Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults

Abstract

Background:Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared to amyloid-beta (Aβ) and tau imaging, it is less specific for Alzheimer’s disease (AD) pathology. This lack of specificity could provide indirect information about potential co-pathologies that cannot be observedin vivo. In this prospective cohort study, we aimed to assess the associations among Aβ, tau, HV, and cognition, measured over a ten-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aβ and tau.Methods:We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI [follow-up duration: 1.3-7.0y], neocortical Aβ imaging on PiB PET scans [1.9-8.5y], entorhinal and inferior temporal tau on Flortaucipir PET scans [0.8-6.0y], and the Preclinical Alzheimer Cognitive Composite [3.0-9.8y] were prospectively collected. We evaluated the longitudinal associations between Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline.Results:We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years old (range: 63-87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2=0.28, p<0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers.Discussion:In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwisein vivo.

Clinically feasible automated MRI volumetry of the brain as a prognostic marker in subjective and mild cognitive impairment

“…In line with our finding, Mungas et al ( 59 ) also found an association between hippocampus atrophy at baseline and cognitive decline measured by annual change in CDR scores. Further, a similar association was found in a recent study from Hanseeu et al ( 60 ) following a cohort of clinically healthy older adults over a decade. Moreover, Verfaillie et al ( 46 ) found that widespread cortical thinning in patients with SCD at baseline at a memory clinic was associated with a faster decline in memory over time.…”

Rodent Models of Alzheimer’s Disease: Past Misconceptions and Future Prospects

“…Unlike other transgenic mice that exhibit hippocampal neurodegeneration from an early age [ 140 , 141 ], this strain shows limited neuronal loss in the hippocampus even up to 17 months old. This resembles the hippocampal degeneration seen in later stages of human AD (where hippocampal volume loss occurs after degeneration of other structures [ 123 ] and correlates with cognitive decline, i.e., is more severe in later stages of the disease [ 142 , 143 ]). Nonetheless, the concurrent presence of Aβ and tau throughout development and maturation in 3xTg-AD mice does not reflect the progressive and potentially sequential appearance of these markers in AD.…”

Application of proteomics in brain's aging research

“…Conventional morphological changes in the aging brain contain cerebral sulci deepening and atrophy (Kochunov et al, 2012;Hanseeuw et al, 2023). Decreases in volume and neuronal plasticity were observed in aging HIP (Burke & Barnes, 2006;Griffioen, 2023).…”