Dement Geriatr Cogn Disord 2014;37:196–206 DOI: 10.1159/000355556 Accepted: September 10, 2013 Published online: October 24, 2013
© 2013 S. Karger AG, Basel 1420–8008/14/0374–0196$39.50/0 www.karger.com/dem
Original Research Article
High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer’s Disease M. Degerman Gunnarsson a L. Kilander a
L. Lannfelt a
M. Ingelsson a
H. Basun a, b
a Department
of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, and b BioArctic Neuroscience, Stockholm, Sweden
Key Words Alzheimer’s disease · Tau · Phosphorylated tau · Beta-amyloid · Cerebrospinal fluid · Rapid cognitive decline · Dying in severe dementia · Mortality Abstract Objective: Cerebrospinal fluid (CSF) amyloid β 42 (Aβ 42), total tau (t-tau) and phosphorylated tau (p-tau) are useful as predictors of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia. However, results are contradictory as to whether these biomarkers reflect the future rate of clinical decline. Methods: This is a retrospective study on 196 patients with AD [mild/moderate AD (n = 72) or AD-MCI (n = 124) at baseline] with a follow-up period of 2–9 years’ duration (median 6 years). Lumbar punctures were performed at baseline as a part of the diagnostic procedure. Results: We found an increased risk of rapid cognitive decline defined as a drop in the Mini-Mental State Examination score of ≥4 points/ year in patients with CSF t-tau concentrations above the median (OR 3.31, 95% CI 1.53–7.16) and CSF p-tau above the median (OR 2.53, 95% CI 1.21–5.26). Patients with CSF t-tau in the highest quartile had a higher risk of dying in severe dementia (HR 4.67, 95% CI 1.16–18.82). Conclusions: In this large AD cohort, we found an association between high levels of CSF ttau and p-tau and a more aggressive course of the disease, measured as a rapid cognitive © 2013 S. Karger AG, Basel decline and a higher risk of dying in severe dementia.
Introduction
Alzheimer’s disease (AD) is characterized by a progressive decline of cognitive functions. In the final stage of severe dementia, the patient will lose the ability to perform all activities of daily living (ADL) and the condition eventually leads to death. The severity of dementia is Malin Degerman Gunnarsson, MD, PhD Department of Public Health and Caring Sciences/Geriatrics Uppsala University, Uppsala Science Park SE–751 85 Uppsala (Sweden) E-Mail malin.degerman.gunnarsson @ pubcare.uu.se
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Dement Geriatr Cogn Disord 2014;37:196–206 DOI: 10.1159/000355556
© 2013 S. Karger AG, Basel www.karger.com/dem
Degerman Gunnarsson et al.: High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer’s Disease
the primary predictor of mortality in advanced AD, together with the general physical health and age of the patient [1]. AD varies widely in its clinical course and rate of cognitive decline [2–4]. In mild cognitive impairment (MCI), low levels of cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and increased levels of tau predict progression to AD dementia [5]. However, concerning the ability of biomarkers to estimate the prognosis in later stages of AD dementia, results from previous studies are open to more than one interpretation. In some longitudinal studies, high CSF total tau (t-tau), phosphorylated tau (p-tau) and/or low Aβ42 have been associated with rapid cognitive decline [6–8], increased mortality as well as a more pronounced hippocampal atrophy and ventricular widening [9–12]. Nevertheless, other studies have not found any association between CSF biomarkers in AD patients and an aggressive course of the disease [13, 14]. t-tau in CSF has been suggested as a general marker of neuronal degeneration [15], while p-tau may be a more specific marker for the formation of neurofibrillary tangles [16, 17]. We investigated whether CSF biomarkers in AD predicted a rapid decline, defined as a deterioration in the Mini-Mental State Examination (MMSE) score of 4 points/year or more, and death in severe dementia. Methods Study Design A total of 429 individuals with memory complaints referred to the Memory Disorder Unit, Department of Geriatrics, Uppsala University Hospital, Uppsala, Sweden, underwent