Alzheimer’s Disease: An In-Depth Look at a Formidable Foe

There is no shortage of disabling and deadly diseases in the world.  However, few match Alzheimer’s disease (AD) when it comes to sheer ability to cause fear and dread.  It’s not a rare disease.  In fact, it’s on the rise.  There is no cure (nor effective treatment yet) and it’s ultimately fatal.  And, most frightening, it robs people of their minds, the very essence of their identities.

In this article, we explore Alzheimer’s in some depth.  We begin by providing an overview of the disease itself, its symptoms and stages of progression.  In addition, we explore the challenges clinicians face when diagnosing AD.

We then transition to a discussion of the current treatments available for AD, as well as new treatments that are on the horizon and the organizations that are developing them.  Finally, we survey emerging market trends and provide our own perspectives on where we think the market for Alzheimer’s therapies is heading.

Alzheimer’s Disease Overview

Alzheimer’s disease is an irreversible, progressive, neurodegenerative disorder that causes significant cognitive impairment in those afflicted with it.   It is the most common form of dementia.  Worldwide, there are about 50 million dementia cases, with 10 million more diagnoses each year, and AD may contribute to 60-70% of those cases.^[1]

In the U.S. alone, approximately 5 million people suffer from AD and it costs the healthcare system in excess of $250 billion.  It is the sixth leading cause of death and it has increased 89% since 2000, emphasizing the need for better prevention and treatment.^[2]

There are two basic types of AD: sporadic and familial.  Sporadic AD is the most common type.  This is the late-onset variety that afflicts people over 65 years of age.  Familial AD, the early onset form, is less common (perhaps 5-10% of cases).  It afflicts people prior to the age of 65 and has a genetic component, often showing positive history of the disease within families.

Symptoms

There are four cardinal symptoms of Alzheimer’s disease:^[3]

1. Memory Impairment – This is the most common initial symptom of dementia. The pattern of memory impairment in AD is distinctive with declarative episodic memory loss (memory of events occurring at a particular place and time). Memory loss focused on recent events is more severely impaired.
2. Executive Function and Judgement / Problem-Solving – The patient will show deficits in working memory, flexible thinking, and self-control.
3. Impairment in Other Cognitive Domains – The patient will show impairments in visuospatial skills and deficits in language (later in the disease course).
4. Behavioural and Psychological Symptoms – Neuropsychiatric symptoms are common in AD, especially as it progresses. Examples can include apathy, irritability, and depression. In some cases, there can be behavioural disturbances such as agitation, aggression, and psychosis (e.g., hallucinations).

Pathology

Research is generally divided into two camps: those that focus on amyloid beta as the cause of AD (amino acids that can form amyloid plaques in the brains of AD patients) and those that focus on Tau, a microtubule-associated protein that can form clumps or “tangles” inside neurons, harming their ability to function.

Amyloid beta (Aß) has been linked to early onset of the disease while higher tau levels have been associated with faster AD progression.  Aß / Tau pathology is still poorly understood with neither one being the clear cause of AD. This makes diagnosing AD and developing treatments difficult.

Other pathologies are also being hypothesized.  One prominent theory is focused on the potential for a metabolic change to cause Alzheimer’s (“Type 3 diabetes”) that is being further studied.

Diagnosis Challenges

Current diagnosis of AD is based on an analysis of symptoms using standardized mental tests and status scales.  These scales identify the presence of dementia and monitor its progression in a patient.

This approach is limited, as most patients remain asymptomatic while pathologic changes are thought to take place.^[4] Also, Alzheimer’s disease is only confirmed post-mortem via autopsy, limiting the ability to track the disease during the patient’s lifetime.

Imaging technologies have been used to aid in diagnosis, but are limited in their effectiveness and coverage:

• Amyloid PET: The FDA agrees that a negative scan decreases the likelihood that a patient has AD.  However, the technique should not be used to assess the severity of the disease.
• Tau PET: Flortaucipir F-18, used to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs), was approved by FDA in May 2020^[5]. Studies showed that tau tracers can track disease progressions, patterns of atrophy, and clinical features better than amyloid PET.

