Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases.

AIM: Brain clusterin is known to be associated with the amyloid-ß deposits in Alzheimer's disease (AD). We assessed the distribution of clusterin immunoreactivity in cerebrovascular disorders, particularly focusing on white matter changes in small vessel diseases. METHODS: Post-mortem brain tissues from the frontal or temporal lobes of a total of 70 subjects with various disorders including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral amyloid angiopathy (CAA) and AD were examined using immunohistochemistry and immunofluorescence. We further used immunogold electron microscopy to study clusterin immunoreactivity in extracellular deposits in CADASIL. RESULTS: Immunostaining with clusterin antibodies revealed strong localization in arterioles and capillaries, besides cortical neurones. We found that clusterin immunostaining was significantly increased in the frontal white matter of CADASIL and pontine autosomal dominant microangiopathy and leukoencephalopathy subjects. In addition, clusterin immunostaining correlated with white matter pathology severity scores. Immunostaining in axons ranged from fine punctate deposits in single axons to larger confluent areas with numerous swollen axon bulbs, similar to that observed with known axon damage markers such as non-phosphorylated neurofilament H and the amyloid precursor protein. Immunofluorescence and immunogold electron microscopy experiments showed that whereas clusterin immunoreactivity was closely associated with vascular amyloid-ß in CAA, it was lacking within the granular osmiophilic material immunolabelled by NOTCH3 extracelluar domain aggregates found in CADASIL. CONCLUSIONS: Our results suggest a wider role for clusterin associated with white matter damage in addition to its ability to chaperone proteins for clearance via the perivascular drainage pathways in several disease states.

DSM-IV and DSM-5 Prevalence of Social Anxiety Disorder in a Population Sample of Older People.

OBJECTIVES: To examine the prevalence of social anxiety disorders (SAD) with (DSM-IV) and without (DSM-5) the person's own assessment that the fear was unreasonable, in a population sample of older adults. Further, to determine whether clinical and sociodemographic correlates of SAD differ depending on the criteria applied. DESIGN: Cross-sectional. SETTING: General population in Gothenburg, Sweden. PARTICIPANTS: A random population-based sample of 75- and 85-year olds (N = 1200) without dementia. MEASUREMENTS: Psychiatric research nurses carried out a semi-structured psychiatric examination including the Comprehensive Psychopathological Rating Scale. DSM-IV SAD was diagnosed with the Mini International Neuropsychiatric Interview. SAD was diagnosed according to DSM-IV and DSM-5 criteria. The 6-month duration criterion in DSM-5 was not applied because of lack of information. Other assessments included the Global Assessment of Functioning (GAF), the Brief Scale for Anxiety (BSA), and the Montgomery Åsberg Depression Rating Scale (MADRS). RESULTS: The 1-month prevalence of SAD was 2.5% (N = 30) when the unreasonable fear criterion was defined in accordance with DSM-IV and 5.1% (N = 61) when the DSM-5 criterion was applied. Clinical correlates (GAF, MADRS, and BSA) were worse in SAD cases identified by either procedure compared with all others, and ratings for those reporting unreasonable fear suggested greater (albeit nonsignificant) overall psychopathology. CONCLUSIONS: Shifting the judgment of how reasonable the fear was, from the individual to the clinician, doubled the prevalence of SAD. This indicates that the DSM-5 version might increase prevalence rates of SAD in the general population. Further studies strictly applying all DSM-5 criteria are needed in order to confirm these findings.

Effect of diagnostic criteria on prevalence of frontotemporal dementia in the elderly.

BACKGROUND: Frontotemporal dementia (FTD) is believed to be rare in the elderly, and the influence of different criteria on the prevalence of FTD is unclear. METHODS: Population-based samples of 70- to 95-year-olds (n = 2462) in Gothenburg, Sweden, underwent neuropsychiatric examinations. Behavioral variant FTD (bvFTD) was diagnosed according to the International Behavioural Variant FTD Criteria Consortium (FTDC), the Frontotemporal Lobe Degeneration Consensus criteria, and the Lund-Manchester Research Criteria. A subset (n = 1074) underwent computerized tomography (CT) of the brain. RESULTS: The prevalence of bvFTD varied between 0.2% and 0.5% at age 70 to 79 years, between 2.5% and 3.6% at age 80 to 89 years, and between 1.7% and 2.2% at age 90 to 95 years. The agreement between different criteria was low to moderate (κ = 0.20-0.42). Among those with bvFTD according to FTDC, 93.3% had frontal and/or temporal lobar atrophy on CT, compared with 12.6% of those without bvFTD (P < .001). CONCLUSIONS: The prevalence of bvFTD was higher than expected in this population. To a large extent, different criteria captured different individuals.