a lumbar puncture (LP) as a part of the diagnostic procedure between 2003 and 2009. All LPs were performed at or close to the baseline assessment (mainly 1–3 months). The diagnosis of probable AD was made according to the NINCDS-ADRDA criteria [18] and the DSM-IV criteria [19]. Of all patients, 196 fulfilled the AD criteria already at baseline (n = 72) or had MCI [20] and subsequently converted to AD during the follow-up period of at least 2 years (maximum 9 years) (n = 124) or to the date of death. Mild dementia was defined as impaired performance in instrumental ADL, and moderate dementia was defined as impaired personal (basic) ADL. All patients had MRI or CT scans consistent with the diagnosis of probable AD, and a majority had also undergone extensive cognitive assessments for diagnostic purpose. CSF concentrations of t-tau, p-tau and Aβ42 were determined using sandwich ELISAs [21] at the same laboratory. Furthermore, the results were taken into account in the diagnostic procedure together with all other information. The diagnoses were continuously reevaluated by a physician at the follow-ups, and all diagnoses were also scrutinized afterwards by one of the authors (M.D.G.) to ensure accuracy. Data on educational level, numbers of medications, cardiovascular disease (heart failure and/or coronary heart disease), diabetes and treatment for hypertension were collected from the medical records. The apolipoprotein E (APOE) genotype was available in 84 subjects. The baseline MMSE result was collected from the testing most closely in time to the LP procedure. Since this was a clinical setting, the intervals of the clinical follow-ups and MMSE testings after baseline varied according to the individual patient’s needs. At least two MMSE results were available for 187 patients, and the intervals between the baseline and the last test varied between 6 months and 7 years, with a mean of 30 months. The decline in MMSE score was calculated as the difference between the scores at baseline and the last available test scores divided by time in months. Rapid decline was defined as a decline of ≥4 points/year in the MMSE score. The digital medical record system kept at the Uppsala County Council, which is common to all health care services including primary care, enabled the follow-up of a majority of the patients even after they had moved to a living home for patients with dementia. Detailed descriptions of the patients’ functional status, cognitive deterioration and all medical details related to the patients’ status were made by general practitioners, nurses or paramedics and were documented in the digital medical record. Dying in severe dementia was identified as death after a prolonged decline over months at the end-stage of AD, being immobilized and dependent in all ADL, in contrast to premature death of other causes. Date of death was available for all patients, but for 8 individuals it was not possible to determine the cause of death due to lack of information from the medical records. The Regional Ethical Committee approved the study.
198
Dement Geriatr Cogn Disord 2014;37:196–206 DOI: 10.1159/000355556
© 2013 S. Karger AG, Basel www.karger.com/dem
Degerman Gunnarsson et al.: High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer’s Disease
Statistical Analyses The Mann-Whitney U test was used for comparison of not normally distributed variables between groups. Logistic regression analyses were performed to determine the odds ratios (OR) of rapid cognitive decline. Patients without at least one MMSE testing at follow-up (n = 9) were coded as nonresponders. Cox proportional hazards models were used to assess the hazard ratios (HR) to die in severe dementia. The 8 individuals without sufficient information in their medical records to determine causes of death were censored as nonresponders at the date of death. Analyses were performed in univariate and multivariate models, adjusted for age, educational level, coronary heart disease/heart failure and baseline AD stage. Separate analyses were also conducted in subjects with mild AD dementia and AD-MCI at baseline, respectively. The level of statistical significance was set at p = 0.05.
