CSF Biomarker Levels Research Articles

Alzheimer's disease with normal CSF biomarkers.

Background/objectives: Alzheimer’s disease (AD) is currently diagnosed clinically using defined symptomatic diagnostic criteria. Pathological levels of CSF-biomarkers, high T-tau, P-tau and low Ab42 have been associated with AD however definition of cut off values differ. New diagnostic criteria that include the pathological CSF biomarkers have been suggested. How many AD patients in a routine clinical population have normal levels of the CSF biomarkers as defined by clinically defined cut-offs? Methods: Out-patients (n=151) with the clinical diagnosis of dementia as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV) and probable or possible AD, according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and related Disorders Association (NINCDS-ADRDA, 1984), were included in this study. The number of symptoms according to these criteria and the levels of the CSF biomarkers Aβ42, T-tau and P-tau were evaluated at baseline. The patients received cholinesterase inhibitor (ChEI) treatment and were assessed with cognitive tests (MMSE, ADAS-cog) longitudinally for up to three years. Short-term ChEI-response was measured as cognitive change after 2 and 6 months of treatment. Long-term outcome was expressed as MMSE and ADAS-cog change per month. Pathological levels of CSF biomarkers were defined as in clinical routine; T-tau > 450 ng/l, P-tau > 60 ng/l and aβ42 < 400 ng/l. Results: In 15 % of the patients all three CSF biomarkers were normal. At baseline these patients had fewer symptoms (NINCDS-ADRDA), higher MMSE score, but then displayed the same rate of longitudinal cognitive decline as patients with pathological biomarkers. Furthermore, patients with normal CSF biomarkers did not differ in age of onset, duration of disease, IADL or ADAS-cog at baseline, completion rate or short-term response to treatment compared to those with pathological CSF biomarkers. Conclusion: Alzheimer’s disease with normal CSF displays the same cognitive short-term response to ChEI-treatment and clinical long-term outcome as patients with pathological CSF. These findings must be considered when defining future diagnostic criteria for AD. (Less)

Predicting MCI outcome with clinically available MRI and CSF biomarkers

To determine the ability of clinically available volumetric MRI (vMRI) and CSF biomarkers, alone or in combination with a quantitative learning measure, to predict conversion to Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). We stratified 192 MCI participants into positive and negative risk groups on the basis of 1) degree of learning impairment on the Rey Auditory Verbal Learning Test; 2) medial temporal atrophy, quantified from Food and Drug Administration-approved software for automated vMRI analysis; and 3) CSF biomarker levels(.) We also stratified participants based on combinations of risk factors. We computed Cox proportional hazards models, controlling for age, to assess 3-year risk of converting to AD as a function of risk group and used Kaplan-Meier analyses to determine median survival times. When risk factors were examined separately, individuals testing positive showed significantly higher risk of converting to AD than individuals testing negative (hazard ratios [HR] 1.8-4.1). The joint presence of any 2 risk factors substantially increased risk, with the combination of greater learning impairment and increased atrophy associated with highest risk (HR 29.0): 85% of patients with both risk factors converted to AD within 3 years, vs 5% of those with neither. The presence of medial temporal atrophy was associated with shortest median dementia-free survival (15 months). Incorporating quantitative assessment of learning ability along with vMRI or CSF biomarkers in the clinical workup of MCI can provide critical information on risk of imminent conversion to AD.

CSF biomarker levels in early and classic onset of Alzheimer's disease

To compare CSF levels of beta-amyloid 1-42(Abeta(1-42)), total tau (Tau) and tau phosphorylated at threonine 181 (pTau-181) between AD patients with different age of onset and controls. Eighty eight AD patients (mean age and SD, 74.29 ± 5.41) with classic onset of the disease (365 years), 35AD patients (mean age and SD, 54.66 ± 5.38) with early onset 50 control subjects (mean age and SD, 70.15 plus or minus 11.10) underwent lumbar puncture. The Innotest ELISA sandwich test (Innogenetics-Belgium) was used for measuring the levels of Tau, pTau-181 and Abeta (1-42). All three biomarkers showed main effects of the diagnosis. When series of ANCOVAs with age as covariate were performed, the significant difference still exists. There were no differences between AD patients with early and classic onset of the disease in the levels of a) Abeta (1-42) 449 ± 209 versus 460 ± 206 pg/ml; b) Tau 697 ± 603 versus 549 ± 298 pg/ml; c) pTau-181 130 ± 88 versus 131 ± 73 pg/ml). The CSF biomarkers may be supportive in the diagnosis of AD in routine clinical practice considering the approaching new target therapeutics.