Higher CSF interleukin-6 and CSF interleukin-8 in current depression in older women. Results from a population-based sample.

OBJECTIVE: The literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6), interleukin-8 (IL-8) and depression in a population-based sample of older women who were followed for 17 years. METHODS: 86 dementia-free women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-3. CSF IL-6 and CSF IL-8 were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria. RESULTS: At baseline, women with ongoing major (n=10) or minor depression (n=9) had higher levels of CSF IL-6 (p=0.008) and CSF IL-8 (p=0.007) compared with those without depression (n=67). Higher CSF IL-8 was related to higher MADRS score (p=0.003). New cases of depression were observed in 9 women during follow-ups. No associations between CSF cytokine levels and future depression could be shown in women without depression at baseline. CONCLUSION: Higher levels of CSF IL-6 and IL-8 were associated with current depression in this population-based sample. CSF IL-6 and CSF IL-8 may play a role in depression in late life.

p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial.

p75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug-placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16 ; ClinicalTrials.gov registration: NCT03069014 .

Lower CSF interleukin-6 predicts future depression in a population-based sample of older women followed for 17 years.

OBJECTIVE: The literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6) and related proinflammatory cytokines and current and future depression in a population-based sample of older women who were followed for 17 years. METHODS: 83 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-3. CSF- IL-6, interleukin-1ß (IL-1ß), interleukin- 8 (IL-8) and tumor necrosis factor-α (TNF-α) were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria. RESULTS: At baseline, women with ongoing depression had lower levels of IL-6 (p<0.04), IL-8 (p<0.05) and TNF-α (p<0.05) compared with those without depression. In women without depression at baseline, lower CSF IL-6 levels predicted depression at one or more follow-up examination (p<0.03). Results from the generalized linear mixed logistic model using all baseline and follow-up data on depression status and Mini Mental State Examination score showed a significant relationship between IL-6 and depression (p=0.005 OR 0.370 CI [0.184-0.744]). CONCLUSION: Lower levels of CSF IL-6 were associated with current depression and with future depression during a follow-up of almost two decades. Our findings suggest that lower levels of CSF IL-6 may be related to depression vulnerability in later life.

Prevalence of cardiovascular disorders and risk factors in two 75-year-old birth cohorts examined in 1976-1977 and 2005-2006.

BACKGROUND AND AIMS: The number of older people are increasing worldwide, and cardiovascular diseases are the major causes of death in western societies. This study examines birth cohort differences in cardiovascular disorders and risk factors in Swedish elderly. METHODS: Representative samples of 75-year-olds living in Gothenburg, Sweden, examined in 1976-1977 and in 2005-2006. Blood pressure, s-cholesterol, s-triglycerides, height, body weight, body mass index, history of myocardial infarction, angina pectoris and stroke/TIA, and diabetes mellitus were measured. RESULTS: The prevalence of total cardiovascular disorders, hypertension and hypercholesterolemia decreased, and the prevalence of stroke increased in both genders. The prevalence of cardiovascular disorders was higher in women than in men in 1976-1977, and higher in men than in women in 2005-2006. The decrease in blood pressure occurred independently of antihypertensive treatment. The prevalence of current smokers decreased in men and increased in women. The prevalence of life-time smokers and diabetes mellitus increased only in women. The proportion on antihypertensive treatment and overweight and obesity increased only in men. Hypertension, overweight and obesity were more common in women in 1976-1977. These sex differences were not observed in 2005-2006. CONCLUSIONS: The overall prevalence of cardiovascular disorders decreased, and sex differences reversed between the 1970s and 2000s among Swedish septuagenarians. Our findings emphasize the importance of environmental factors, not only for the prevalence of cardiovascular disorders, but also as explanations for sex differences. Reasons for changes could be increased survival in those with disorders and risk factors, changes in lifestyle and diet, and better preventive strategies, such as treatment of hypercholesterolemia and hypertension.

Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial.

Tau plays a key role in Alzheimer's disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989 .

A population-based study on dementia and stroke in 97 year olds.

