Alzheimer's Markers Seen Way Before Symptoms
"Neurologists and other Alzheimer's disease experts contacted by MedPage Today and ABC News agreed that the study findings were important, but many said the study fell short of "landmark" status because of the methodology."|
By John Gever, Senior Editor, MedPage Today
Published: July 12, 2012
· Beta amyloid protein measurements may begin to show abnormalities more than 2 decades before overt symptoms of Alzheimer's disease are seen.
· Point out that imaging and cerebrospinal fluid analyses of patients with a powerful genetic predisposition to Alzheimer's disease showed that levels of AB42 (a form of beta amyloid protein with 42 amino acids) began to decline about 25 years before expected symptom onset.
Beta amyloid protein measurements may begin to show abnormalities more than 2 decades before overt symptoms of Alzheimer's disease appear, researchers said.
Imaging and cerebrospinal fluid (CSF) analyses of patients with a powerful genetic predisposition to Alzheimer's disease showed that AB42 (a form of beta amyloid protein with 42 amino acids) levels began to decline about 25 years before expected symptom onset, according to Randall Bateman, MD, of Washington University in St. Louis, and colleagues.
In addition, beta amyloid plaques could be imaged in patients' brains some 15 years before expected symptom onset, the researchers reported online in the New England Journal of Medicine.
"Our findings indicate the Alzheimer's disease process begins more than 20 years before the clinical onset of dementia," Bateman and colleagues concluded.
The results were some of the first major data to be reported from a project called DIAN, the Dominantly Inherited Alzheimer Network. This is a prospective cohort study involving a projected 400 asymptomatic individuals whose family history suggests they may carry genetic mutations associated with autosomal dominant Alzheimer's disease, an early-onset form of the condition.
In the current study, Bateman and colleagues analyzed data on 128 DIAN participants, including 88 who carried the Alzheimer-associated mutations in the PSEN1, PSEN2, and/or APP genes. The 40 noncarriers served as a control group for comparison. About one-quarter of carriers and noncarriers alike were positive for the epsilon-4 variant of APOE.
Although at this point the data are cross-sectional rather than longitudinal, the idea is that findings in DIAN mutation carriers prior to symptom onset may also apply to more common forms of the disease. The snapshots of individual participants, who are at different stages of the pre-symptomatic phase, can be assembled into a picture of the disease course over time, the researchers believe.
They are also operating under an assumption that the trajectory of biomarkers and symptoms in autosomal dominant Alzheimer's disease is similar to that in sporadic, late-onset forms, except that it begins at a younger age.
The primary evaluations carried out in the study were measurements of AB42, AB40 (a 40-residue version of beta amyloid), and tau protein in CSF and brain scans using positron emission tomography and the Pittsburgh Compound B beta amyloid tracer. The latter allows detection and quantification of amyloid plaques in the brain.
Symptoms were evaluated with the Clinical Dementia Rating-Sum of Boxes, scored from 0 (normal cognition) to 18 (total impairment).
DIAN participants' mean age at the evaluations was 39. Among the 88 mutation carriers, half were already symptomatic.
Noncarriers were largely free of amyloid plaques, according to the PET results. Plaques were detectable in the precuneus in participants estimated to be 15 years away from symptom onset, with the plaque volume increasing with the approach of projected symptom onset.
The CSF analyses indicated that levels of tau protein were increased in carriers 15 years before expected symptom onset, relative to noncarriers of similar age. At 10 years from expected symptom onset, AB42 in CSF began to be significantly lower in carriers. Plasma AB42 was increased in carriers relative to noncarriers at 15 years from expected symptom onset.
Bateman and colleagues developed a combined model incorporating the imaging, biochemical, and clinical data. It indicated that the decline in CSF AB42 levels in mutation carriers relative to noncarriers began 25 years before expected symptom onset.
Clinical signs of cognitive impairment were noticeable 10 years out, and global cognitive impairment was evident 5 years before.
Neurologists and other Alzheimer's disease experts contacted by MedPage Today and ABC News agreed that the study findings were important, but many said the study fell short of "landmark" status because of the methodology.
Murali Doraiswamy, MD, of Duke University, was among the more enthusiastic commentators. "The DIAN study is poised to become the road map for all Alzheimer's disease diagnostic and treatment studies over the next 10 years," he said in an email.