Cerebrospinal fluid and serum autoantibodies against neurocytoskeletal proteins in patients with Alzheimer's disease

states. The optimalprocess of clinical assessmentmay includemultiple technologies such as neuropsychological assessment, neuroimaging, and fluid biomarker analysis, each used at appropriate time points in a staged diagnostic pathway. EDAR is a Europe-wide prospective longitudinal study assessing the potential for CSF and other biomarkers, including cognition, in the early diagnosis of AD. Methods: Patients with mild cognitive impairment, AD and other dementias and healthy elderly controls (total n 1⁄4 144) were recruited from seven centres across Europe. Memory, attention and executive functions were assessed using the Cambridge Neuropsychological Test Battery (CANTAB). Cerebrospinal fluid was obtained on a single occasion and assayed using Luminex for As1-42, total tau and hyperphosphorylated tau. Results: Lower CSF As1-42 levels were associated with poorer performance on CANTAB paired associates learning (rho1⁄4 -.3, p< .001) and spatial working memory (rho1⁄4-.3, p1⁄4 .002) tests, andwith slower (rho1⁄4-.3, p1⁄4 .001) andmore variable (rho1⁄4-.4, p< .001) choice reaction time. The tau:As1-42 ratiowas lower in individuals with better episodic memory and less variable choice reaction time (both rho 1⁄4 .2, p 1⁄4 .01). High P-tau181P levels were associated with faster simple reaction time (rho 1⁄4 -.3, p 1⁄4 .001). CSF biomarker levels appeared unrelated to scores on tests of semantic memory and executive function. Associations between cognitive and CSF biomarkers differed between diagnostic groups. Conclusions: Among healthy and impaired elderly individuals, scores on computerised cognitive tests are correlated with CSF biomarkers of amyloid and tau pathologies.

Applying the new research diagnostic criteria: MRI findings and neuropsychological correlations of prodromal AD

We describe the neuroimaging characteristics of prodromal AD (PrdAD) patients diagnosed using the new research criteria in a clinical setting. In order to further characterize these patients, we also study the relationship between neuropsychology, CSF biomarkers and magnetic resonance imaging (MRI) findings. 76 participants--24 controls (CTR), 20 amnesic patients, and 32 Alzheimer's disease (AD) patients--were included in the study. PrdAD was defined on the basis of an objective episodic memory deficit and an AD CSF profile. Structural MRI was performed in all participants. After FWE correction, voxel-based morphometry (VBM) analysis of PrdAD patients versus CTR showed significant clusters of decreased gray matter (GM) volume in the left hemisphere regions including the parahippocampal gyrus, uncus, precuneus, and middle frontal gyrus. We did not find differences in brain atrophy between PrdAD and mild AD patients. Some significant associations were found between CSF levels and episodic and semantic fluency tests in the PrdAD group. Correlations in the PrdAD group revealed that patients with higher scores on delayed free recall had significantly greater GM volume in the left superior temporal gyrus (t = 6.64, p < 0.0001). PrdAD patients presented mainly medial temporal GM atrophy, which was related with significant episodic memory impairment. The cognitive deficit observed in PrdAD patients was also associated with CSF biomarker levels.

Novel CSF biomarkers for frontotemporal lobar degenerations

To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau). CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD. CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases. Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.

Cerebrospinal fluid biomarkers and cognitive performance in non-demented patients with Parkinson’s disease

We tested the hypothesis that levels of CSF biomarkers associated with dementia and cognitive impairment are correlated with cognitive performance in non-demented Parkinson’s disease (PD) patients. Twenty-two non-demented patients with PD underwent neuropsychological testing and lumbar puncture to collect CSF. We correlated performance scores on the Logical Memory (delayed), Category Fluency, Digit Symbol, and Trails B minus A with CSF concentrations of amyloid (A) β42, total tau (t-tau), Aβ42/t-tau, and Brain Derived Neurotrophic Factor (BDNF). We observed significant associations between performance on the Digit Symbol test and CSF levels of Aβ42, Aβ42/t-tau, and BDNF, and between performance on the Category Fluency (vegetable) and Aβ42/t-tau. While several of these associations were attenuated by adjusting for age, our results suggest that it may be possible to use CSF biomarkers to characterize pathophysiologic processes underlying even mild cognitive deficits in non-demented PD patients.