Results
The demographic and clinical characteristics of the 196 AD patients are shown in tables 1 and 2. A total of 61% of the patients were in the MCI stage at the time of the LP procedure, whereas 29% of the patients were in the mild dementia stage. The patients were followed for a median period of 6 years (2–9 years). The mean deterioration in MMSE score over 12 months was approximately 1.5 points and 21% of the cases were classified as rapid decliners, i.e. they lost 4 points/year or more. In addition, 23% of the patients performed equal or marginally better on the last testing compared to baseline. In these patients, the mean interval between tests was approximately 23 months. All patients except 7 were treated with cholinesterase inhibitors or memantine during at least one period. During the follow-up period of up to 9 years, 66 patients died, 32 of them in severe dementia. Pneumonia or other infections were the terminal cause of death in about half of the patients, and heart failure was the second most common terminal cause of death. There was no association between age and total mortality. The APOE genotype was available in 84 individuals only [ε4/4 (n = 24), ε4/3 (n = 39), ε4/2 (n = 1) and ε4 noncarriers (n = 20)], and it was not included in the analyses. Importantly, concentrations of CSF t-tau, p-tau and Aβ42 did not differ between patients in the MCI stage and patients with mild/moderate dementia at baseline. Rapid Decline We found no association between rapid decline and age, APOE genotype, education, markers of comorbidity or baseline stage of AD (table 3). Moreover, rapid decliners (18% of MCI cases, 30% of mild dementia and 13% of moderate dementia cases) did not differ in performance on MMSE at baseline as compared to the nonrapid decliners (mean 23.2 ± 4.4 points vs. mean 23.7 ± 4.9 points, p = 0.36). Split by medians, the OR of rapid decline in patients with high CSF t-tau was 3.31 (95% CI 1.53–7.16), and the OR in patients with CSF p-tau above the median was 2.53 (95% CI 1.21–5.26), adjusting for age, education, heart disease and mild/moderate dementia stage at baseline. Using a MMSE cutoff score of ≥5 points/year, the OR in patients with CSF t-tau above the median was 5.45 (95% CI 1.93– 15.42) and p-tau was 3.83 (95% CI 1.50–9.81) for rapid decline in a multivariate model. The risk of rapid decline was substantially increased for patients in the highest quartiles of t-tau and p-tau as compared to those with low tau levels (table 4). Individuals in the lowest quartile of CSF Aβ42 had an OR of 2.23 (95% CI 1.04–4.68), using the second to fourth quartile as a reference group. However, there was a tendency towards a U-shaped association between Aβ42 and rapid decline. Compared to participants in the three highest quartiles, subjects in the lowest quartile of the Aβ42/t-tau ratio (OR 3.37, 95% CI 1.60–7.09), Aβ42/p-tau ratio (OR 2.65, 95% CI 1.26–5.59) and p-tau/t-tau (OR 3.22, 95% CI 1.53–6.78) ratio had a higher risk of rapid decline in the same multivariate models. When stratifying for AD stage at baseline, high CSF t-tau showed a significant association with rapid decline both in the MCI stage
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Dement Geriatr Cogn Disord 2014;37:196–206 DOI: 10.1159/000355556
© 2013 S. Karger AG, Basel www.karger.com/dem
Degerman Gunnarsson et al.: High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer’s Disease
Table 1. Demographics, clinical
characteristics and CSF biomarkers in the study population
Variables
Patients (n = 196)
Follow-up period, years Age at baseline, years MCI Mild/moderate dementia MMSE score, points Female gender Years of education ≤7 8–12 ≥13 Number of medications Coronary heart disease/heart failure Baseline AD stage/MMSE score points MCI Mild dementia Moderate dementia CSF biomarkers t-tau, ng/l MCI Mild/moderate dementia p-tau, ng/l MCI Mild/moderate dementia Aβ42, ng/l MCI Mild/moderate dementia All three biomarkers normala Low Aβ42, normal t-tau and p-tau Low Aβ42, high t-tau or p-tau Normal Aβ42, high t-tau and/or p-tau All three biomarkers pathological Rapid declinerb MCI Mild dementia Moderate dementia Death during follow-up MCI Mild dementia Moderate dementia Death in severe dementia during follow-up MCI Mild dementia Moderate dementia
