Cognitively normal seniors with brain amyloid experienced accelerated cognitive decline over as few as 3-4 years, compared with those who had no brain amyloid at baseline.

At 4 years’ follow-up, prodromal Alzheimer’s disease (AD) had developed in 32% of amyloid-positive people and 15% of the amyloid-normal people – a 16.9% difference. Extrapolating the limited 10-year data they collected, the authors projected that after a decade, 88% of the amyloid-positive cohort would have progressed, compared with 29% of the amyloid-normal cohort.

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The finding not only strengthens the association of amyloid with Alzheimer’s disease, but suggests once again that the disease process may be well underway before clinical symptoms appear, Michael C. Donohue, PhD, and his colleagues reported (JAMA. 2017 Jun 13;317[22]:2305-16).

“This suggests that elevated brain amyloid may indicate a presymptomatic stage of disease rather than a risk factor for disease,” wrote Dr. Donohue of the University of Southern California, San Diego. “AD is a gradually progressive disorder that can be identified at the asymptomatic phase using biomarkers of amyloid.”

The study is a project of the Alzheimer’s Disease Neuroimaging Initiative, an ongoing natural history study assessing the clinical, imaging, genetics, and biomarkers of aging, from normal aging to early and late mild cognitive impairment, dementia, or AD.

This particular substudy tracked the association of baseline amyloid-beta 42 (AB₄₂) and cognition among 445 patients, 202 of whom had elevated brain amyloid as measured by cerebrospinal fluid or brain imaging with florbetapir. They were followed for a mean of 3 years, although a limited number of patients had up to 10 years’ worth of data.

The primary endpoints were score changes on four cognitive batteries: the Preclinical Alzheimer Cognitive Composite, the Mini-Mental State Examination; the Clinical Dementia Rating Scale Sum of Boxes, and the Logical Memory Delayed Recall.

At baseline, mean patient age was 74 years, although amyloid-positive patients were slightly older (74.7 years vs. 73.4 years). The mean educational attainment was 16.4 years. Slightly more patients in the amyloid-positive group reported subjective memory complaints (25% vs. 22%). Significantly more had at least one APOE-e4 allele of the apolipoprotein E gene (42% vs. 16%). All were cognitively normal as measured by the four tests. A fifth measure, the Alzheimer’s Disease Assessment Scale 13-item cognitive subscale, was also within normal limits for both groups, but that was not included in the follow-up analysis.

In addition to showing AB₄₂ deposits in the brain and/or decreased AB₄₂ in cerebrospinal fluid (indicating increased binding in the brain), amyloid-positive patients also had significantly different levels of tau. CSF total tau was 76.8 pg/mL in the amyloid-positive group, compared with 59.4 pg/mL in the amyloid-normal group. CSF phosphorylated tau also was elevated in the amyloid-positive group (38.1 pg/mL vs. 26.5 pg/mL). Increased CSF tau is an indicator of neuronal injury.

The mean follow-up time was 3.9 years. At last contact, only four patients had died; 36% were lost to follow-up. Significantly more in the amyloid-positive group had progressed to Alzheimer’s dementia (13 vs. 7). Twenty in the positive group and nine in the negative group had started an antidementia medication.

At 4 years, the amyloid-positive group had declined significantly from baseline on all four cognitive measures, performing significantly worse than the amyloid-negative group on each. The amyloid-negative group, conversely, had either stayed steady or experienced nonsignificant change on the tests.

“The [Preclinical Alzheimer Cognitive Composite] assessment captures performance on tasks of episodic memory, orientation, and executive function – the prominent domains of AD-related cognitive decline,” the authors wrote. “This finding strengthens the link between elevated amyloid and the primary manifestations of AD. Individuals with normal amyloid remain free of AD-pattern impairment for many years.

“The longitudinal curves demonstrated that those participants with elevated amyloid were more likely to develop early symptoms consistent with prodromal amyloid within 6 years,” the researchers added.

The study also tracked biomarker changes in AB₄₂, tau, and ventricular and hippocampal volume. These markers changed in both groups – although in each case, the changes associated with amyloid positivity were more pronounced.

Nevertheless, the biomarker data offered a more complex picture. “Measures of CSF tau, phosphorylated tau, and AB₄₂ showed marked differences between groups at baseline,” the investigators noted. “Longitudinal change … was similar across groups, suggesting that they are sensitive to elevated amyloid but do not reflect cognitive and clinical decline once amyloidosis is established. Brain atrophy, as reflected by enlargement of ventricular size, showed change in participants with elevated amyloid. This trend is consistent with brain atrophy with normal aging that is aggravated in the presence of amyloid.”

The finding that AB₄₂ can identify patients on the path to cognitive decline suggests that the protein is more than a risk factor for AD – it is, rather, a marker of presymptomatic disease.

“AD is a gradually progressive disorder that can be identified at the asymptomatic phase using biomarkers of amyloid,” Dr. Donohue and his colleagues said. If that view is accepted, it would change the way potential therapeutics are viewed, from agents that reduce the risk of disease to agents that actively manage disease, even if given presymptomatically.

“This view is important in weighing therapeutic options from a regulatory perspective and for an individual,” the investigators noted. “Accurate characterization of the potential progression of earliest symptoms may inform discussion of the utility of screening people for amyloid abnormalities, with or without effective therapeutic options.”

The Alzheimer’s Disease Neuroimaging Initiative is funded by grants from the Alzheimer’s Association, the National Institutes of Health, and numerous pharmaceutical companies. Dr. Donohue reported financial relationships with Eli Lilly and Neurotrack.

msullivan@frontlinemedcom.com

On Twitter @Alz_gal

Brain amyloid may herald decline in cognitively normal seniors