Oh brother, where art tau? Amyloid, neurodegeneration, and cognitive decline without elevated tau

Abstract

Highlights Amyloid, tau and neurodegeneration are Alzheimer’s disease (AD) biomarkers. Mild cognitive impairment (MCI) cases were grouped using the “A/T/(N)” model. A+T-N+ MCI had less episodic memory loss and slower decline than A+T+N+ MCI. A+T-N+ MCI was more like A-T-N+ than A+T+N+ MCI on whole brain cortical thickness. A+T-N+ MCI’s less “AD-like” profile suggests that non-AD pathologies drive symptoms.

Differential diagnosis of amnestic dementia patients based on an FDG‐PET signature of autopsy‐confirmed LATE‐NC

“…On the other hand, negative tau (or amyloid) biomarker findings in older amnestic patients are unlikely to be specific for LATE-NC because there are several different impactful pathologic conditions (often present in combination) associated with advanced age. 1,2,41,44 In addition to lower AD biomarker levels, patients with a LATE-NClike FDG-PET pattern showed several clinical and genetic features that were previously linked to LATE-NC in pathologic studies, particularly older age, a more memory-predominant cognitive profile with an overall slower disease course, as well as enrichment for the TMEM106B risk allele. 3,11,14 In line with the intermediate APOE ε4 prevalence reported for autopsy-confirmed LATE-NC cases, 15,16 patients with a LATE-NClike FDG-PET pattern also showed a significantly lower APOE ε4 allele load compared to typical AD-like patients, albeit still enriched compared to a population level of ≈25%.…”

“…However, analysis of pathologically well‐validated molecular AD biomarkers 34 demonstrated that these individuals indeed had significantly lower levels of AD pathology, indicating that other, non‐AD pathologic factors account for their cognitive deficits. Previous research has suggested to pre‐screen older amnestic patients by a negative amyloid or tau biomarker finding, which would exclude AD as the principal pathologic substrate for the cognitive deficits 21,39–41 . Correspondingly, Botha et al 21 .…”

“…Hence, suprathreshold CSF p‐tau181 levels may not necessarily indicate neurofibrillary tangle pathology levels that would be sufficient to account for a clinical dementia syndrome. On the other hand, negative tau (or amyloid) biomarker findings in older amnestic patients are unlikely to be specific for LATE‐NC because there are several different impactful pathologic conditions (often present in combination) associated with advanced age 1,2,41,44 …”

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

“…Similarly, medial temporal hypometabolism on FDG-PET was recently suggested as a biomarker of LATE, based on both autopsy-validated and a large cross-sectional FDG data set. 25 Increasing evidence suggests that medial temporal atrophy and dysfunction occurring in the absence of Aβ 26 or tau 27 pathology are associated with cognitive decline. Further work should better determine the sensitivity of different tau-PET tracers to PART to better distinguish the respective contributions of PART and LATE to hippocampal atrophy and cognitive decline.…”

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…Cerebrovascular disease is a well‐known risk factor for AD and is found as a co‐pathology in 70% of people diagnosed with AD dementia. Risk of cardiovascular disease is associated with cerebrovascular dysfunction, and high scores on the Framingham General Cardiovascular Disease Risk Score were associated with worse baseline and longitudinal measures of glucose metabolism, executive function and other cognitive measures, and clinical progression 239 . Recent ADNI studies have continued to investigate the effects of cerebrovascular disease on disease progression using measures of CBF, an indicator of neurovascular function detected using arterial spin labeling MRI, and WMH burden, an MRI marker of small vessel cerebrovascular disease.…”