6 (2–9) 70 (46–86) 70±8 70±7 24±4 111 (57) 106 (54) 49 (25) 41 (21) 3±2 26 (13) 124 (63)/26±3 57 (29)/21±4 15 (8)/16±6 718±492 709±356 734±669 100±48 101±45 0.97±54 354±131 353±126 355± 140 4 (2) 26 (13) 41 (21) 19 (10) 106 (54) 41 (21) 22 (18) 17 (30) 2 (13) 66 (34) 34 (27) 23 (40) 9 (60) 32 (16) 16 (13) 10 (18) 6 (40)
Values are medians (ranges), means ± SD, or n (%). a Reference values: Aβ >450 ng/l, t-tau
© 2013 S. Karger AG, Basel 1420–8008/14/0374–0196$39.50/0 www.karger.com/dem
Original Research Article
High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer’s Disease M. Degerman Gunnarsson a L. Kilander a
L. Lannfelt a
M. Ingelsson a
H. Basun a, b
a Department
of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, and b BioArctic Neuroscience, Stockholm, Sweden
Key Words Alzheimer’s disease · Tau · Phosphorylated tau · Beta-amyloid · Cerebrospinal fluid · Rapid cognitive decline · Dying in severe dementia · Mortality Abstract Objective: Cerebrospinal fluid (CSF) amyloid β 42 (Aβ 42), total tau (t-tau) and phosphorylated tau (p-tau) are useful as predictors of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia. However, results are contradictory as to whether these biomarkers reflect the future rate of clinical decline. Methods: This is a retrospective study on 196 patients with AD [mild/moderate AD (n = 72) or AD-MCI (n = 124) at baseline] with a follow-up period of 2–9 years’ duration (median 6 years). Lumbar punctures were performed at baseline as a part of the diagnostic procedure. Results: We found an increased risk of rapid cognitive decline defined as a drop in the Mini-Mental State Examination score of ≥4 points/ year in patients with CSF t-tau concentrations above the median (OR 3.31, 95% CI 1.53–7.16) and CSF p-tau above the median (OR 2.53, 95% CI 1.21–5.26). Patients with CSF t-tau in the highest quartile had a higher risk of dying in severe dementia (HR 4.67, 95% CI 1.16–18.82). Conclusions: In this large AD cohort, we found an association between high levels of CSF ttau and p-tau and a more aggressive course of the disease, measured as a rapid cognitive © 2013 S. Karger AG, Basel decline and a higher risk of dying in severe dementia.
Introduction
Alzheimer’s disease (AD) is characterized by a progressive decline of cognitive functions. In the final stage of severe dementia, the patient will lose the ability to perform all activities of daily living (ADL) and the condition eventually leads to death. The severity of dementia is Malin Degerman Gunnarsson, MD, PhD Department of Public Health and Caring Sciences/Geriatrics Uppsala University, Uppsala Science Park SE–751 85 Uppsala (Sweden) E-Mail malin.degerman.gunnarsson @ pubcare.uu.se
197
Dement Geriatr Cogn Disord 2014;37:196–206 DOI: 10.1159/000355556
© 2013 S. Karger AG, Basel www.karger.com/dem
Degerman Gunnarsson et al.: High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer’s Disease
the primary predictor of mortality in advanced AD, together with the general physical health and age of the patient [1]. AD varies widely in its clinical course and rate of cognitive decline [2–4]. In mild cognitive impairment (MCI), low levels of cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and increased levels of tau predict progression to AD dementia [5]. However, concerning the ability of biomarkers to estimate the prognosis in later stages of AD dementia, results from previous studies are open to more than one interpretation. In some longitudinal studies, high CSF total tau (t-tau), phosphorylated tau (p-tau) and/or low Aβ42 have been associated with rapid cognitive decline [6–8], increased mortality as well as a more pronounced hippocampal atrophy and ventricular widening [9–12]. Nevertheless, other studies have not found any association between CSF biomarkers in AD patients and an aggressive course of the disease [13, 14]. t-tau in CSF has been suggested as a general marker of neuronal degeneration [15], while p-tau may be a more specific marker for the formation of neurofibrillary tangles [16, 17]. We investigated whether CSF biomarkers in AD predicted a rapid decline, defined as a deterioration in the Mini-Mental State Examination (MMSE) score of 4 points/year or more, and death in severe dementia. Methods Study Design A total of 429 individuals with memory complaints referred