Reciprocal Predictive Relationships between Amyloid and Tau Biomarkers in Alzheimer's Disease Progression: An Empirical Model

Abstract

There is an urgent need to understand the relationships between amyloid-␤ (A␤) and tau in the progression of Alzheimer's disease to identify treatment targets. Here we examine reciprocal predictions of brain A␤ burden quantified by positron emission tomography and CSF concentrations of A␤42 and phosphorylated tau (p-tau). Each biomarker was examined over 48 months in two separate cross-lagged models; one in asymptomatic healthy elderly people (men and women), and one in patients with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI). The models examine predictions of each biomarker on the progression of the others, considering each previous and concurrent measure. In healthy elderly, lower CSF A␤42 predicted A␤ deposition and reciprocally, A␤ burden predicted a decrease in CSF A␤42. Lower CSF A␤42 predicted an increase in CSF p-tau, and CSF p-tau predicted A␤ deposition. In AD/MCI, lower CSF A␤42 predicted A␤ deposition and A␤ burden reciprocally predicted CSF A␤42 changes; however, in contrast to healthy elderly, CSF p-tau concentrations did not predict A␤ biomarkers, or vice versa. In post hoc models examining cognitive status, CSF A␤42 predicted Mini Mental State Examination (MMSE) scores in healthy elderly, whereas A␤ burden and CSF p-tau predicted MMSE scores in AD/MCI. The findings describe reciprocal predictions between A␤ and tau biomarkers in healthy elderly and they implicate mechanisms underlying low CSF A␤42 in Alzheimer's disease pathogenesis and progression. In symptomatic Alzheimer's disease, CSF A␤42 and A␤ deposition predicted each other; however, A␤ and CSF p-tau progressed independently and they independently predicted cognitive decline.

Subtle cognitive impairment as a marker of Alzheimer's pathologies and clinical progression in cognitively normal individuals

“…In any case, our data demonstrated a predictive relationship of CSF Aβ 1‐42 on amyloid PET and supported the temporal evolution of the first appearance of CSF abnormality followed by PET abnormality 33 . Although CSF and PET Aβ biomarkers track the same protein, they deliver unique information about the underlying AD pathogenesis process 34,35 . The different performance of baseline SCI in predicting subsequent CSF and PET pathologies was consistent with the temporal evolution, in which abnormality initially appeared in CSF, followed by PET 33 .…”

“…33 Although CSF and PET Aβ biomarkers track the same protein, they deliver unique information about the underlying AD pathogenesis process. 34,35 The different performance of baseline SCI in predicting subsequent CSF and PET pathologies was consistent with the temporal evolution, in which abnormality initially appeared in CSF, followed by PET. 33 It is reasonable to speculate that SCI performed a more accurate prediction of amyloid PET than CSF.…”

Multiple markers contribute to risk of progression from normal to mild cognitive impairment

“…All participants in HABS provided written informed consent prior to study procedures. At study entry, all participants were clinically normal, had a global CDR of 0 ( Morris, 1993 ), Mini-Mental State Examination (MMSE) ≥ 27 with educational adjustment ( Folstein et al, 1975 ), Geriatric Depression Scale < 11 ( Yesavage et al, 1982 ), and performed within education-adjusted norms on Logical Memory delayed recall ( Wechsler, 1987 ). All participants were screened for major neurological, psychiatric or unstable medical illnesses.…”

“…Cognition was measured with a battery of neuropsychological and behavioral tasks selected primarily to represent domains of episodic memory, executive function, and processing speed. Episodic memory was assessed using the delayed recall score from the Wechsler Memory Scale-Revised Logical Memory subtest ( Wechsler, 1987 ), the free recall score from the Free and Cued Selective Reminding Test ( Grober et al, 2000 ), and the delayed recall score from Six-Trial Selective Reminding Test ( Masur et al, 1990 ). Executive function was assessed by Letter-Number Sequencing from the Wechsler Adult Intelligence Scale-III (the number of trials correctly completed); ( Wechsler, 1997 ) phonemic fluency (the sum of the words produced in response to the letters F, A, S, each over 60 s); ( Spreen and Benton, 1977 ) and the Trail Making Test (time to complete Form B minus Form A) ( Reitan, 1958 ).…”

Age, vascular disease, and Alzheimer’s disease pathologies in amyloid negative elderly adults

“…Relationships between tau and a number of other variables have been reported, including age [ 29 – 33 ], sex [ 33 , 34 ], apolipoprotein E (APOE) genotype [ 31 , 35 , 36 ], and vascular risk factors including white matter hyperintensities (WMH) [ 25 , 37 , 38 ] and blood pressure [ 39 – 41 ]. The question of how these factors relate to tau among Aβ- individuals who are not (yet) on the AD pathway is not fully understood.…”