The amyloid hypothesis of Alzheimer’s disease (AD) has dominated AD discussions and research, since its conception in the mid-1980s. Could there be more behind AD pathogenesis than the presence of amyloid plaques? The search to unravel the mysteries of AD have revealed several other mechanisms of disease.

The amyloid hypothesis labels the accumulation of amyloid beta-peptide (Aβ) plaques in the brain as a major driving force behind AD development. These Aβ plaques are reported to wreak havoc in the brain — resulting in neuronal and neurotransmitter destruction.

Aβ plaque-targeting treatment modalities that have been researched include active and passive immunisation against Aβ plaques, and drugs that modify enzymes involved in Aβ plaque formation (γ-secretase APP cleaving enzyme, presenilin, BACE1). However, all clinical trials looking into these components have so far yielded no tangible results, with some major phase 3 trials halted prematurely.

The presence and role of Aβ plaque accumulation in AD is indisputable. Nonetheless, it makes one wonder why is this hypothesis failing clinically? Researchers have suggested that Aβ plaques could, instead, be a result of other pathogenic processes rather than the cause of neuronal damage.

Neuroinflammation as a precipitant of neuronal damage in AD

Inflammatory processes in the brain have been thought to contribute towards the development of not just AD; but other neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis. Prolonged activation of brain microglia (a brain macrophage) have been shown to devour brain neurons uncontrollably — resulting in AD. Observational studies have revealed that long term usage of simple non-steroidal anti-inflammatory drugs — like naproxen and ibuprofen — may confer protective effects against AD.

“There’s clearly an inflammatory change in patients with the disease,” remarked George Perry, a neuroscience professor at University of Texas at San Antonio and editor of the Journal of Alzheimer’s Disease.

“Inflammation is critical to ageing and plays an underlying role in the whole process,” he added.

Scientists have been investigation different parts of the immune cycle as potential therapeutic targets. One of them is the protein C1q, a protein marker that flags neurons for immune destruction. Animal studies have already verified that blocking these protein functions have spared neurons that would otherwise be destroyed.

A study published in August 2017, in The Journal of Cell Biology (JCB), by researchers from Yale brought forth the important role of lysosomes in AD pathogenesis. Lysosomes work by clearing damaged cellular protein and cell debris.

The team demonstrated that mice with reduced function of the JIP3 gene (needed for proper lysosomal function) displayed increased Aβ plaque deposition. This exciting discovery paves the road for restoration of lysosomal function as a new therapeutic approach to AD.

Genetics as the master puppeteer behind cellular processes in AD

The function of JIP3 gene also illustrates the role of genetics as the master puppeteer behind our cellular functions. AD has many established genetic components. Clusters of families with PSEN1, PSEN2 or APP gene mutations all display early-onset AD.

Along the same line of thought, it is possible that all the other pathways of disease — neuroinflammation, lysosomal dysfunction, protein accumulation — are dictated by different genes. Any alteration or mutation in these genes could, theoretically, give rise to AD. The presence of the APOE4 gene is a known risk factor for developing AD. New genes such as PLCG2, ABI3 and TREM2 are currently being investigated as candidate genes for AD.

Epigenetics – the study of processes that regulate expression of genes — has also been widely researched in the context of AD. Oryzon Genomics, a company based in Spain has already made headway in producing a drug called ORY-2001 that targets the enzymes LSD1 and MAOB. These enzymes act to promote the expression of neuroprotective genes.

“Oryzon is the leading program in the world for epigenetic therapy for Alzheimer’s,” said Dr Howard Fillit, chief science officer of the Alzheimer’s Drug Discovery Foundation (an Oryzon sponsor). “We’re very excited about that effort.”

Patients desperately self-experimenting in n=1 studies

These progresses, although significant, remain decades away from mass production. For patients with early stage AD or who are known APOE4 carriers – the clock is ticking.

APOE4 carriers have a one in 10 chance of developing AD by the age of 65; and a 50% chance by the time they hit 85. As such, these patients are doing everything they can to prevent the disease. Supplements such as gingko bilboa and omega-3 are being consumed by the truck-load. Ketogenic diets and episodic fasting have also gained popularity over the years — in hopes that it will delay the onset of dementia.

Could there be other ways to prevent development of Alzheimers disease?
Could there be other ways to prevent development of Alzheimers disease?

Dr Robert Mahley, an Alzheimer’s researcher in the University of California who first discovered the APOE4 gene remains skeptical, however. “The data, I must say, is soft… It’s very hard to prove these lifestyle things. Lifestyle is a soft science, and nutrition is a soft science — because people respond to diets very differently.”

However, for these patients, even tiny bits of hope are bright lights against the bleak reality. “I feel very compelled to demystify this disease… and I feel motivated to save every brain cell I can,” says Betty Gleason Lacy, an APOE4 carrier.

Future for a cure rests on simultaneous development of accurate detection methods for AD

Taken together, it is clear that AD is a multifactorial disease. Furthermore, AD has a pre-symptomatic phase that spans decades. During this phase, disease processes insidiously chips away at brain reserves. Development of tests that can accurately identify the presence of these disease processes become vital. These tests can then guide the timing of administration of any anti-Alzheimer’s therapy, which is extremely important to achieve a disease modifying effect.

In the meantime, AD remains a debilitating and incurable condition. Till science can catch up with the disease, physicians can only hope to provide the best possible quality of life to their patients. MIMS

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