to the Memory Disorder Unit, Department of Geriatrics, Uppsala University Hospital, Uppsala, Sweden, underwent a lumbar puncture (LP) as a part of the diagnostic procedure between 2003 and 2009. All LPs were performed at or close to the baseline assessment (mainly 1–3 months). The diagnosis of probable AD was made according to the NINCDS-ADRDA criteria [18] and the DSM-IV criteria [19]. Of all patients, 196 fulfilled the AD criteria already at baseline (n = 72) or had MCI [20] and subsequently converted to AD during the follow-up period of at least 2 years (maximum 9 years) (n = 124) or to the date of death. Mild dementia was defined as impaired performance in instrumental ADL, and moderate dementia was defined as impaired personal (basic) ADL. All patients had MRI or CT scans consistent with the diagnosis of probable AD, and a majority had also undergone extensive cognitive assessments for diagnostic purpose. CSF concentrations of t-tau, p-tau and Aβ42 were determined using sandwich ELISAs [21] at the same laboratory. Furthermore, the results were taken into account in the diagnostic procedure together with all other information. The diagnoses were continuously reevaluated by a physician at the follow-ups, and all diagnoses were also scrutinized afterwards by one of the authors (M.D.G.) to ensure accuracy. Data on educational level, numbers of medications, cardiovascular disease (heart failure and/or coronary heart disease), diabetes and treatment for hypertension were collected from the medical records. The apolipoprotein E (APOE) genotype was available in 84 subjects. The baseline MMSE result was collected from the testing most closely in time to the LP procedure. Since this was a clinical setting, the intervals of the clinical follow-ups and MMSE testings after baseline varied according to the individual patient’s needs. At least two MMSE results were available for 187 patients, and the intervals between the baseline and the last test varied between 6 months and 7 years, with a mean of 30 months. The decline in MMSE score was calculated as the difference between the scores at baseline and the last available test scores divided by time in months. Rapid decline was defined as a decline of ≥4 points/year in the MMSE score. The digital medical record system kept at the Uppsala County Council, which is common to all health care services including primary care, enabled the follow-up of a majority of the patients even after they had moved to a living home for patients with dementia. Detailed descriptions of the patients’ functional status, cognitive deterioration and all medical details related to the patients’ status were made by general practitioners, nurses or paramedics and were documented in the digital medical record. Dying in severe dementia was identified as death after a prolonged decline over months at the end-stage of AD, being immobilized and dependent in all ADL, in contrast to premature death of other causes. Date of death was available for all patients, but for 8 individuals it was not possible to determine the cause of death due to lack of information from the medical records. The Regional Ethical Committee approved the study.
198
Dement Geriatr Cogn Disord 2014;37:196–206 DOI: 10.1159/000355556
© 2013 S. Karger AG, Basel www.karger.com/dem
Degerman Gunnarsson et al.: High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer’s Disease
Statistical Analyses The Mann-Whitney U test was used for comparison of not normally distributed variables between groups. Logistic regression analyses were performed to determine the odds ratios (OR) of rapid cognitive decline. Patients without at least one MMSE testing at follow-up (n = 9) were coded as nonresponders. Cox proportional hazards models were used to assess the hazard ratios (HR) to die in severe dementia. The 8 individuals without sufficient information in their medical records to determine causes of death were censored as nonresponders at the date of death. Analyses were performed in univariate and multivariate models, adjusted for age, educational level, coronary heart disease/heart failure and baseline AD stage. Separate analyses were also conducted in subjects with mild AD dementia and AD-MCI at baseline, respectively. The level of statistical significance was set at p = 0.05.