BACKGROUND: the number of nonagenarians increases dramatically worldwide. OBJECTIVES: to examine the prevalence of stroke/transient ischaemic attack (TIA) and dementia, their inter-relationship and their relation to 2-year mortality and institutionalisation in 97 year olds. METHODS: a population-based sample of 97 year olds (n=591) was examined. Information on stroke/TIA was obtained from self-reports, key informants and hospital discharge registers. Dementia was diagnosed according to DSM-III-R criteria. RESULTS: the response rate was 65%. The prevalence of dementia was 32.7% in men and 59.3% in women (P<0.001). The prevalence of stroke/TIA was 21.5% (17.8% in men, 22.3% in women). Stroke/TIA was related to dementia in women (odds ratio=1.9, 95% CI: 1.2-3.0), but not in men. Dementia, but not stroke/TIA, was related to 2-year mortality and institutionalisation in logistic regression models. CONCLUSION: dementia was very common in this age group, and related to mortality and institutionalisation. Stroke/TIA in 97 year olds showed less association with dementia, mortality and institutionalisation than reported in studies of younger elderly populations. The finding that stroke was not associated with dementia in men needs to be taken cautiously due to the small number of men. The findings also emphasise that more studies are needed to scrutinise the aetiology of dementia in nonagenarians.

One-month prevalence of mental disorders in a population sample of 95-year olds.

OBJECTIVE: To determine the 1-month prevalence of mental disorders among 95-year olds. DESIGN: Cross-sectional population sample of 95-year olds. SETTING: : All 95-year olds born in the period 1901-1903 living in Gothenburg, Sweden, were invited. Elderly living in both community settings and nursing homes were included. PARTICIPANTS: In total, 338 95-year olds (response rate: 65%) were examined (263 women, 75 men). MEASUREMENTS: All participants were examined by psychiatrists using the Comprehensive Psychopathological Rating Scale and cognitive tests. Mental disorders were classified according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria. RESULTS: Two-third of all 95-year olds had a mental disorder. In the total sample of 95-year olds, the 1-month prevalence was 52% for dementia, 8% for depression, 4% for anxiety, and 3% for psychotic disorders. Almost one-third (29%) of the nondemented 95-year olds fulfilled criteria for a psychiatric disorder: 17% had depression, 9% anxiety, and 7% psychotic disorder. CONCLUSIONS: The combined prevalence of mental disorders was high among 95-year olds, even after excluding dementia. These findings emphasize the importance of research, care, and detection of psychiatric problems in this age group.

Onset and rate of cognitive change before dementia diagnosis: findings from two Swedish population-based longitudinal studies.

We used data from two population-based longitudinal studies to estimate time of onset and rate of accelerated decline across cognitive domains before dementia diagnosis. The H70 includes an age-homogeneous sample (127 cases and 255 non-cases) initially assessed at age 70 with 12 follow-ups over 30 years. The Kungsholmen Project (KP) includes an age-heterogeneous sample (279 cases and 562 non-cases), with an average age of 82 years at initial assessment, and 4 follow-ups spanning 13 years. We fit mixed linear models to the data and determined placement of change points by a profile likelihood method. Results demonstrated onset of accelerated decline for fluid (speed, memory) versus crystallized (verbal, clock reading) abilities occurring approximately 10 and 5 years before diagnosis, respectively. Although decline before change points was greater for fluid abilities, acceleration was more pronounced for crystallized abilities after the change points. This suggests that onset and rate of acceleration vary systematically along the fluid-crystallized ability continuum. There is early onset in fluid abilities, but these changes are difficult to detect due to substantial age-related decline. Onset occurred later and acceleration was greater in crystallized abilities, suggesting that those markers may provide more valid identification of cases in later stages of the prodromal phase.

Psychotic symptoms in a population-based sample of 85-year-old individuals with dementia.

Psychotic symptoms are common in elderly persons with dementia. These symptoms affect a person's ability to function in daily life and put strain on the caregiver. Most studies focus on psychotic symptoms in clinical samples with Alzheimer disease (AD). Thus, their prevalence and relation with dementia subtype and severity in very old populations is unclear. We assessed a representative sample of 85-year-old individuals living in Gothenburg, Sweden (n = 494) using neuropsychiatric examinations, key informant interviews, and medical record reviews; 147 had dementia. Dementia and its severity were diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders (Third Edition, Revision [DSM-III-R]) criteria. Alzheimer disease according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria was diagnosed in 64 persons and vascular dementia (VaD) according to Erkinjuntti criteria was observed in 69. Fourteen had dementia due to other causes. Psychotic symptoms were classified according to DSM-III-R. The prevalence of psychotic symptoms in this very old population was 36% among AD cases compared to 54% in VaD cases (P = .04). Proportions with psychotic symptoms increased with increasing dementia severity in individuals with AD. No such association could be shown in those with VaD. This finding of a high proportion of psychotic symptoms also in individuals with mild severity of VaD should alert health professionals to evaluate dementia in very old patients who present with hallucinations or delusions.

Psychotropic drug use in relation to mental disorders and institutionalization among 95-year-olds: a population-based study.