Biochemical studies in Normal Pressure Hydrocephalus (NPH) patients: Change in CSF levels of amyloid precursor protein (APP), amyloid-beta (Aβ) peptide and phospho-tau

Normal Pressure Hydrocephalus (NPH) is one of the causes of dementia of the elderly characterized by impaired mental function, gait difficulties and urinary incontinence. Previously, it was proposed that some of the NPH patients may develop Alzheimer’s disease (AD) like pathology. Aim of this study was to compare levels of different CSF biomarkers, including total secreted β-amyloid precursor protein (sAPP), sAPP-alpha form (sAPPα), amyloid-beta (Aβ) peptide, total-tau protein and hyperphosphorylated-tau protein in subjects from NPH and Non-NPH Control (NNC). CSF was collected from 23 NPH patients and 13 Non-NPH controls by lumber puncture. Western blot analysis was performed to measure levels of sAPP-total. ELISA was used separately to determine levels of sAPPα, Aβ peptide, total-tau and phospho-tau proteins. We found a significant decrease in levels of total secreted APP, sAPPα and Aβ (1–42) in the CSF sample of NPH patients vs. NNC. We did not observe any change in levels of total-tau or phospho-tau in NPH vs. NNC subjects. Notably, phospho-tau level was significantly increased in the NPH patients, who were suffering from the disease for more than one year, vs. NNC. Among five biomarkers studied, decreased sAPP, sAPPα and Aβ (1–42) levels in CSF can be molecular markers to distinguish NPH cases from NNC. Disease severity can also be assessed by increased levels of CSF phospho-tau protein and the ratio of phospho-tau to Aβ (1–42), which might be a useful tool for predicting conversion of NPH individuals to other neurodegenerative disorders including Alzheimer’s disease (AD).

CSF amyloid β 1-42 predicts cognitive decline in Parkinson disease

Cognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease. A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid β 1-42 (Aβ(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time. Lower baseline CSF Aβ(1-42) was associated with more rapid cognitive decline. Subjects with CSF Aβ(1-42) levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline. Reduced CSF Aβ(1-42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.

Standardization of CSF sampling to minimize variation in CSF biomarker levels

Standardization of CSF sampling to minimize variation in CSF biomarker levels

Cerebrospinal fluid ß-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain

The proposed research criteria of prodromal Alzheimer's disease (AD) emphasize the use of biomarkers in addition to the presence of impairment of episodic memory. Atrophy of the medial temporal lobe structures and changes in the levels of CSF tau protein and beta-amyloid 42 (Aß42) peptide in patients with AD are well documented in single center and multicenter studies, and these biomarkers also predict AD in amnestic MCI. However, the relationship between e.g. CSF biomarkers and neuropathologic changes in the brain is not well established. Objective: To study the relationship between antemortem CSF biomarker levels and AD-type neuropathologic changes in the brain. Methods: We studied correlations between levels of CSF Ab42, total tau, and phosphorylated tau (ptau) with neuropathologic changes in the postmortem brain in 123 patients (79 clinically diagnosed AD, 29 other dementia, and 15 other neurologic disease). All study subjects underwent clinical evaluation and provided antemortem lumbar CSF samples. CSF markers were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Aß, hyperphosphorylated tau, and alpha-synuclein. Also vascular pathology was assessed. Results: CSF Aß42, tau and ptau levels were significantly related to amyloid load and the presence of neurofibrillary tangles (NFT) in the brain. CSF Aß42 level correlated inversely with total Aß load in the brain, and CSF tau level correlated with results of immunohistochemistry for tau and with neocortical NFTs. Alpha-synuclein or vascular pathology did not influence CSF biomarker concentrations. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Aß42 level and of increased CSF tau level. Based on the ratio of ptau level to Aß42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of AD-type brain pathology. Conclusions: CSF Aß42 and tau proteins are associated with amyloid and tau pathology but not with alpha-synuclein or vascular pathology. The combination of low Aß42 and high tau levels in CSF predicted AD pathologic features with high accuracy and may be helpful in diagnosing the presence of AD pathologic changes in the brain.

