Olfactory Bulb Amyloid-β Correlates With Brain Thal Amyloid Phase and Severity of Cognitive Impairment

Abstract

The Alzheimer disease (AD) neuropathological hallmarks amyloid β (Aβ) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aβ throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aβ and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aβ was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aβ and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aβ pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology.

Signatures for Viral Infection and Inflammation in the Proximal Olfactory System in Familial Alzheimer’s Disease

“…Our studies find that even in patients predisposed to AD due to a genetic mutation of PS1 there is evidence of viral infection in the OB suggesting that viral infection and inflammatory response in the OT are part of the etiology of the disease. Taken together with a parallel body of literature indicating that early AD is characterized by smell loss 1-3 , amyloid deposition in the olfactory epithelium (OE), and olfactory sensory neuron (OSN) dysfunction 4, 5 , our study raises the possibility that viral infection of the OB/OT accelerates AD. Because sniff-induced beta and theta-coupled gamma oscillations generated in the OB are directionally coupled to the hippocampus 25-28 , smell loss would result in decreased hippocampal gamma oscillations that have been postulated to lead to neurodegeneration and cognitive decline 29-31 .…”

“…Thus, it is essential to identify contributory pathological processes in early disease to prevent progression to dementia, disability, and death. An early process in AD, prior to clinical dementia, is a deficit in the sense of smell 1-3 accompanied by amyloid-beta (Aβ) deposition in the olfactory bulb (OB) 4, 5 . The OB receives olfactory input from olfactory sensory neurons in the olfactory epithelium (OE) 3, 6 then transmits olfactory information via the olfactory tract (OT) to the entorhinal cortex and hippocampus, brain regions essential for learning and memory that are affected in AD.…”

Odor identification score as an alternative method for early identification of amyloidogenesis in Alzheimer’s disease

“…Tau is believed to be the primary protein involved in the pathogenesis of olfactory impairment in AD. However, it has been reported that while Aβ pathology in the OB aligns with AD manifestation, Tau pathology in the OB is universally present in older adults and does not serve as an indicator of AD severity 37 . This suggests that Aβ deposition in the OB may serve as an early marker of AD onset.…”

“…Furthermore, 5 × Familial AD mice, a model for AD pathology, display high levels of Aβ accumulation in the olfactory sensory network 36 . In humans, amyloid deposition directly affects olfactory regions in the brain, leading to olfactory impairment 37 . Autopsy studies on 536 cases examining OB neuropathology in AD cases showed Aβ accumulation in the OB starting from stage 0 of Tahl Aβ phase, progressing as they advance to stage 5 37 .…”

“…The A/T/N classification system based on CSF biomarkers captures pathological brain changes at an earlier stage compared to PET imaging. Therefore, odor identification impairments precede stage 0 of the Tahl Aβ phase, characterized by Aβ42 accumulation in the OB 37 . Olfactory impairment also occurs shortly after the onset of Aβ42 accumulation in the cerebral cortex.…”