Elevated Brain Amyloid Linked to Later Cognitive Decline

June 21, 2017

Raised levels of amyloid in the brain in cognitively normal individuals in their 70s was associated with a higher likelihood of cognitive decline in the following few years, in a new study.

The study, published in the June 13 issue of JAMA, was conducted by a team led by Michael C. Donohue, PhD, Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego.

"Our results support a growing body of evidence that Alzheimer's is a progressive disease that starts many years before the onset of symptoms," Dr Donohue commented to Medscape Medical News.

He cautioned, however, that their findings are not proving causality. "We are just showing an association. It is difficult to make recommendations based on these findings until we have a therapy which has been shown to slow the development of cognitive impairment," he said. "We need to see whether intervening earlier with a drug therapy that lowers amyloid levels is an effective mean of preventing or slowing cognitive decline." 

But an accompanying editorial concludes, "These findings pave the way for the development of preventive strategies that ultimately may enable persons with AD [Alzheimer's Disease] to live without dementia."

For the study, the researchers analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a natural history study in which elderly volunteers with a range of cognitive function, from normal cognition to mild cognitive impairment and dementia, undergo memory testing every year as well as sampling of cerebrospinal fluid (CSF) and brain imaging to measure various biomarkers.

The current analysis involved 445 cognitively normal individuals (mean age, 74 years) in the United States and Canada who were observed for a median of 3.1 years, with a few people followed for 10 years, to study the relationship between brain amyloid levels at baseline based on brain scans or spinal tap and subsequent cognitive function.

At baseline, 243 individuals were classified as having normal amyloid levels and 202 as having elevated levels on positron emission tomography (PET) amyloid imaging or CSF assay.

Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC, a sum of 4 baseline standardized Z scores); Mini-Mental State Examination (MMSE); Clinical Dementia Rating Sum of Boxes (CDR–Sum of Boxes); and Logical Memory Delayed Recall.

The mean score for PACC at baseline was 0.00; MMSE, 29.0; CDR–Sum of Boxes, 0.04; and Logical Memory Delayed Recall, 13.1.

Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points; P < .001), MMSE (mean difference, 0.56 points; P < .001), and CDR–Sum of Boxes (mean difference, 0.23 points; P = .002). For Logical Memory Delayed Recall, the between-group score was not statistically significant at 4 years (mean difference, 0.73; P = .056).

Dr Donohue noted that progression of CDR scores of half a point or more at 4 years had occurred in 30% in the raised amyloid group vs 15% in those without raised amyloid; and by 10 years the figures for such progression were 88% vs 30%, although only 20 participants were followed for this long.

The researchers say their results suggest that elevated brain amyloid in clinically normal individuals may represent the presymptomatic stage of AD, but additional follow-up of the ADNI cohort will be important to confirm these observations.

Dr Donohue notes that clinical trials of new drug therapies are underway in individuals with raised amyloid levels but normal cognition. The A4 study is testing the antiamyloid antibody solanezumab (Lilly), and other studies are evaluating β-secretase 1 inhibitors in this population to see whether they can prevent or delay cognitive decline.

"Our study is encouraging for those trials. It supports the idea of early intervention," he said.

He added that trials ongoing at present can be described as secondary prevention as individuals already have raised amyloid levels and the studies are investigating whether drug therapy can slow or stop further amyloid accumulation and cognitive decline. Future studies could look at whether it is possible to stop amyloid accumulation in the first place. That could be thought of as primary prevention. 

Dr Donohue explained that previous studies have reported about 30% of individuals in their 70s have raised amyloid levels but in this study it was nearer 50%. He suggested this may be because amyloid was measured by both PET and CSF sampling but only had to be positive on one of these, while other studies have generally used only one measure.

"Also our population was people who volunteered to be included in this research, so although they had normal cognition at baseline they may have had a particular interest in the field of Alzheimer's, such as a family history or subjective memory issues." 

The researchers point out that current estimates on the prevalence of AD — at 5 to 6 million cases in the United States and more than 30 million worldwide — are based on the occurrence of dementia.  But if preclinical stages are also included, the numbers of affected individuals would be more than doubled.           

In an accompanying editorial, Pieter Jelle Visser, MD, and Betty Tijms, PhD, VU University Medical Center Amsterdam, the Netherlands, say this finding, together with those from other cohorts, "clearly indicates that amyloid pathology in cognitively normal older persons is not a benign phenomenon of normal aging but part of a progressive neurodegenerative disease."

They say this has far-reaching implications, including AD being thought of a brain disease that a person can live with for a relatively long time without having any major cognitive impairment, and the consideration of secondary prevention.

The editorialists note that if drugs that can slow disease progression and delay the onset of dementia are found, this outcome may not be evident until 15 to 20 years later. Difficult decisions will have to be made about the cost-effectiveness of such treatment because many people will likely die of other causes before developing dementia, but waiting until an individual has developed dementia is also problematic as the treatment will be less effective.

This work was supported by Biomarkers Across Neurodegenerative Disease grant from the Alzheimer's Association, Michael J. Fox Foundation, Weston Brain Institute, ADNI, National Institutes of Health, Department of Defense, National Institute on Aging, National Institute of Biomedical Imaging and Bioengineering, AbbVie, Alzheimer's Drug Discovery Foundation, Araclon Biotech, BioClinica, Biogen, Bristol-Myers Squibb, CereSpir, Eisai, Elan Pharmaceuticals, Eli Lilly, EuroImmun, F. Hoffmann-La Roche, Genentech, Fujirebio, GE Healthcare, IXICO, Janssen Alzheimer Immunotherapy Research & Development, Johnson & Johnson Pharmaceutical Research & Development, Lumosity, Lundbeck, Merck, Meso Scale Diagnostics, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals, Pfizer, Piramal Imaging, Servier, Takeda, Transition Therapeutics, and the Canadian Institutes of Health Research. Dr Donohoe reports receipt of grants from the National Institutes of Health, the Alzheimer's Association, the Michael J. Fox Foundation, and the W. GarfieldWeston Foundation during the conduct of the study; and receipt of personal fees for scientific advisory board participation from Neurotrack and Eli Lilly outside the submitted work. Disclosures for coauthors appear in the paper. Dr Visser reports receipt of grants from Innovative Medicine Initiative and Biogen, nonfinancial support from GE Healthcare, and consultancy agreements from Eli Lilly and Janssen Pharmaceuticals. 

JAMA. Published June 13, 2017. Abstract, Editorial

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