Diagnostic Impact of CSF Biomarkers in a Local Hospital Memory Clinic

Background: CSF biomarkers amyloid-β 1–42 (Aβ42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) are useful diagnostic markers for Alzheimer’s disease (AD). We examined the impact of these biomarkers in the diagnostic process in a non-academic memory clinic. Methods: One hundred and nine patients with available CSF were included from the local hospital memory clinic. Initially, patients were clinically diagnosed, and the clinician indicated their confidence in the diagnosis. Next the CSF results were presented, and the clinician re-evaluated his initial diagnosis. The main outcomes were changes in initial diagnosis and diagnostic confidence. Results: Forty-seven patients were initially diagnosed with AD, 26 were diagnosed with another type of dementia, 18 were diagnosed with mild cognitive impairment, and 18 received a non-dementia diagnosis. All biomarkers distinguished between AD and non-dementia (p < 0.01); tau and ptau-181 also distinguished AD from other types of dementia (p < 0.001). After CSF biomarker levels were revealed, 11 diagnoses changed. In 31% of the diagnoses, the clinician gained confidence, while in 10% confidence decreased. Conclusion: We found that knowledge of CSF biomarker profiles changed the diagnosis in 10% of the cases, and confidence in the diagnosis increased for one third of the patients.

CSF biomarkers predict a more malignant outcome in Alzheimer disease

To investigate if patterns of CSF biomarkers (T-tau, P-tau, and Abeta42) can predict cognitive progression, outcome of cholinesterase inhibitor (ChEI) treatment, and mortality in Alzheimer disease (AD). We included outpatients with AD (n = 151) from a prospective treatment study with ChEI. At baseline, patients underwent cognitive assessments and lumbar puncture. The patients were assessed longitudinally. The 5-year survival rate was evaluated. CSF-Abeta42, T-tau, and P-tau were analyzed at baseline. K-means cluster analysis including the 3 CSF biomarkers was carried out. Cluster 1 contained 87 patients with low levels of Abeta42 and relatively low levels of T-tau and P-tau. Cluster 2 contained 52 patients with low levels of Abeta42 and intermediate levels of T-tau and P-tau. Cluster 3 contained 12 patients with low levels of Abeta42 and very high levels of CSF T-tau and P-tau. There were no differences between the clusters regarding age, gender, years of education, baseline instrumental activities of daily living, or APOE genotype. Even though there was no difference between cluster 3 and the other clusters in disease duration or global rating, the patients in cluster 3 performed worse on cognitive tests already at baseline. Patients in cluster 3 exhibited a very poor outcome of ChEI treatment. Finally, cognition deteriorated faster over time and the mortality rate was substantially increased in cluster 3. A subgroup of patients with Alzheimer disease with extreme levels of CSF biomarkers exhibits worse clinical outcomes over time, including faster progression of cognitive deficits, no response to ChEI treatment, and a higher mortality.

CSF Biomarkers in Prediction of Cerebral and Clinical Change in Mild Cognitive Impairment and Alzheimer's Disease

Brain atrophy and altered CSF levels of amyloid beta (Abeta(42)) and the microtubule-associated protein tau are potent biomarkers of Alzheimer's disease (AD)-related pathology. However, the relationship between CSF biomarkers and brain morphometry is poorly understood. Thus, we addressed the following questions. (1) Can CSF biomarker levels explain the morphometric differences between normal controls (NC) and patients with mild cognitive impairment (MCI) or AD? (2) How are CSF biomarkers related to atrophy across the brain? (3) How closely are CSF biomarkers and morphometry related to clinical change [clinical dementia rating sum of boxes (CDR-sb)]? Three hundred seventy participants (105 NC, 175 MCI, 90 AD) from the Alzheimer's Disease Neuroimaging Initiative were studied, of whom 309 were followed for 1 year and 176 for 2 years. Analyses were performed across the entire cortical surface, as well as for 30 cortical and subcortical regions of interest. Results showed that CSF biomarker levels could not account for group differences in brain morphometry at baseline but that CSF biomarker levels showed moderate relationships to longitudinal atrophy rates in numerous brain areas, not restricted to medial temporal structures. Baseline morphometry was at least as predictive of atrophy as were CSF biomarkers. Even MCI patients with levels of Abeta(42) comparable with controls and of p-tau lower than controls showed more atrophy than the controls. Morphometry predicted change in CDR-sb better than did CSF biomarkers. These results indicate that morphometric changes in MCI and AD are not secondary to CSF biomarker changes and that the two types of biomarkers yield complementary information.

