Amyloid Accumulation Doesn't Always Precede Cognitive Decline

Damian McNamara

January 06, 2020

Amyloid accumulation may not always come before cognitive decline, new data suggest.

Findings from the Alzheimer's Disease Neuroimaging Initiative (ADNI) show cognitive deficits on neuropsychological testing arose before amyloid plaque build-up and cortical thinning on PET or MRI scans. Participants with objectively defined subtle cognitive difficulties (Obj-SCD), in fact, were nearly three times more likely to be diagnosed with MCI later. For example, 46% of the Obj-SCD cohort developed MCI at 48 months vs 17% of a control group.

"Our results suggest that subtle cognitive difficulties can be reliably measured and, on average, predict faster rates of amyloid accumulation and entorhinal cortex thinning than those with normal cognition," lead author Kelsey R. Thomas, PhD, Research Health Scientist at the VA San Diego Healthcare System in California, told Medscape Medical News.

"Therefore, sensitive neuropsychological assessment, even a relatively brief battery of tests, can provide meaningful prognostic information about future risk for Alzheimer's disease progression," she added.

The study was published online December 30 in the journal Neurology.

Searching for Subtle Signals

Although some prior research has used subjective testing to detect cognitive decline, Thomas and colleagues opted to measure deficits objectively.

This approach allowed them to identify subtle difficulties even when a person tested in a normal range overall. As an example, a person might be able to recall an average number of correct words during a list-learning test, but may also add incorrect words.

"This is the first study, to our knowledge, to investigate the relationship between Obj-SCD, defined using sensitive neuropsychological measures, and the trajectory of amyloid PET changes," the investigators note.

They studied data for 747 older adults without dementia at baseline enrolled in ADNI. Within this population, they compared PET, MRI, and neuropsychological performance among 153 Obj-SCD participants, 289 with MCI, and 305 cognitively normal participants. Florbetapir PET scans and T1-weighted anatomical MRI were performed at baseline and at 12, 24, 36, and 48 months.

Those in the Obj-SCD group featured slightly higher amyloid levels at baseline than the cognitively normal cohort, but the difference was not statistically significant.

Predicting Faster Brain Changes

Compared with cognitively normal participants, those with Obj-SCD demonstrated faster increases in their amyloid PET standardized uptake value ratio (t[1109.08] = 2.58; P = .010; r = 0.077). However, people with MCI did not differ significantly from those in the Obj-SCD or cognitively normal groups in the rate of amyloid accumulation over 48 months.

Entorhinal cortex thinning was significantly faster in the Obj-SCD participants (t[540.45] = −2.95, P =.003, r = −0.126) and MCI group (t[590.28] = −6.57, P < .001, r = −0.261) compared with the cognitively normal group over 48 months.

Thomas and colleagues also tracked hippocampal volume loss. Compared with the cognitively normal group, participants with MCI had a faster rate of hippocampal volume loss over 48 months (t[525.68] = −4.06, P < .001, r = 0.174). In contrast, the volume loss rate for participants with Obj-SCD did not statistically differ from that of cognitively normal participants (t[478.21] = −1.79, P = .074, r = −0.082) or people with MCI (t[511.81] = 1.62, P = .105, r = 0.071).

The researchers note, "the finding that the Obj-SCD group had faster entorhinal cortical thinning, but only trend level changes in hippocampal volume relative to the cognitively normal group, may suggest that Obj-SCD captures individuals very early in the neurodegenerative process."

The Obj-SCD criteria are in development for clinical use but, for now, remain a research tool. To adapt to clinical use would require no more than 1 hour of neuropsychological testing that covers the domains of memory, attention/executive functioning, and language, Thomas said. "This approach is arguably more accessible to many individuals than expensive and invasive biomarker testing."

The investigators noted some study limitations. The population was highly educated, mostly white, and very healthy, so generalizability to more diverse, community-based samples is unknown, for example. They also note the 48-month follow-up could be too short to detect all changes in brain structure.  

Thomas and colleagues would like to study the role of tau pathology in future studies. One aim is to determine whether tau deposition influences changes in the entorhinal cortex and hippocampus associated with the subtle cognitive difficulties observed in the Obj-SCD groups.

"We know there is a consistent association between tau and cognitive functioning," Thomas said. The findings that Obj-SCD predicted entorhinal cortex thinning whereas MCI predicted more widespread medial temporal lobe atrophy are consistent with Braak staging for the spreading of tau pathology, she added.

"Therefore, we plan to investigate whether tau is already present in the brain when someone is first classified as having subtle cognitive difficulties." 


Challenging the Role of Amyloid

"In this issue of Neurology, Thomas et al tested the specific hypothesis that if amyloid deposition occurs long before downstream detectable effects on cognition, the presence of cognitive deficits should not precede accumulating rates of amyloid deposition. They found, however, that they do," write Beth E. Snitz, PhD, a neuropsychologist at the University of Pittsburgh School of Medicine in Pennsylvania, and Adam M. Brickman, PhD, College of Physicians and Surgeons, Columbia University, New York City, in an accompanying editorial.

"In a large cohort of older adults without dementia, a subgroup with objectively defined subtle cognitive difficulties identified on neuropsychological testing at baseline showed increasing brain amyloid deposition on PET imaging over 4 years, despite having baseline amyloid levels that were similar to those characterized as cognitively normal."

The results of this study challenge prevailing models of both the initiating role of amyloid and the requirement of biomarker evidence of amyloid for defining the Alzheimer continuum, added Snitz and Brickman.

"A second important point in the Thomas et al article," the editorialists say, "is the demonstration that subtle objective cognitive deficits can be measured reliably and predict important biological changes associated with Alzheimer disease."

Thomas, Snitz, and Brickman have disclosed no relevant financial relationships. Grants from the NIH, the Alzheimer's Association and the US Department of Veterans Affairs Clinical Sciences Research and Development Service funded the study. The Alzheimer's Disease Neuroimaging Initiative and an award from the Department of Defense provided additional support.

Neurology. Published online December 30, 2019. Abstract, Editorial

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