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A Small Change with Big Implications for Alzheimer’s Research

Posted on October 14th, 2016 by in Pharma R&D


Many an undergrad biochemistry student is challenged to remember the difference between the amino acids valine and isoleucine. They differ by a single methyl group in their side chains (isoleucine has one more than valine) and are so structurally and biochemically similar that they are classified together as a group called the branched chain amino acids. And yet, this seemingly small change of replacing valine with isoleucine at residue 717 in the amino acid sequence of the amyloid precursor protein (APP) results in the development of an autosomal dominant form of Alzheimer’s disease (Goate et al., 1991). This mutation, designated APPV717I, turned out to be just the first of several missense mutations (nucleotide changes that result in substitution of one amino acid for another) in the APP gene encoded on chromosome 21 that have been reported as pathogenic for AD. See AlzForum: APP for a current listing of APP mutations. Missense mutations in two other genes, presenilin -1 (PS-1) on chromosome 14, and presenilin-2 (PS-2) on chromosome 1, also result in familial forms of AD. Over 180 mutations in PS-1 have been identified (AlzForum:PS-1), making it the most common genetic cause of familial AD, while pathogenic mutations in PS-2 are less common (AlzForum:PS-2).

Many of these pathogenic mutations result in increased production of longer isoforms of Abeta compared to shorter forms of Abeta peptide, often captured in the early literature as an increased Abeta 42/40 ratio. One could envision how mutations in APP, the precursor protein for Abeta, could affect its production. However, the biochemical underpinnings of how mutations in PS-1 and PS-2 were associated with AD was unclear until it was discovered that these genes encode unusual membrane-bound aspartic acid proteases that form the catalytic subunits of gamma-secretase, the enzyme complex that generates Abeta.

Thus, mutations on three different genes, each on a different chromosome, all lead to alterations in the APP processing pathway and cause autosomal dominant forms of AD. Collectively these gene mutations have offered strong genetic support for the Amyloid-beta Cascade hypothesis for AD. They have also significantly advanced discovery research in AD around this hypothesis. Much of what we know about the processing of the amyloid-beta peptide has arisen from both cell and animal models expressing one or more of the FAD genes and most, if not all, of the disease-modifying drugs that have entered clinical trials have gone through one of these mutated models sometime during their development. And yet, individuals and families with these autosomal dominant FAD mutations largely have been excluded from participating in those clinical trials. This almost cruel exclusion is finally changing with the establishment of a series of secondary prevention trials in asymptomatic autosomal dominant mutation carriers.

Dominantly Inherited Alzheimer’s Network (DIAN)

The Dominantly Inherited Alzheimer’s Network (DIAN) began in 2008 as an observational study to collect longitudinal cognitive and biomarker data in subjects at risk for carrying one of the autosomal dominant FAD genes. A therapeutic trials unit (DIAN-TU) led by Dr. Randall Bateman at Washington University School of Medicine was added to leverage this longitudinal DIAN data and design a secondary prevention trial in individuals at risk for developing familial AD. The hypothesis to be tested is that attacking amyloid-beta pathology before cognitive symptoms appear will be more effective at delaying progression to dementia than treatment later in the disease course. The first trial has completed enrollment of 200 subjects randomized between placebo and two experimental Abeta immunotherapies, solanezumab and gantenerumab. The trial runs for two years in a biomarker mode, and then an additional two years evaluating a variety of cognitive endpoints with results expected in 2019. As opposed to conventional trials, drop-out rates are very low, which adds to the statistical power of this small trial. For additional details, see NCT01760005.

Alzheimer’s Prevention Initiative (api)

DIAN includes family members with mutations in all three FAD genes (e.g., APP, PS-1, and PS-2). Thus, one of the unknowns in the DIAN-TU is whether the disease encoded by so many different FAD mutations will respond uniformly to treatment. The Alzheimer’s Prevention Initiative (API) championed by Dr. Eric Reiman at the Banner Alzheimer’s Institute in Arizona has taken the opposite approach and is conducting a clinical trial with an extremely large Columbian family (over 5,000 members) that has a single FAD mutation (PSEN1 E280A) responsible for their Alzheimer’s disease (NCT01998841). The initial trial in this cohort will be completely enrolled by the end of this year, and asymptomatic mutation carriers will be assigned to either placebo (n=100) or crenezumab (n=100), another experimental Abeta immunotherapy, and treated for five years with a specialized composite cognitive test as the primary endpoint. Results are expected from this trial in 2020.

Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4)

A secondary prevention trial for AD complementary to those above on autosomal dominant AD is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial (NCT02008357). The A4 trial, championed by Reisa Sperling at Harvard Medical School, takes advantage of the knowledge that amyloid-beta plaque deposition in the brain takes place years prior to the onset of dementia but places these individuals at risk for Alzheimer’s disease. This trial is planned to enroll 1,150 subjects aged 65-80 years with evidence of amyloid pathology. Subjects will be randomized between placebo and Solanezumab and treated for 3.25 years. Estimated date of primary data collection is 2020.

Closing Thoughts

The Amyloid-beta Cascade Hypothesis has been a predominant framework for AD drug discovery the past 25 years and built largely upon the insights learned from genetic mutations resulting in familial forms of AD. The current secondary prevention trials are dominated by Abeta immunotherapy treatments, which have had decidedly mixed clinical trial results in AD patients with mild-to-moderate dementia. It is hoped that secondary prevention trials with these agents in asymptomatic subjects at risk for AD will prove to be more effective at delaying the onset of clinical dementia. Positive clinical data with these Abeta immunotherapies, or follow-up trials in these same cohorts with other treatment modalities like BACE1 inhibitors, anti-tau therapeutics, or combinations of the above, will offer this underserved population heretofore unavailable treatment options, and hopefully translate to the larger sporadic AD population. If so, that nearly undetectable simple change from valine to isoleucine discovered nearly 25 years ago will have been one of the big keys to unlocking a discovery for the treatment of Alzheimer’s disease.

Conflict of interest: As a former employee at Eli Lilly and Co, I was involved in the early preclinical development of solanezumab, as well as other AD-related drugs discovery projects, and currently own stock in the company.

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