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

Abstract

Background We recently reported that CSF phosphorylated tau (p-Tau181) relative to Aβ40 (CSF p-Tau/Aβ40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau181 alone. While elevations of CSF p-Tau/Aβ40 can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity. Methods We examined relationships between CSF p-Tau/Aβ40, and CSF Aβ42/Aβ40, Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer’s disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had 18F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ40 associations with these measures as well. Results Elevated CSF p-Tau/Aβ40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ42/Aβ40, higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements. Conclusions These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.

Interactions between apolipoprotein E, sex, and amyloid-beta on cerebrospinal fluid p-tau levels in the European prevention of Alzheimer's dementia longitudinal cohort study (EPAD LCS)

“…For example, sex differences in the prevalence of vascular-related risk factors exist where males have more vascular risk factors and vascular events than females before the ages of 70-75, 35 which have been associated with levels of CSF p-tau and Aβ 42 . 36 , 37 , 38 Sleep disturbances and increased wakefulness have been associated with Aβ and tau accumulation, as well as tau phosphorylation. 39 , 40 Insomnia is almost 1.5 times more common in females than males 41 and has been reported to be increased in APOE ε4 carriers, 42 although no known study has examined any sex- APOE interactions in association with sleep disturbances.…”

Altered serum amyloid beta and cerebral perfusion and their associations with cognitive function in patients with subcortical ischemic vascular disease

“…However, Aβ40/42 ratio was found to be positively correlated with WMHV in the whole SIVD patients. Recent studies found that Aβ0 and Aβ2 levels in cerebrospinal fluid were associated with WMHV ( Osborn et al, 2018 ; Guo et al, 2021 ), suggesting that Aβ40 and Aβ42 levels may be associated with white matter damage in SIVD patients. At the same time, we also found that WMHV was negatively correlated with CBF in the whole brain and GM, overall cognition, information processing speed, and executive function, while Jann et al (2021) also found that WMHV was associated with whole-brain perfusion and executive function in cerebral small vessel disease patients, which was similar to our findings.…”

Initial levels of β-amyloid and tau deposition have distinct effects on longitudinal tau accumulation in Alzheimer’s disease

“…Modeling methodology differences might underlie the discrepancies. While the local Aβ and tau interaction (Aβ × tau) within the same region was modeled in their study [22], we used a summary cortical SUVR of several areas [31] to represent cortical Aβ burden, and Aβ plaques and regional tau tangles were modeled separately to distinguish their respective contributions in the downstream tau accumulations. Therefore, our ndings suggest that tau propagations depend more on existing tau tangles than cortical Aβ plaques in late tau-affected ROIs of Temporal-metaROI when Aβ plaques and tau tangles are already widespread in neocortex and Temporal-metaROI.…”

“…FBP or FBB standardized uptake value ratios (SUVRs) were obtained by normalizing regional FBP or FBB uptake to that in the whole cerebellum reference region. One AD summary cortical SUVR was calculated as a volume-weighted SUVR of frontal, cingulate, parietal, and lateral temporal regions, and A+ was de ned as AD summary cortical SUVR of FBP ≥1.11 or FBB ≥1.08, and FBP and FBB SUVRs were converted to Centiloids as described previously [31].…”