CSF biomarker levels in early and classic onset of Alzheimer's disease

To compare CSF levels of beta-amyloid 1-42 (Abeta(1-42)), total tau (Tau) and tau phosphorylated at threonine 181 (pTau-181) between AD patients with different onset of the disease and controls. 76 AD patients (mean age and SD, 74.29± 5.41) with classic onset of the disease ([[Unsupported Character - ?]]65 years), 35AD patients (mean age and SD, 54.66± 5.38) with early onset (<65 years) and 35 control subjects (mean age and SD, 70.15 ± 11.10) underwent lumbar puncture. The Innotest, ELISA sandwich test (Innogenetics-Belgium) was used for measuring the levles of Tau, pTau-181 and Abeta(1-42). All three biomarkers showed main effects of diagnosis (p< 0.001). When series of ANCOVAs, with age as covariate were performed, the significant difference still exist. There were no difference according to age of onset among AD patients with classic and early onset of the disease (Abeta(1-42) 449 ± 209 versus 460 ± 206 pg/ml; Tau 697± 603 versus 549± 298 pg/ml; pTau-181; 130± 88 versus 131± 73 pg/ml). The obtained results suggest that these biomarkers may be supportive in the diagnosis of AD in routine clinical paractice considering the approaching new target therapeutics.

CSF biomarkers in relationship to cognitive profiles in Alzheimer disease

To investigate the relationship between CSF biomarkers and cognitive profiles in Alzheimer disease (AD). We included 177 patients with AD. Digit Span, Visual Association Test (VAT), VAT object naming, Trail Making Test (TMT), and category fluency were used to assess cognitive functions. Disease severity was assessed using Mini-Mental State Examination; functional impairment was rated by Clinical Dementia Rating. In CSF, levels of amyloid-beta 1-42 (Abeta(1-42)), tau, and tau phosphorylated at threonine 181 (p-tau) were measured. K-means cluster analysis was performed with the three biomarkers to obtain three clusters. Multivariate analysis of variance for repeated measures was performed with CSF cluster as between-subjects factor, neuropsychological z scores as within-subjects variable, and age, sex, and education as covariates. Cluster 1 consisted of 88 patients (49%) with relatively high levels of Abeta(1-42) and low levels of tau and p-tau. Cluster 2 contained 72 patients (41%) with relatively low levels of Abeta(1-42) and high levels of tau and p-tau. Cluster 3 was made up of 17 patients (10%) with low levels of Abeta(1-42) and very high levels of tau and p-tau. No differences between clusters on age, sex, education, APOE genotype, disease duration, functional impairment, or disease severity were found. Patients in cluster 3 performed worse on VAT, TMT-A and -B, and fluency. Clusters of CSF biomarker levels are related to cognitive profiles in Alzheimer disease. A subgroup of patients with extremely high CSF levels of tau and tau phosphorylated at threonine 181 shows a distinct cognitive profile with more severe impairment of memory, mental speed, and executive functions, which cannot be explained by disease severity.

P3-079: CSF biomarker levels, APOE genotype and the effect of aging

P3-079: CSF biomarker levels, APOE genotype and the effect of aging

P3-098: Whole-brain atrophy rate and CSF biomarker levels in mild cognitive impairment and Alzheimer's disease: A longitudinal study

P3-098: Whole-brain atrophy rate and CSF biomarker levels in mild cognitive impairment and Alzheimer's disease: A longitudinal study

P3-095: Levels of CSF biomarkers predict rate of cognitive decline in individuals with very mild dementia of the Alzheimer's type

P3-095: Levels of CSF biomarkers predict rate of cognitive decline in individuals with very mild dementia of the Alzheimer's type

CSF biomarker levels in early and late onset Alzheimer's disease

ObjectiveTo compare CSF levels of beta-amyloid 1–42 (Aβ1–42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) between AD patients and controls according to age. Methods248 AD patients (48% men) and 127 controls (51% men, 22 volunteers and 105 subjective complainers) underwent lumbar puncture. Both patients and controls were divided into a young (<65 years) and old (≥65 years) group. ResultsAll three biomarkers showed main effects of diagnosis (p<0.001). There was an interaction between diagnosis and age for all three biomarkers (p<0.05), as old controls had lower Aβ1–42 and higher (p)tau than young controls (Aβ1–42 699±250 versus 866±191pg/ml, tau 408±245 versus 243±102pg/ml, ptau-181 60±28 versus 42±15pg/ml), but there was no difference according to age among AD patients (Aβ1–42 451±178 versus 425±146pg/ml, tau 741±460 versus 798±467pg/ml, ptau-181 91±42 versus 91±41pg/ml). ConclusionWe found that the older control group had lower Aβ1–42 and higher (p)tau compared to the younger control group. This suggests that older individuals may have AD pathology, even in the absence of objective cognitive impairment.