Results
The demographic and clinical characteristics of the 196 AD patients are shown in tables 1 and 2. A total of 61% of the patients were in the MCI stage at the time of the LP procedure, whereas 29% of the patients were in the mild dementia stage. The patients were followed for a median period of 6 years (2–9 years). The mean deterioration in MMSE score over 12 months was approximately 1.5 points and 21% of the cases were classified as rapid decliners, i.e. they lost 4 points/year or more. In addition, 23% of the patients performed equal or marginally better on the last testing compared to baseline. In these patients, the mean interval between tests was approximately 23 months. All patients except 7 were treated with cholinesterase inhibitors or memantine during at least one period. During the follow-up period of up to 9 years, 66 patients died, 32 of them in severe dementia. Pneumonia or other infections were the terminal cause of death in about half of the patients, and heart failure was the second most common terminal cause of death. There was no association between age and total mortality. The APOE genotype was available in 84 individuals only [ε4/4 (n = 24), ε4/3 (n = 39), ε4/2 (n = 1) and ε4 noncarriers (n = 20)], and it was not included in the analyses. Importantly, concentrations of CSF t-tau, p-tau and Aβ42 did not differ between patients in the MCI stage and patients with mild/moderate dementia at baseline. Rapid Decline We found no association between rapid decline and age, APOE genotype, education, markers of comorbidity or baseline stage of AD (table 3). Moreover, rapid decliners (18% of MCI cases, 30% of mild dementia and 13% of moderate dementia cases) did not differ in performance on MMSE at baseline as compared to the nonrapid decliners (mean 23.2 ± 4.4 points vs. mean 23.7 ± 4.9 points, p = 0.36). Split by medians, the OR of rapid decline in patients with high CSF t-tau was 3.31 (95% CI 1.53–7.16), and the OR in patients with CSF p-tau above the median was 2.53 (95% CI 1.21–5.26), adjusting for age, education, heart disease and mild/moderate dementia stage at baseline. Using a MMSE cutoff score of ≥5 points/year, the OR in patients with CSF t-tau above the median was 5.45 (95% CI 1.93– 15.42) and p-tau was 3.83 (95% CI 1.50–9.81) for rapid decline in a multivariate model. The risk of rapid decline was substantially increased for patients in the highest quartiles of t-tau and p-tau as compared to those with low tau levels (table 4). Individuals in the lowest quartile of CSF Aβ42 had an OR of 2.23 (95% CI 1.04–4.68), using the second to fourth quartile as a reference group. However, there was a tendency towards a U-shaped association between Aβ42 and rapid decline. Compared to participants in the three highest quartiles, subjects in the lowest quartile of the Aβ42/t-tau ratio (OR 3.37, 95% CI 1.60–7.09), Aβ42/p-tau ratio (OR 2.65, 95% CI 1.26–5.59) and p-tau/t-tau (OR 3.22, 95% CI 1.53–6.78) ratio had a higher risk of rapid decline in the same multivariate models. When stratifying for AD stage at baseline, high CSF t-tau showed a significant association with rapid decline both in the MCI stage
199
Dement Geriatr Cogn Disord 2014;37:196–206 DOI: 10.1159/000355556
© 2013 S. Karger AG, Basel www.karger.com/dem
Degerman Gunnarsson et al.: High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer’s Disease
Table 1. Demographics, clinical
characteristics and CSF biomarkers in the study population
Variables
Patients (n = 196)
Follow-up period, years Age at baseline, years MCI Mild/moderate dementia MMSE score, points Female gender Years of education ≤7 8–12 ≥13 Number of medications Coronary heart disease/heart failure Baseline AD stage/MMSE score points MCI Mild dementia Moderate dementia CSF biomarkers t-tau, ng/l MCI Mild/moderate dementia p-tau, ng/l MCI Mild/moderate dementia Aβ42, ng/l MCI Mild/moderate dementia All three biomarkers normala Low Aβ42, normal t-tau and p-tau Low Aβ42, high t-tau or p-tau Normal Aβ42, high t-tau and/or p-tau All three biomarkers pathological Rapid declinerb MCI Mild dementia Moderate dementia Death during follow-up MCI Mild dementia Moderate dementia Death in severe dementia during follow-up MCI Mild dementia Moderate dementia
6 (2–9) 70 (46–86) 70±8 70±7 24±4 111 (57) 106 (54) 49 (25) 41 (21) 3±2 26 (13) 124 (63)/26±3 57 (29)/21±4 15 (8)/16±6 718±492 709±356 734±669 100±48 101±45 0.97±54 354±131 353±126 355± 140 4 (2) 26 (13) 41 (21) 19 (10) 106 (54) 41 (21) 22 (18) 17 (30) 2 (13) 66 (34) 34 (27) 23 (40) 9 (60) 32 (16) 16 (13) 10 (18) 6 (40)
Values are medians (ranges), means ± SD, or n (%). a Reference values: Aβ >450 ng/l, t-tau
