While many studies have tracked the mental abilities of healthy people who test positive for Alzheimer’s biomarkers, few have examined the very old over the long term. Now, a group led by Beth Snitz at the University of Pittsburgh details how Aβ accumulation and hippocampal atrophy correlate with cognitive performance over an average of 12 years in people with an average age of 86. They report that while amyloid-positive individuals were more likely to develop deficits in many cognitive domains, those who lost only hippocampal volume tended to experience just memory loss. The findings, published in the November 6 JAMA Neurology, dissect how different pathologies affect different cognitive abilities, and shed light on the long-term consequences of Suspected Non-Alzheimer Pathophysiology (SNAP).
- AD-related biomarkers in very old, healthy people foreshadow long-term cognitive trajectories.
- As in younger cohorts, Aβ accumulation predicts global cognitive decline.
- Hippocampal atrophy without Aβ buildup, SNAP, correlates only with memory loss.
“This study is unique in examining a very old cohort with long follow-up,” said David Knopman, Mayo Clinic, Rochester, Minnesota.
Cognitively healthy people with amyloidosis and some sign of neurodegeneration, be it high levels of tau in cerebrospinal fluid, brain hypometabolism, and/or hippocampal atrophy (Aβ+/ND+), run a higher risk of becoming cognitively impaired late in life than people with no pathology (Aβ–/ND–). Aβ+/ND– individuals have slightly less risk than Aβ+/ND+ people, but the fate of people who have only the neurodegenerative biomarker (Aβ–/ND+) are less clear (Jack et al., 2016). Several dedicated SNAP studies that measured hippocampal volumes, cortical glucose metabolism, or tau in the cerebrospinal fluid, however, found no effects of SNAP on future cognition (Sep 2015 news; Burnham et al., 2016; Mormino et al., 2016; Soldan et al., 2016).
To assess the fate of older people who tested positive for either amyloidosis, neurodegeneration, or both, first author Yujing Zhao analyzed data from the Gingko Evaluation of Memory Study (GEMS). GEMS enrolled 3,069 participants age 75 or older who had normal cognition or mild cognitive impairment (MCI). Zhao used data from the 175 volunteers who took part in an imaging substudy. They had an average age of 78. Of these, 140 were cognitively healthy at time of enrollment while 35 had MCI. At baseline, and annually thereafter, all underwent cognitive testing, while seven to nine years after enrollment, when they were 86 years old on average, they had amyloid PET and structural MRI scans. The researchers classified individuals as Aβ+ if their global cortical PiB uptake was 1.57 times or more of that in a cerebellar reference region, and as ND+ if they had hippocampal atrophy.
At the time of imaging, 42 participants were classified as Aβ–/ND–, 32 were Aβ+/ND–, 35 deemed Aβ–/ND+, and 66 were Aβ+/ND+, a distribution similar to that of another cohort in their mid- to late-80s (Jack et al., 2014). Each class followed a distinct trajectory of cognitive decline (image above). Consistent with previous studies, Aβ+/ND+ individuals deteriorated the fastest across all cognitive domains tested, including memory, attention, reaction speed and vigilance, task-switching, reasoning, and verbal fluency, while the Aβ+/ND– group developed trouble with memory, attention, task-switching, and verbal fluency.
Notably, people in the Aβ–/ND+ (SNAP) group showed signs of memory decline. Their visual memory test scores deteriorated faster than did those of Aβ–/ND– individuals. “We saw greater separation among the biomarker groups when we did the analysis by adding a quadratic term,” noted Snitz. Previous studies had used linear fits for the data. “We know from longitudinal studies that cognitive change often doesn’t occur linearly, however, the follow-up needs to be long enough and the assessments frequent enough to test for patterns of acceleration or deceleration over time,” Snitz added.
“It is possible that their quadratic model captures decline better,” agreed Samantha Burnham from the Commonwealth Scientific and Industrial Research Organisation (CSIRO) in Australia. Burnham found that people classified as SNAP in the Australian Imaging, Biomarker, and Lifestyle (AIBL) study sometimes had slightly poorer composite cognitive scores than Aβ–/ND– individuals at baseline, but maintained those scores across the next seven years. Still, she was excited the new results mostly mirrored findings that Aβ+/ND– and Aβ+/ND+ individuals declined faster than Aβ–/ND–. Claudia Kawas, a GEM study investigator at the University of California, Irvine, emphasized the importance of age. She wondered if the older GEM cohort, 86 at time of imaging versus 73 in AIBL, might have different etiologies underlying SNAP, since various non-AD pathologies become more frequent and worsen with age.
Snitz’s study also highlighted Aβ’s role in fueling cognitive deterioration. Some postmortem studies suggested that after 80, Aβ plaques no longer correlate strongly with dementia (Savva et al., 2009; Haroutunian et al., 2008). “In this study you see a real impact of β-amyloid, even in old age,” noted Pieter Jelle Visser, VU University Medical Center in Amsterdam, adding that the finding aligns with another recent study of subjects from the AD Neuroimaging Initiative (ADNI) (Donohue et al., 2017).
Snitz thinks more insights lie ahead. “We are continuing to follow these oldest-old volunteers and we know biomarker status has changed for many,” she wrote. Visser suggested including neurodegeneration biomarkers beyond hippocampal atrophy, and applying multivariate analyses to continuous measurements, rather than categorizing them as simply positive or negative. This approach could yield more informative, unbiased insights into how cognitive performance and pathology relate to each other, he said. Knopman said that a next important step will be to include tau pathology as a separate marker from hippocampal volume and glucose metabolism, as proposed in the new amyloid/tau/neurodegeneration classification system (Aug 2016 news). “I think it will increase clarity,” he said.—Marina Chicurel
- Suspected Non-Alzheimer Pathophysiology: It’s Not Exactly a Snap
- Staging of Alzheimer’s, the Second: Neurodegeneration Does Not Equal Tauopathy
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