Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

BACKGROUND: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid ß. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid ß production. METHODS: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aß37, Aß38, Aß40, Aß42, and Aß43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [11C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [18F] fluorodeoxyglucose (FDG)-PET, CSF Aß42-to-Aß40 ratio (Aß42/40), CSF log10 (phosphorylated tau 181), CSF log10 (phosphorylated tau 217), and MRI-based hippocampal volume. FINDINGS: Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p<0·0001). GSC was associated with MMSE (ß=0·08, SE 0·03; p=0·0043), CDR-SB (-0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB-PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). INTERPRETATION: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid ß production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. FUNDING: US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III.