Cortical thickness, brain metabolic activity, and in vivo amyloid deposition in asymptomatic, middle-aged offspring of patients with late-onset Alzheimer's disease

AbstractNo in vivo human studies have examined the prevalence of Alzheimer’s disease (AD) neuropathology in individuals with alcohol-use disorder (AUD), although recent research suggests that a relationship between the two exists. Therefore, this study used Pittsburgh Compound-B ([11C]PiB) PET imaging to test the hypothesis that AUD is associated with greater brain amyloid (Aβ) burden in middle-aged adults compared to healthy controls. Twenty healthy participants (14M and 6F) and 19 individuals with AUD (15M and 4F), all aged 40–65 years, underwent clinical assessment, MRI, neurocognitive testing, and positron emission tomography (PET) imaging. Global [11C]PiB standard uptake value ratios (SUVRs), cortical thickness, gray matter volumes (GMVs), and neurocognitive function in subjects with AUD were compared to healthy controls. These measures were selected because they are considered markers of risk for future AD and other types of neurocognitive dysfunction. The results of this study showed no significant differences in % global Aβ positivity or subthreshold Aβ loads between AUD and controls. However, relative to controls, we observed a significant 6.1% lower cortical thickness in both AD-signature regions and in regions not typically associated with AD, lower GMV in the hippocampus, and lower performance on tests of attention as well as immediate and delayed memory in individuals with AUD. This suggest that Aβ accumulation is not greater in middle-aged individuals with AUD. However, other markers of neurodegeneration, such as impaired memory, cortical thinning, and reduced hippocampal GMV, are present. Further studies are needed to elucidate the patterns and temporal staging of AUD-related pathophysiology and cognitive impairment. Imaging β-amyloid in middle age alcoholics as a mechanism that increases their risk for Alzheimer’s disease; Registration Number: NCT03746366.

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Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer’s disease trigger BACE1 accumulation in axonal swellings

Science Translational Medicine ◽

10.1126/scitranslmed.aba1871 ◽

2020 ◽

Vol 12 (570) ◽

pp. eaba1871

Author(s):

Selene Lomoio ◽

Rachel Willen ◽

WonHee Kim ◽

Kevin Z. Ho ◽

Edward K. Robinson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variant ◽

Late Onset ◽

Early Stage ◽

Loss Of Function ◽

Axonal Trafficking ◽

Axonal Swellings

Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer’s disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the β-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo. We show that BACE pharmacological inhibition ameliorates BACE1 axonal trafficking and diminishes axonal dystrophies in Gga3 null neurons in vitro and in vivo. These data indicate that axonal accumulation of BACE1 engendered by GGA3 loss of function results in local toxicity leading to axonopathy. Gga3 deletion exacerbates axonal dystrophies in a mouse model of AD before β-amyloid (Aβ) deposition. Our study strongly supports a role for GGA3 in AD pathogenesis, where GGA3 loss of function triggers BACE1 axonal accumulation independently of extracellular Aβ, and initiates a cascade of events leading to the axonal damage distinctive of the early stage of AD.

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