But, he continued, "longitudinal DIAN findings will need to confirm what is being reported here. One also has to bear in mind that there are more than 200 different mutations known to cause familial Alzheimer's disease and that there is likely significant heterogeneity within DIAN families that is yet to be teased out."
Ronald Petersen, MD, of the Mayo Clinic in Rochester, Minn., was more skeptical. "Very interesting data but more useful for hypothesis generation than having direct implications at present," he said in an email.
He added, "This may be an unusual form of the Alzheimer's disease process and not generalizable to the disease as it exists in the community."
Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease
Randall J. Bateman, M.D., Chengjie Xiong, Ph.D., Tammie L.S. Benzinger, M.D., Ph.D., Anne M. Fagan, Ph.D., Alison Goate, Ph.D., Nick C. Fox, M.D., Daniel S. Marcus, Ph.D., Nigel J. Cairns, Ph.D., Xianyun Xie, M.S., Tyler M. Blazey, B.S., David M. Holtzman, M.D., Anna Santacruz, B.S., Virginia Buckles, Ph.D., Angela Oliver, R.N., Krista Moulder, Ph.D., Paul S. Aisen, M.D., Bernardino Ghetti, M.D., William E. Klunk, M.D., Eric McDade, M.D., Ralph N. Martins, Ph.D., Colin L. Masters, M.D., Richard Mayeux, M.D., John M. Ringman, M.D., Martin N. Rossor, M.D., Peter R. Schofield, Ph.D., D.Sc., Reisa A. Sperling, M.D., Stephen Salloway, M.D., and John C. Morris, M.D. for the Dominantly Inherited Alzheimer Network
July 11, 2012
The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.
In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.
Concentrations of amyloid-beta (Aß)42 in the CSF appeared to decline 25 years before expected symptom onset. Aß deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the MiniŠMental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others;
Alzheimer's disease is the most common cause of dementia and is currently estimated to affect more than 5 million people in the United States, with an expected increase to 13 million by the year 2050. The typical clinical presentation is progressive loss of memory and cognitive function, ultimately leading to a loss of independence and causing a heavy personal toll on the patient and the family. The costs of care of patients with Alzheimer's disease in 2010 were estimated at more than $172 billion in the United States, an annual cost that is predicted to increase to a trillion dollars by 2050 unless disease-modifying treatments are developed.1
Alzheimer's disease has been hypothesized to begin decades before the first symptoms manifest.2-4 Thus, longitudinal studies of Alzheimer's disease biomarkers take many years to show the full pathologic cascade of events that lead to dementia. Furthermore, trials of disease-modifying treatment require large numbers of patients over extended periods owing to the slow progression of cognitive symptoms.5,6 Therefore, well-validated biomarkers of Alzheimer's disease processes are needed to improve the design of clinical trials, develop more effective therapeutics, and offer the opportunity for prevention trials.7
On the basis of the amyloid hypothesis,8 amyloid-beta (Aß) is currently the most common disease-modifying target. Recent research indicates that the targeting of amyloidosis in familial amyloid polyneuropathy improves clinical outcomes.9-11 However, the order and timing of amyloidosis and other Alzheimer's disease processes that lead to clinical dementia are not well understood. We hypothesized that autosomal dominant Alzheimer's disease and the more common late-onset Alzheimer's disease12 have similar pathophysiological features. Although autosomal dominant Alzheimer's disease accounts for a relatively small proportion (approximately 1%) of cases of Alzheimer's disease, increasing evidence13 suggests that it overlaps with sporadic Alzheimer's disease. Mutations in one of three genes (APP, PSEN1, and PSEN2) have been identified that cause alterations in Aß processing and lead to Alzheimer's disease with complete penetrance. The age at clinical onset of autosomal dominant Alzheimer's disease is similar between generations14 and is affected mostly by the mutation type and background family genetics.15 We compared a wide range of pathophysiological markers between mutation carriers and noncarriers as a function of the parental age at onset in order to evaluate the cascade of events that lead to dementia. Clinical, cognitive, imaging, and biochemical measures were compared between mutation carriers and noncarriers in the first large international cohort of families with autosomal dominant Alzheimer's disease.
