Tau-aggregation inhibitor therapy for Alzheimer's disease

Many trials of drugs aimed at preventing or clearing β-amyloid pathology have failed to demonstrate efficacy in recent years and further trials continue with drugs aimed at the same targets and mechanisms.

The Alzheimer neurofibrillary tangle is composed of tau and the core of its constituent filaments are made of a truncated fragment from the repeat domain of tau. This truncated tau can catalyze the conversion of normal soluble tau into aggregated oligomeric and fibrillar tau which, in turn, can spread to neighbouring neurons. Tau aggregation is not a late-life process and onset of Braak stage 1 peaks in people in their late 40s or early 50s. Tau aggregation pathology at Braak stage 1 or beyond affects 50% of the population over the age of 45.

The initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau-tau binding domain and it is self-propagating thereafter. The initiating substrate complex is most likely formed as a consequence of a progressive loss of endosomal-lysosomal processing of neuronal proteins, particularly of membrane proteins from mitochondria. Mutations in the APP/presenilin membrane complex may simply add to the age-related endosomal-lysosomal processing failure, bringing forward, but not directly causing, the tau aggregation cascade in carriers.

Methylthioninium chloride (MTC), the first identified Tau Aggregation Inhibitor (TAI), offers an alternative to the amyloid approach and phase 3 trials are underway with a reduced version of methylthioninium that has greater tolerability and better absorption than MTC.

New clinical trials to test Alzheimer’s drugs

Participant enrollment to start in early 2014

Two new clinical trials funded largely by NIA—a major Alzheimer’s prevention study and a test of a promising insulin therapy in people with mild cognitive impairment or mild Alzheimer’s disease—are set to begin recruiting participants in early 2014.

The much-anticipated trials are being conducted by the Alzheimer’s Disease Cooperative Study (ADCS), an NIA-funded consortium of more than 76 research sites in the United States and Canada, coordinated by the University of California, San Diego. The ADCS focuses on evaluating interventions that will benefit Alzheimer’s patients across the disease spectrum.

Journal of the American Geriatrics Society Angiotensin-Converting Enzyme Inhibitors and Alzheimer's Disease Progression in Older Adults

Results From the Reseau sur la Maladie d'Alzheimer Francais Cohort

Maria E. Soto, MD, Gabor Abellan van Kan, MD, Fati Nourhashemi, MD, PhD, Sophie Gillette-Guyonnet, PhD, Matteo Cesari, MD, PhD, Christelle Cantet, MS, Yves Rolland, MD, PhD, Bruno Vellas, MD, PhD

J Am Geriatr Soc. 2013;61(9):1482-1488.

Objectives To assess whether angiotensin-converting enzyme inhibitor (ACE-I) treatment is associated with less cognitive decline in older adults with Alzheimer's disease (AD) than in those using other hypertensive or no drugs.
Design Four-year prospective multicenter cohort study with a biannual assessment.
Setting Memory clinics from 16 university hospitals in France.
Participants Community-dwelling older adults with mild to moderate AD (N = 616).
Measurements Participants were stratified into four groups according to type and duration of antihypertensive drug treatment. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE). Linear mixed-effects models were used to assess differences in decline in MMSE score between the four groups. Hypertension at each visit was included in the model.
Results Sixty-one participants had used ACE-Is continuously, 57 had used them intermittently, 189 had used other antihypertensive drugs, and 309 never used any antihypertensive drugs. Continuous ACE-Is users had a 4-year decline in MMSE of 6.4 ± 1.6 points (P < .001), intermittent ACE-Is users of 7.9 ± 1.1 points (P < .001), continuous or intermittent users of other antihypertensive drugs of 8.8 ± 0.7 points (P < .001), and never-users of 10.2 ± 0.6 points (P < .001). MMSE decline between the four groups was significantly different (adjusted P = .02). In subgroup analysis, the 118 (19.2%) participants who had continuously or intermittently used ACE-Is had a significant difference in 4-year MMSE decline from the 498 (80.8%) who had never used ACE-Is (7.5 ± 0.9 vs 9.7 ± 0.4; P = .03).
Conclusion The use of ACE-Is in older adults with AD is associated with a slower rate of cognitive decline independent of hypertension. Future research is needed to explore the role of ACE-Is in long-term AD progression.

No Effect of Multivitamins on Cognition

aking a daily multivitamin was not associated with cognitive benefits over a 12-year treatment period in male doctors aged 65 years or older in the large-scale Physicians' Health Study II (PHS II).
The study, published online December 17 in Annals of Internal Medicine, was conducted by a group led by Francine Grodstein, ScD, Brigham and Women's Hospital, Boston, Massachusetts.
"These data do not provide support for use of multivitamin supplements in the prevention of cognitive decline," the authors conclude. But they add that it is important to consider other health effects of multivitamin supplementation, including modest protection against overall cancer risk in the PHS II with long-term use.

New Alzheimer's Drug on the Market by 2017?

(Reuters) - Danish pharmaceutical group Lundbeck said on Monday that it hopes to launch a new Alzheimer's medicine in 2017 in what would be the first new drug for the condition in more than a decade.

Merck's Alzheimer's Drug Goes to Phase III After Review

(Reuters) - Merck & Co said on Tuesday it will advance its experimental Alzheimer's drug into late-stage trials among patients with mild to moderate disease, after an independent monitoring board reviewed its safety and recommended the trial continue to recruit patients.