (rho=-17, p<.01) and p-tau231 (rho=-22, p<.001). In cohort 1 and 2, plasma p-tau217 showed significantly higher concentrations in MCI AB+ as compared to CN AB+. Furthermore, plasma p-tau217 demonstrates similar biomarker elevations when compared to CN AB- controls in both cohorts. Conclusions: Our findings show that, unlike p-tau181 and p-tau231, plasma p-tau217 aligns consistently with cognitive status in AB+ individuals, potentially reducing disagreements between clinical and biochemical findings. Plasma p-tau217 associations with baseline and future cognitive decline make it a valuable complement to clinical evaluation in preclinical and prodromal AD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Authors funding information is provided in the manuscript ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized aggregated level data will be shared by request from a qualified academic investigator for the sole purpose of replicating procedures and results presented in the article, and as long as data transfer is in agreement with EU legislation on the general data protection regulation and decisions by the Ethical Review Boards in charge of each of the cohorts used for this study.

AbstractStaging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer’s disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ (“A”) and neurodegeneration (“N”) abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.

Cerebrospinal fluid total-tau (t-tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer’s disease (AD). In order to adjust for age-related increases in t-tau and NfL, cross-sectional age-adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41-78 years (CN, n=137). The age-adjusted norms for t-tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD-MCI, n=144). Furthermore, while NfL was correlated with higher age in AD-MCI, no significant correlation was found for t-tau. The cox proportional hazard models, applied in 429 participants with baseline t-tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age-adjustments (HR=3.39 for t-tau and HR=3.17 for NfL), as compared to using our norms (HR=2.29 for t-tau and HR=1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age-related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy.

Objective: The Delis-Kaplan Executive Function System (D-KEFS) Color-Word-Interference Test (CWIT; AKA Stroop test) is a widely used measure of processing speed and executive function. While test materials and instructions have been translated to Norwegian, only American age-adjusted norms from D-KEFS are available in Norway. We here develop norms in a sample of 1011 Norwegians between 20 and 85 years. We provide indexes for stability over time and assess demographic adjustments applying the D-KEFS norms. Method: Participants were healthy Norwegian adults from Center for Lifespan Changes in Brain and Cognition (LCBC) (n = 899), the Dementia Disease Initiation (n = 77), and Oslo MCI (n = 35). Using regression-based norming, we estimated linear and non-linear effects of age, education, and sex on the CWIT 1-4 subtests. Stability over time was assessed with intraclass correlation coefficients (ICC). The normative adjustment of the D-KEFS norms was assessed with linear regression models. Results: Increasing age was associated with slower completion on all CWIT subtests in a non-linear fashion (accelerated lowering of performance with older age). Women performed better on CWIT-1&3. Higher education predicted faster completion time on CWIT-3&4. The original age-adjusted norms from D-KEFS did not adjust for sex or education. Furthermore, we observed significant, albeit small effects of age on all CWIT subtests. ICC analyses indicated moderate to good stability over time. Conclusion: We present demographically adjusted regression-based norms and stability indexes for the D-KEFS CWIT subtests. US D-KEFS norms may be inaccurate for Norwegians with high or low educational attainment, especially women.

Background Brain innate immune activation is associated with Alzheimer’s disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles. Methods We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline ( n = 535) and follow-up ( n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aβ42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A−/T−/N−, A+/T−/N−, A+/T+ or N+, or A−/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group. Results Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis ( p < 0.001, A+/T+ or N+ and A−/T+ or N+, compared to A−/T−/N−). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T−/N− cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine ( p < 0.001) and MCP-1 ( p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile ( p < 0.01). Conclusions Immune hypoactivation and reduced neuron–microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.

The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer's disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer's disease pathology. Linear regression was used to assess the influence of CSF determined A & beta;-plaque (A & beta;-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between A & beta;-/A & beta;+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both A & beta;+ compared to A & beta;- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between A & beta;- vs. A & beta;+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.

Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer's disease continuum and controlled with normal markers (A-/T-/N-, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n = 12), from A+/T-/N- to A+/T or N+ (n = 12), remained stable A+/T-/N- (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A-/T-/N- (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T-/N- (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = -0.29, P = 0.0006) than neurogranin (b = -0.20, P = 0.002) and BACE1 (b = -0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer's disease subgroups, putatively with different options for treatment.

OBJECTIVE:We aim to develop 2-year cognitive change norms for adults ages 41-84 for six cognitive tests, and to evaluate these norms in groups with AD biomarkers. BACKGROUND:Practice effects are common in repeated neuropsychological testing. Not accounting for practice effects may obscure cognitive decline in early Alzheimer's disease (AD). METHOD:We developed standardized regression-based change norms from normative samples consisting of healthy controls from the Dementia Disease Initiation study (n = 125), the Trønderbrain study (n = 57), and the Gothenburg mild cognitive impairment (MCI) study (n = 65). Norms were applied in a sample with cognitive symptoms (subjective cognitive decline or MCI) and AD cerebrospinal fluid (CSF) biomarkers (n = 246), classified according to the A/T/N system. RESULTS:The change norms adjusted for pertinent demographics and practice effects. The group with cognitive complaints displayed a trend toward cognitive decline compared to the normative group, with the A +T/N + subgroup showing the most marked decline. This was observed in tests of episodic memory and cognitive flexibility/divided attention. CONCLUSIONS:We present 2-year cognitive change norms for adults between 41 and 84 years, adjusted for practice and demographics. A web-based change norm calculator is provided. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Importance:Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear. Objectives:To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden. Design, Setting, and Participants:This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-β 42 (Aβ42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022. Main Outcomes and Measures:Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels. Results:A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; β = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; β = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aβ42 burden (β = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: β = -0.884; 95% CI, 0.223 to -0.395; P < .001; CSF phosphorylated tau levels: β = -0.672; 95% CI, -1.022 to -0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001). Conclusions and Relevance:The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.

ABSTRACT Research in Parkinson’s or Alzheimer’s disease suggests that hand function is affected by neurodegenerative diseases. However, little is known about the relationship between hand function and mild cognitive impairment (MCI). Therefore, we conducted a kinematic analysis of unimanual hand movements in MCI patients to answer whether manual asymmetries and manual dexterity are affected or preserved in this condition. Forty-one MCI patients and fifty healthy controls were tested with the Purdue Pegboard test. All participants were right-handed. Kinematic analyses (by hand) were calculated for path length, angle, and linear and angular velocities during reaching, grasping, transport and inserting. Group differences were tested by with factorial MANOVAs and laterality indexes (LI) were assessed. Groups were compared on “Right–Left” hand correlations to identify kinematics that best single-out patients. Kinematics from grasping and inserting were significantly more deteriorated in the MCI group, while outcomes for reaching and transport denoted superior performance. LIs data showed symmetry of movements in the MCI group, during reaching and transport. Comparisons of “Right–Left” hand correlations revealed that kinematics in reaching and transport were more symmetrical in patients. This study showed a deterioration of fine manual dexterity, an enhancement in gross dexterity of upper-limbs, and symmetrical movements in MCI patients.