We analyzed 128 participants from the DIAN cohort (Table 1). The mutation types reflected the distribution of mutations described in the literature, with 40 PSEN1, 3 PSEN2, and 8 APP pedigrees.20 As expected with an autosomal dominant inheritance pattern, approximately 50% of the asymptomatic participants were mutation carriers. There were no significant differences in the presence of an APOE ε4 allele or sex between asymptomatic mutation carriers and noncarriers. The mean (±SD) age of parental onset of symptoms was 45.7±6.8 years. The DIAN parental age of symptom onset was correlated with the age of symptom onset for symptomatic offspring (Pearson correlation coefficient, 0.56; P<0.001).
Clinical and Neuropsychometric Findings
We measured clinical impairment with the use of the Clinical Dementia RatingŠSum of Boxes (CDR-SOB), with scores ranging from 0 (cognitive normality) to 18 (maximal cognitive impairment). Significant differences in CDR-SOB scores were detected between mutation carriers and noncarriers 5 years before expected symptom onset (Figure 1A and Table 2.). Noncarriers had stable CDR-SOB scores of 0 throughout the relative age range, whereas carriers had increasing CDR-SOB scores at higher values of estimated years from expected symptom onset. In this cohort, participants had a CDR rating of mild dementia (CDR 1) at a mean of 3.3±5.3 years after the parent's age of symptom onset.
Significant differences in MMSE scores between mutation carriers and noncarriers were detected at assessments performed 5 years before expected symptom onset; carriers had decreasing MMSE scores at higher values of estimated years from expected symptom onset (Figure 1B). We found significant cognitive impairment in mutation carriers, as compared with noncarriers, in the delayed-recall portion of the Logical Memory test21 10 years before expected symptom onset (Table 2). Noncarriers remained stable in performance from 30 years before to 20 years after expected symptom onset (Figure 1C).
MRI structural measures of hippocampal volume were compared between mutation carriers and noncarriers with the use of an a priori hypothesis of increased atrophy in mutation carriers. Increased atrophy of bilateral hippocampi was detected in mutation carriers 15 years before expected symptom onset (Table 2). As expected, there was an age-dependent decrease in hippocampal volumes in noncarriers (Figure 1D).22
Cerebral Glucose Metabolism
FDG-PET measures of cerebral glucose use in the precuneus were compared with the use of an a priori hypothesis of decreased metabolism in mutation carriers to determine regional metabolic defects. The precuneus region, which is known to be an area of early deposition in both sporadic Alzheimer's disease and autosomal dominant Alzheimer's disease,4,23,24 was chosen for analysis of amyloid deposition. A significant decrease in cerebral metabolism in the precuneus was detected in mutation carriers 10 years before expected symptom onset (Figure 1E and Table 2).
PIB-PET measures of fibrillar Aß deposition25 in the precuneus were compared with the use of an a priori hypothesis of increased regional amounts of amyloid deposition in mutation carriers. There was no detectable amyloid deposition in noncarriers. All noncarriers had PIB-PET SUVR values of less than 0.88. As compared with noncarriers, mutation carriers had significant amyloid deposition in the precuneus 15 years before expected symptom onset (Figure 1F and Table 2). The amount of amyloid deposition in mutation carriers increased as a function of estimated years from expected symptom onset at least until clinical symptom onset.
In mutation carriers, levels of tau in the CSF were increased 15 years before expected symptom onset (Figure 1G and Table 2). Concentrations of Aß42 in the CSF decreased as a function of estimated years from expected symptom onset and were pseudonormal at approximately 20 years before expected symptom onset, reaching low levels 10 years before expected symptom onset (Figure 1H). The decrease by half in Aß42 in the CSF and the increase in tau in the CSF were similar in magnitude to those typically observed in late-onset sporadic Alzheimer's disease.26 Plasma Aß42 levels were elevated in mutation carriers, as compared with noncarriers (Figure 1I).
The order and rate of pathophysiological changes in autosomal dominant Alzheimer's disease were estimated with the use of an analysis of the relationship among clinical, cognitive, imaging, and biochemical measures in the DIAN cohort (Figure 2). Beginning 25 years before expected symptom onset, Aß42 concentrations in the CSF in mutation carriers appeared to decline, as compared with those in noncarriers. Aß deposition as measured by PIB-PET (Figure 3 and see Video 1, available at NEJM.org) was detected at least 15 years before expected symptom onset (Table 2). Increases in levels of tau in the CSF and in brain atrophy were detected approximately 15 years before expected symptom onset, followed by cerebral hypometabolism and impaired episodic memory approximately 10 years before expected symptom onset and global cognitive impairment starting at 5 years before expected symptom onset.