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.”
The National Institute on Aging funded the study.
Study authors reported relationships with C2N Diagnostics, Merck, Novartis, Lilly, Genentech, AstraZeneca, Pfizer, Bayer, Bristol-Myers Squibb, Eisai, Janssen, and Avid. One co-author holds an intellectual property interest in the amyloid plaque imaging agent used in the study.
Primary source: New England Journal of Medicine
Source reference: Bateman R, et al “Clinical and biomarker changes in dominantly inherited Alzheimer’s disease N Engl J Med 2012; DOI:10.1056/NEJMoa202753.