Background and purpose Alzheimer's disease (AD) is considered a clinical and biological continuum identified via cerebrospinal fluid (CSF) or imaging biomarkers. Chronic hypoperfusion is held as one of the main features of Alzheimer's disease, as part of the processes causing neuronal degeneration. The mechanism responsible for such condition is still debated, although recently a direct connection with amyloid peptides has been shown. Here the aim was to investigate whether measures of hypoperfusion change along the AD continuum. Methods Seventy patients with mild AD were recruited and stratified according to their CSF biomarker profile—as indicated by the National Institute on Aging and Alzheimer’s Association research framework—into patients with either isolated amyloid pathology (A+T−) or full‐blown AD (A+T+), and further layered according to apolipoprotein E genotype. After evaluation of vascular risk factors, a transcranial Doppler was performed on each patient, to evaluate mean flow velocity and pulsatility index in the middle cerebral artery, and to calculate the breath‐holding index. Patients were compared to a cohort of 17 healthy controls. Results The breath‐holding index was reduced in the AD continuum and was inversely correlated to CSF amyloid β42 levels. Such correlation was stronger in the A+T+ than in the A+T− group, and unexpectedly reached statistical significance only in the E3 and not in the E4 genotype carriers. Conclusions These results suggest a tight and effective relationship between amyloid β42, vascular hypoperfusion, cerebrovascular reactivity and epsilon genotype.

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Background and purpose Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD) and shares some pathological pathways, such as activation of amyloid cascade and tau phosphorylation. The aim of the present study was to investigate to what extent DM could impact on neurodegeneration within the AD continuum, using β amyloid (A: Aβ1‐42) and phosphorylated tau (T: p‐tau) biomarkers to discriminate patients by Alzheimer's pathological change (A+/T–) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association classification. In addition, we aimed to evaluate whether APOE genotype interacts with tau protein and glucose metabolism dysfunction to affect the pathological process. Methods For this retrospective observational study, 1350 patients were recruited. The patients underwent a complete clinical investigation, neuropsychological assessment, lumbar puncture for cerebrospinal fluid (CSF) biomarkers analysis and APOE genotyping. Results A total of 607 patients fulfilled the clinical criteria of mild cognitive impairment or early dementia. In A+T– patients (n = 350), DM did not influence CSF biomarker levels, while among A+T+ patients (n = 257) those with DM showed increased total tau (t‐tau) levels compared to non‐DM patients (DM: 919.4 ± 444 vs. non‐DM: 773.1 ± 348.2; p = 0.04), but similar p‐tau (p = 0.72) and Aβ1‐42 levels (p = 0.83). Furthermore, multivariable regression analyses showed a significant association between DM and t‐tau CSF levels, adjusting for age and sex, in APOE E4+ carriers (coefficient 222.83, 95% confidence interval 47.49–398.1; p = 0.01), but not in APOE E4‐ (p = 0.53). Conclusions The present study shows a clear dependency of CSF t‐tau levels on DM for APOE E4+ AD patients, suggesting important differences between APOE E4‐related and non‐related disease, with key implications for AD pathophysiology and treatment.

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