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Author(s): Brian Lawlor 1,2,*, Ricardo Segurado 3,4, Sean Kennelly 5,6, Marcel G. M. Olde Rikkert 7, Robert Howard 8, Florence Pasquier 9, Anne Börjesson-Hanson 10, Magda Tsolaki 11, Ugo Lucca [...], Background This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. Methods and findings NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of [greater than or equal to]12 and Conclusions The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. Trial registration Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Background: β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer’s disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. Methods: In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6–8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1–40 [Aβ1–40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated. Results: In both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aβ1–40 levels from baseline at day 28 in both the 10-mg (67–68%) and 50-mg (87–90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were − 69.37 (− 72.25; − 61.50) and − 92.74 (− 100.08; − 85.39), and for Japanese with preclinical AD, they were − 62.48 (− 78.32; − 46.64) and − 80.81 (− 96.13; − 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60–70% and 90% Aβ1–40 reductions, respectively. The trend of the reduction was similar across the Aβ1–37, Aβ1–38, and Aβ1–42 fragments in both atabecestat dose groups, consistent with Aβ1–40. CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period. Conclusions: JNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aβ1–40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults. Trial registration: ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015. [ABSTRACT FROM AUTHOR]

Approximately 100,000 persons live with Alzheimer's disease in Sweden. As the population ages, the need for diagnostics and disease-modifying treatment grows. Previously available treatments provide moderate symptom relief but do not affect disease progression. New antibody treatments show promising results and are typically well tolerated. However, adverse events include brain edema and hemorrhages, which can be detected early by MRI. These treatments require substantial resources, including increased use of MRI and radiological expertise. The introduction of new therapies will lead to higher regional healthcare costs and demands for specialized diagnostics. Implementing these therapies therefore necessitates national preparation and planning for coordinated and efficient management, addressing the significant societal and economic challenges posed by Alzheimer's disease.