Strong Support for Amyloid as Dementia Prevention Target

Megan Brooks

April 08, 2020

The first published data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial support the hypothesis that higher brain amyloid levels represent an early preclinical stage of Alzheimer's disease (AD).

An analysis of screening data from the trial showed that elevated amyloid in clinically normal older adults was associated with lower cognitive test scores and increased self-reports of subtle changes in cognitive function.

Elevated amyloid was also associated with older age, family history of dementia and APOE ε4 allele but not with other putative AD risk factors, including female sex, lower education, decreased physical activity, body mass index, and other lifestyle factors.

The study was published online April 6 in JAMA Neurology.

A Pioneering Study

In a journal podcast, principal A4 investigator Reisa Sperling, MD, said because the analysis had "power to see very small effects," she was "a little surprised" there was no association with lifestyle factors.

"I think this suggests that those lifestyle factors primarily affect resilience or vulnerability to pathology and that the main thing that drives at least amyloid pathology is age and genetics," said Sperling, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts.

With completion expected in late 2022, the A4 study is a phase 3 secondary prevention trial testing whether the anti-amyloid monoclonal antibody solanezumab (Eli Lilly) can slow cognitive decline associated with elevated brain amyloid if started before clinical symptoms appear. 

"A major issue for amyloid-targeting Alzheimer's disease clinical trials, and one that is being addressed with the A4 study, is that previous trials may have been intervening too late in the disease process to be effective," Richard Hodes, MD, director of the National Institute on Aging, said in a statement.

"A4 is pioneering in the field because it targets amyloid accumulation in older adults at risk for developing dementia before the onset of symptoms," Hodes added.

The study is being conducted at 67 sites in the US, Canada, Australia, and Japan.

Investigators did a cross-sectional analysis of demographic, cognitive, and amyloid positron emission tomography (PET) imaging data (collected between 2014 and 2017) for 4486 clinically normal A4 participants (mean age, 71 years, 59% women). Based on the screening PET algorithm, 1323 (29.5%) were categorized as having elevated amyloid beta (Aβ+) and 3163 (70.5%) as not having elevated amyloid beta (Aβ−).

Aβ+ participants were more likely than Aβ− participants to have a family history of dementia (74% vs 68%) and to have at least one APOE ε4 allele (58% vs 25%).

Aβ+ participants were slightly older than their Aβ− peers, but with no differences in sex or any self-reported lifestyle factors, including exercise; use of alcohol, caffeine, or tobacco; or body mass index.

No Protective Effect of Higher Education

"Our findings, consistent with recent longitudinal studies investigating the association of sex and physical activity, suggest that these risk factors for AD dementia may play a role in the vulnerability/resilience to cognitive decline in the setting of elevated Aβ rather than serving as a risk factor for Aβ accumulation itself," Sperling and colleagues write.

There was also no protective effect of higher education on amyloid burden.

"We've known for a while that education seems to be protective from getting a diagnosis of Alzheimer's dementia and I've always thought, unfortunately, that education allows us to hide our cognitive impairment for a longer time period — not that it really protects against Alzheimer's," Sperling said during the podcast.

"We hypothesize that those with lower levels of education may show evidence of cognitive decline earlier," she added.

Aβ+ participants performed worse on the screening Preclinical Alzheimer Cognitive Composite (PACC, Cohen d = −0.32; P < .001), which includes the Mini-Mental State Examination (MMSE) score, Digit Symbol Substitution test, Logical Memory (LM) Delayed Recall-IIa and the Free and Cued Selective Reminding Test (FCSRT). 

This effect size was somewhat diminished after accounting for age, sex, and education covariates, but it remained highly significant (Cohen d = −0.18; P < .001).

Aβ+ participants also self-reported greater subjective decline in cognitive function over the past year on the Cognitive Function Index (CFI, Cohen d = 0.31; P < .001); study partners also reported that the Aβ+ participants had greater recent declines, albeit with a smaller effect size (Cohen d = 0.23).

The CFI is a key secondary outcome in the A4 Study. It consists of a 15-item questionnaire administered separately to the participant and his or her partner that asks for yes, no, and maybe responses about changes in cognitive function over the past 12 months.

The investigators note that work is underway to determine whether some combination of test scores, subjective reports, family history, genetic testing, and eventually blood-based biomarkers of amyloid and tau protein can improve the accuracy of predicting amyloid status in cognitively normal adults.

Prevention Trials Feasible

Commenting on the A4 data for Medscape Medical News, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation, said the associations in this cross-sectional data are "interesting."

"The data advance our knowledge and perspective in that these are people who have rather modest or mild amyloid deposition, but they clearly have some complaints of cognitive changes subjectively and can be identified as having some mild cognitive deficits," Fillit said. 

"With this kind of data, it is very clear that we can identify people with disease much earlier and that beta amyloid as a biomarker seems to identify people at greater risk of progression, at least in this cross-sectional study," Fillit added.

He said the A4 screening data also demonstrates the feasibility of doing a prevention trial. The screening protocol represents a "methodology that is viable." However, once a blood test takes over for PET imaging, "these kinds of prevention trials will be more efficient and less expensive," he noted.

This study was funded by the National Institute on Aging, Eli Lilly and Co, and several philanthropic organizations. Sperling reported grant support from the National Institutes of Health (NIH), Eli Lilly, Alzheimer's Association, GHR Foundation, Fidelity, and Gates Ventures; nonfinancial support from CogState and Mount Sinai; grants and personal fees from Janssen; and personal fees from AC Immune, Biogen, Neurocentria, Eisai, Roche, Takeda, and Novartis. Fillit has disclosed no relevant financial relationships.

JAMA Neurology. Published online April 6, 2020. Abstract

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