Glymphatic perivascular exchange is supported by the astroglial water channel aquaporin-4 (AQP4), which localizes to perivascular astrocytic endfeet surrounding the cerebral vasculature. In aging mice, impairment of glymphatic function is associated with reduced perivascular AQP4 localization, yet whether these changes contribute to the development of neurodegenerative disease, such as Alzheimer’s disease (AD), remains unknown. Using post mortem human tissue, we evaluated perivascular AQP4 localization in the frontal cortical gray matter, white matter, and hippocampus of cognitively normal subjects and those with AD. Loss of perivascular and increasing cellular localization of AQP4 in the frontal gray matter was specifically associated with AD status, amyloid β (Aβ) and tau pathology, and cognitive decline in the early stages of disease. Using AAV-PHP.B to drive expression on non-perivascular AQP4 in wild type and Tg2576 (APPSwe, mouse model of Aβ deposition) mice, increased cellular AQP4 localization did not slow glymphatic function or change Aβ deposition. Using the Snta1 knockout line (which lacks perivascular AQP4 localization), we observed that loss AQP4 from perivascular endfeet slowed glymphatic function in wild type mice and accelerated Aβ plaque deposition in Tg2576 mice. These findings demonstrate that loss of perivascular AQP4 localization, and not increased cellular AQP4 localization, slows glymphatic function and promotes the development of AD pathology. To evaluate whether naturally occurring variation in the human AQP4 gene, or the alpha syntrophin (SNTA1), dystrobrevin (DTNA) or dystroglycan (DAG1) genes (whose products maintain perivascular AQP4 localization) confer risk for or protection from AD pathology or clinical progression, we evaluated 56 tag single nucleotide polymorphisms (SNPs) across these genes for association with CSF AD biomarkers, MRI measures of cortical and hippocampal atrophy, and longitudinal cognitive decline in the Alzheimer’s Disease Neuroimaging Initiative I (ADNI I) cohort. We identify 25 different significant associations between AQP4, SNTA1, DTNA, and DAG1 tag SNPs and phenotypic measures of AD pathology and progression. These findings provide complimentary human genetic evidence for the contribution of perivascular glymphatic dysfunction to the development of AD in human populations.

Age-associated dementias are neuropathologically characterized by the identification of hallmark intracellular and extracellular deposition of proteins, i.e., hyperphosphorylated-tau, amyloid-β, and α-synuclein, or cerebrovascular lesions. The neuropathological assessment and staging of these pathologies allows for a diagnosis of a distinct disease, e.g., amyloid-β plaques and hyperphosphorylated tau pathology in Alzheimer's disease. Neuropathological assessment in large scale cohorts, such as the UK’s Brains for Dementia Research (BDR) programme, has made it increasingly clear that the ageing brain is characterized by the presence of multiple age-associated pathologies rather than just the ‘pure’ hallmark lesion as commonly perceived. These additional pathologies can range from low/intermediate levels, that are assumed to have little if any clinical significance, to a full-blown mixed disease where there is the presence of two distinct diseases. In our recent paper (McAleese et al. 2021 Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia, https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12291, Alzheimer's & Dementia), using the BDR cohort, we investigated the frequency of multimorbidity and specifically investigated the impact of additional low-level pathology on cognition. In this study, of 670 donated post-mortem brains, we found that almost 70% of cases exhibited multimorbidity and only 22% were considered a pure diagnosis. Importantly, no case of Lewy Body dementia or vascular dementia was considered pure. A key finding is that the presence of low levels of additional pathology increased the likelihood of having mild dementia vs mild cognitive impairment by almost 20-fold, indicating low levels of additional pathology do impact the clinical progression of a distinct disease. Given the high prevalence and the potential clinical impact, cerebral multimorbidity should be at the forefront of consideration in dementia research.

Constipation is a common but not a universal feature in early PD, suggesting that gut involvement is heterogeneous and may be part of a distinct PD subtype with prognostic implications. We analysed data from the Parkinson’s Incidence Cohorts Collaboration, composed of incident community-based cohorts of PD patients assessed longitudinally over 8 years. Constipation was assessed with the MDS-UPDRS constipation item or a comparable categorical scale. Primary PD outcomes of interest were dementia, postural instability and death. PD patients were stratified according to constipation severity at diagnosis: none (n=313, 67.3%), minor (n=97, 20.9%) and major (n=55, 11.8%). Clinical progression to all 3 outcomes was more rapid in those with more severe constipation at baseline (Kaplan Meier survival analysis). Cox regression analysis, adjusting for relevant confounders, confirmed a significant relationship between constipation severity and progression to dementia, but not postural instability or death. Early constipation may predict an accelerated progression of neurodegenerative pathology. Conclusions: We show widespread cortical and subcortical grey matter micro-structure associations with schizophrenia PRS. Across all investigated phenotypes NDI, a measure of the density of myelinated axons and dendrites, showed the most robust associations with schizophrenia PRS. We interpret these results as indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks mediating the genetic risk for schizophrenia.