Going to Biomarker Extremes to Find Rare Alzheimer’s Variants

Researchers have identified potential Alzheimer’s mutations by focusing their attention on people whose biomarkers reach extreme ends of the spectrum. As reported in the August 22 PLoS Genetics, scientists from Washington University in St. Louis, Missouri, found variants both known and novel when they sequenced major AD genes in people with very high or very low amounts of tau and amyloid β in their cerebrospinal fluid (CSF). Led by senior author Carlos Cruchaga, the researchers were surprised to find one of the risk variants was a polymorphism in presenilin 1 (PS1) that had previously been deemed non-pathogenic. When they considered this variant in the context of ApoE4, they found it conferred as much risk as a second copy of that allele. Someone carrying a single copy of both the PS1 variant and ApoE4 has 10 times the risk of someone with wild-type presenilin and no ApoE4, the researchers calculated. As scientists hunt for rare variants, it is important to consider that mutations may still be risk factors even if they exist in people without AD, Cruchaga said.

Biomarkers can predict risk for Alzheimer’s several years before symptoms appear

Brain imaging and spinal-fluid testing can help predict which cognitively normal older people will develop Alzheimer’s disease as many as 7.5 years before symptoms appear, according to a new study supported in part by the NIA. The findings confirm the power of biomarkers as predictors of disease risk in the earliest, symptom-free stages of Alzheimer’s disease. These biomarkers may prove to be valuable tools in testing promising treatments in future studies. While not typically used in clinical practice, investigators worldwide are studying, refining, and standardizing biomarkers aimed at identifying who is at risk for developing Alzheimer’s, the most common form of dementia in older adults. The biomarkers in this study, published May 7 in Neurology, included positron emission tomography (PET) scans of the brain to detect deposits of the telltale protein beta-amyloid, as well as levels of beta-amyloid and another protein, tau, found in cerebrospinal fluid. The research team, at Washington University School of Medicine in St. Louis, tracked the cognition of 201 dementia-free volunteers, ages 45 to 88, at the school’s Alzheimer’s Disease Research Center.
The researchers found that abnormal levels of biomarkers identified in PET scans and lumbar punctures could predict who would develop cognitive impairment among the volunteers who were followed for an average of 3.7 years, but in some cases as long as 7.5 years. Some 28 volunteers (14 percent) of the group developed memory loss and other signs of cognitive impairment. Abnormal levels of all biomarkers predicted the development of Alzheimer’s dementia equally well, the study found. Older participants, men, and African Americans who developed dementia did so faster than those who were younger, female, and white, the researchers report. In a few cases, participants with abnormal biomarker levels remained cognitively normal, perhaps because of “cognitive reserve,” the ability of some brains to cope with or stave off decline.
Reference: Roe CM, et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later.

Reference: Roe CM, et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 2013;80(19):1784-91.

Association of plasma and cortical amyloid beta is modulated by APOE ε4 status

Background

Apolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aβ) and fibrillar brain Aβ measured by Pittsburgh compound B positron emission tomography ([¹¹C]PiB PET) has not been assessed.

Methods

Ninety-six Alzheimer's Disease Neuroimaging Initiative participants with [¹¹C]PiB scans and plasma Aβ_1–40 and Aβ_1–42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [¹¹C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aβ_1–40, Aβ_1–42, and Aβ_1–40/Aβ_1–42 with [¹¹C]PiB uptake.

Results

In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ_1–40/Aβ_1–42 and [¹¹C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ_1–40/Aβ_1–42 improved the explained variance in [¹¹C]PiB binding compared with using APOE and plasma Aβ_1–40/Aβ_1–42 as separate terms.

Conclusions

The results suggest that plasma Aβ is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.

Fig. 1. (A–D) Scatterplots of plasma Aβ_1–40/Aβ_1–42 vs average regional [¹¹C]PiB uptake from the (Average regional [¹¹C]PiB uptake = Plasma Aβ_1–40/Aβ_1–42 + APOE ε4 status + [Plasma Aβ_1–40/Aβ_1–42 × APOE ε4 status]) model (A and B), and plasma Aβ_1–40/Aβ_1–42 vs mean [¹¹C]PiB uptake from the cluster identified in the (Voxel [¹¹C]PiB uptake = Plasma Aβ_1–40/Aβ_1–42 + APOE ε4 status + [Plasma Aβ_1–40/Aβ_1–42 × APOE ε4 status]) model (C and D). Aβ, amyloid beta; PiB, Pittsburgh compound B; APOE, apolipoprotein E.

Figure options

Fig. 2. Brain regions (R, right; L, left) identified in the (Voxel [¹¹C]PiB uptake = Plasma Aβ_1–40/Aβ_1–42 + APOE ε4 status + [Plasma Aβ_1–40/Aβ_1–42 × APOE ε4 status]) model (voxel-level threshold of P < .005 [uncorrected], cluster size ≥ 200 voxels). The red-to-yellow scale indicates increasing statistical significance of association. PiB, Pittsburgh compound B; Aβ, amyloid beta; APOE, apolipoprotein E.

Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals

Hypothetical model of preclinical Alzheimer's disease (AD). According to the proposed model, the group currently defined as 'preclinical AD' is heterogeneous and comprises two subpopulations. Firstly, there is the group of individuals at different stages of preclinical AD defined by the biomarkers indicated in the lower panel of the figure. All of these individuals will progress to dementia, and we call this phase 'presymptomatic AD'. The second group comprises individuals who are positive for amyloid markers and neuronal injury markers, and fall into one of the stages of preclinical AD, based on the current classification. However, this population has efficient active compensatory mechanisms, and remains resistant to dementia (stable asymptomatic cerebral amyloidosis).

Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'.

BMC Medicine 2012, 10:127 doi:10.1186/1741-7015-10-127 © 2012 Lazarczyk et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials

The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.

Citation: Holland D, McEvoy LK, Desikan RS, Dale AM, for the Alzheimer’s Disease Neuroimaging Initiative (2012) Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials. PLoS ONE 7(10): e47739. doi:10.1371/journal.pone.0047739

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Biomarkers for Alzheimer’s disease – spinal taps, brain scans, blood tests and the critical role of brain donation

By Professor Simon Lovestone

Professor of Old Age Psychiatry, NIHR Biomedical Research Centre for Mental Health, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF

Suppose you have memory problems and go to your doctor - what happens next? At best, and the best is not always achieved, then an assessment of memory and other cognitive function is made and, in some cases, a referral is made to a memory clinic where there may be more memory tests and perhaps a brain scan. If the outcomes of these tests are not severe enough to warrant a clear-cut diagnosis then, usually, the cognitive tests are repeated after a year to see if they have got worse. This is unsatisfactory as the wait must seem interminable to patients and their relatives. For professionals too, not being able to make an early diagnosis is frustrating.

When treatments for Alzheimer's disease (AD) go beyond symptomatic treatment to therapies for the illness itself, this wait will be unacceptable since it is in this early phase, before dementia is established, that the drugs are most likely to be effective. This, then, is one of the most important drivers for research into 'biomarkers' of AD. A biomarker is a biological signal that can be detected for diagnosis, ideally very early and before doctors are currently able to diagnose the condition. Biomarkers are also useful as the basis of tests for measuring how a disease is progressing. This latter use of biomarkers would be especially useful in research to find new treatments for dementia. Currently clinical trials rely almost entirely on memory tests which are sometimes less reliable than we would like as measures of disease. A biomarker that reflected the disease progression in the brain would be immensely useful as a measure against which to judge new treatments.

Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer's disease.

Progranulin (GRN) mutations are associated with different clinical phenotypes, including Frontotemporal Lobar Degeneration (FTLD), Corticobasal Degeneration and Alzheimer's disease (AD). In addition, the range of age at onset is very wide and patients presenting initial symptoms around eighty years have been described. Previous studies demonstrated that progranulin plasma levels determination may be a reliable method to identify GRN deletion carriers. We thus evaluated progranulin plasma levels in all patients followed at our Alzheimer's Centre whose plasma was available (n=176) and found four patients displaying low values. Three of them carried the CACT deletion in exon 7 and their clinical diagnosis was behavioral variant Frontotemporal Dementia. We also identified a patient carrying a previously reported CAGT deletion in exon 5. Here, we report on this case. The onset of symptoms was at 77 years and the initial diagnosis was of amnestic Mild Cognitive Impairment (aMCI), which converted to AD six months later. In the following years, the patient also developed behavioral disturbances, gait apraxia and parkinsonian symptoms. At present, she is 84 years old and is still followed-up periodically. This case confirms progranulin plasma levels as a reliable biomarker to identify GRN deletion carriers and discriminate between FTLD and other dementias which may mimic it. We thus encourage the inclusion of this non-invasive and easy test in clinical practice.

J Neurol Sci. 2009 Dec 15;287(1-2):291-3

CSF Markers: Goodbye, Research Use Only; Hello, Clinical

This is Part 1 of a two-part series. See also Part 2.
What a difference a year can make. At the 2011 Alzheimer’s Association International Conference in Paris, France, leading scientists in the CSF Alzheimer’s biomarker field met to tackle the vexing problem of measurement variability with the available commercial assays. Alas, back then a listener could be forgiven for thinking of the Tower of Babel, as groups presented their own stance and talked past each other as much as finding common ground.

Alzheimer's Disease and Non-Demented High Pathology Control Nonagenarians: Comparing and Contrasting the Biochemistry of Cognitively Successful Aging

Amyloid plaques stained by the Campbell-Switzer technique.

The histological fields are representative of the amyloid plaque burden shown in 40 µm coronal sections of the frontal lobe.

The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer's disease (AD) dementia and correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitively intact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator of neurotoxicity and dementia, specific protective mechanisms must enable these HPC to evade cognitive decline. We evaluated the neuropathological and biochemical differences existing between non-demented (ND)-HPC and an age-matched cohort with AD dementia. The ND-HPC selected for our study were clinically assessed as ND and possessed high amyloid plaque burdens. ELISA and Western blot analyses were used to quantify a group of proteins related to APP/Aβ/tau metabolism and other neurotrophic and inflammation-related molecules that have been found to be altered in neurodegenerative disorders and are pivotal to brain homeostasis and mental health. The molecules assumed to be critical in AD dementia, such as soluble or insoluble Aβ40, Aβ42 and tau were quantified by ELISA. Interestingly, only Aβ42 demonstrated a significant increase in ND-HPC when compared to the AD group. The vascular amyloid load which was not used in the selection of cases, was on the average almost 2-fold greater in AD than the ND-HPC, suggesting that a higher degree of microvascular dysfunction and perfusion compromise was present in the demented cohort. Neurofibrillary tangles were less frequent in the frontal cortices of ND-HPC. Biochemical findings included elevated vascular endothelial growth factor, apolipoprotein E and the neuroprotective factor S100B in ND-HPC, while anti-angiogenic pigment epithelium derived factor levels were lower. The lack of clear Aβ-related pathological/biochemical demarcation between AD and ND-HPC suggests that in addition to amyloid plaques other factors, such as neurofibrillary tangle density and vascular integrity, must play important roles in cognitive failure (Full text).

Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates

AbstractWe measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.

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