BACKGROUND: The prevalence of psychotropic drug use is high among the elderly, but research on how psychotropic drugs are used among individuals aged 90 years and older is limited. An increased knowledge on this topic may contribute to improved prescribing patterns in this vulnerable population. The aim of this study was to assess the use of psychotropic drugs in relation to mental disorders and institutionalization among 95-year-olds and to identify use of potentially inappropriate psychotropic drugs. METHODS: All 95-year-olds born in 1901-1903 living in nursing homes or community settings in Gothenburg, Sweden were invited to participate. The response rate was 65% and 338 95-year-olds were examined (263 women, 75 men). Psychotropic drug use in relation to mental disorders and institutionalization was assessed. Information on drug use was collected primarily from multi-dose drug dispensing lists. Participants were examined by trained psychiatrists using the Comprehensive Psychopathological Rating Scale and a battery of cognitive tests. Dementia, depression, anxiety and psychotic disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R). RESULTS: Sixty percent of the 95-year-old participants used psychotropic drugs; hypnotics were most common (44%). Potentially inappropriate psychotropics were observed in one third (33%). Antidepressants were used by 7% of the participants without dementia who fulfilled criteria for a depressive disorder, while 56% used hypnotics and 30% used anxiolytics. CONCLUSIONS: The high prevalence of psychotropic drug use and the nonspecific nature of these treatments among 95-year-olds indicate a need for improvement in prescribing patterns.

The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial.

We examined the effects of a dihydropyridine calcium channel blocker nilvadipine with anti-inflammatory properties on cognition and cerebrospinal fluid (CSF) biomarkers by baseline Alzheimer's disease (AD) severity. Exploratory analyses were performed on the dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in AD subjects stratified by baseline AD severity into very mild (MMSE ≥ 25), mild (MMSE 20-24) and moderate AD (MMSE < 20). The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS). Cerebrospinal fluid biomarkers Aß38, Aß40, Aß42, neurofilament light chain (NFL), neurogranin, YKL-40, total tau and P181 tau (ptau) were measured in a subset of samples (n = 55). Regression analyses were adjusted for confounders to specifically examine the influence of nilvadipine and baseline AD severity on cognitive outcomes over 78-weeks. Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed a greater cognitive decline on the ADAS-Cog 12 test and the ADCOMS. A lower decline was observed after nilvadipine treatment for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. Cerebrospinal fluid Aß42/Aß40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Among moderate AD subjects, levels of ptau, total tau, neurogranin and YKL-40 increased in subjects treated with nilvadipine compared to placebo. These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients. Trial Registration: NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340 EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27.

Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer's disease.

Amyloid ß (Aß) and tau are key hallmark features of Alzheimer's disease (AD) neuropathology. The interplay of Aß and tau for cognitive impairment in early AD was examined with cross-sectional analysis, measured by cerebrospinal fluid biomarkers (Aß1-42, total tau [t-tau], and phosphorylated tau [p-tau181P]), and on cognitive performance by the repeatable battery for assessment of neuropsychological status (RBANS). Participants (n = 246) included cognitively normal (Aß-), mild cognitively impaired (Aß-), preclinical AD (Aß+), and prodromal AD (Aß+). Overall, cognitive scores (RBANS total scale score) had a moderate negative correlation to t-tau (n = 246; r = -0.434; p < 0.001) and p-tau181P (r = -0.389; p < 0.001). When classified by Aß status, this correlation to t-tau was applicable only in Aß+ participants (n = 139; r = -0.451, p < 0.001) but not Aß- participants (n = 107; r = 0.137, p = 0.16), with identical findings for p-tau. Both tau (p < 0.0001) and interaction of Aß1-42 with tau (p = 0.006) affected RBANS, but not Aß1-42 alone. Cognitive/memory performance correlated well with cerebrospinal fluid tau levels across early stages of AD, although the correlation is Aß dependent.

Low Cerebrospinal Fluid Aß42 and Aß40 are Related to White Matter Lesions in Cognitively Normal Elderly.

BACKGROUND: Low cerebrospinal fluid (CSF) levels of Aß42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Aß interacts with different brain pathologies early in the disease process is limited. We examined how CSF Aß markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old. OBJECTIVE: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia. METHODS: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aß42 and Aß40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed. RESULTS: In 85-year-olds without dementia, lower levels of both CSF Aß42 and CSF Aß40 were associated with WMLs. CSF Aß42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aß42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs. CONCLUSIONS: Our findings may suggest that there is an interrelationship between Aß and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aß42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Aß deposition than cortical degeneration.