Current diagnosis techniques are summarized below, together with an overview of their pros and cons.

Table 1: Current Alzheimer’s Disease Diagnosis Techniques

Disease Stages

Alzheimer’s disease is said to have four key stages, described below^[6]:

1. Prodromal AD: This stage is also referred to as mild cognitive impairment (MCI) with biomarker evidence of AD. research suggests that these patients have the best chance to respond to potential disease modifying therapies (DMTs).
2. Mild: The patient may function independently but there may be a feeling of memory lapses. Symptoms will become noticeable but perhaps not be widely apparent.
3. Moderate: This is the longest stage and can last for years. As the disease progresses, the patient will require greater levels of care. Here, the dementia symptoms become more pronounced and the patient can become frustrated and angry.
4. Severe: This is the final stage of the disease in which dementia symptoms become severe. Patients may still say words or phrases, but communication is generally difficult. As patients progress, personalities may shift, and they will need extensive care.

Current Treatments

Current treatments focus mostly on treating the symptoms and they have limited benefit due to the progressive nature of the disease.  The FDA-approved treatments for Alzheimer’s disease are summarized in Table 2.

Table 2: FDA-Approved Treatments for Alzheimer’s Disease

Until very recently, no DMTs slowing the progression of the disease were available. As such, there was a very high unmet need for this in AD.  Biogen’s Aduhelm™ (aducanumab) is the first DMT approved for the treatment of Alzheimer’s disease (more details about this treatment below).  Long term, key opinion leaders tend to think that the greatest chance for success will come from combining preventive, symptomatic and DMT treatments.

Aducanumab

Development Journey / Pre-Approval

Aduhelm™ (aducanumab) is a human monoclonal antibody targeting Aβ and is the first DMT in Alzheimer’s. Compared to other DMTs currently in development for AD, aducanumab stops the formation of oligomers,^[7] a secondary nucleation process fuelled by interactions between monomers and fibrils. This could potentially be beneficial for dampening amyloid toxicity.

The drug was discovered by Swiss biotech company, Neurimmune Therapeutics, together with a team of researchers at the University of Zurich. Aducanumab was subsequently licensed to Biogen in November of 2007.^[8]  The deals of this agreement have been updated, most recently in May of 2018, when Biogen reduced previously negotiated royalty rates payable on the potential future sales of aducanumab.^[9]

Previously, in March 2014, Biogen had entered into a co-development agreement with Eisai. Under the terms of this agreement,^[10] each company will leverage their geographic strengths for commercialization but for the most part, Biogen has led the clinical development of aducanumab (Eisai started to contribute to 45% of clinical trial expenses only in January of 2019).

Aducanumab showed early promise with a phase 1b trial that involved 200 patients.  The trial showed evidence of improved cognition in patients with early signs of the disease 54 weeks after starting treatment. These results prompted Biogen to jump straight to phase 3 trials.^[11]

Two identical phase 3 clinical trials (ENGAGE and EMERGE) of aducanumab were initiated in August 2015 and included over 2,500 people with MCI due to AD or mild AD (as assessed by a positive Amyloid PET scan).  The trials were halted in March 2019 after interim analyses predicted the primary endpoint would not be met.

Subsequent analyses including the accrual of additional blinded data suggested dose-dependent positive effects of the drug indicating that the EMERGE trial met its primary outcome while the ENGAGE trial did not. A Phase 3b open-label extension assessing safety and tolerability of higher aducanumab doses and longer treatment duration was initiated in January of 2020 (EMBARK).

The regulatory approval process started in July of 2020 when Biogen requested an FDA priority review.  It later requested an EMA review and it filed for approval in Japan.  Before this, aducanumab had received an FDA fast-track designation (Sept 2016), PRIME designation in Europe (May 2016), and Sakigake designation in Japan (April 2017), supporting the idea that it addresses a high unmet need in AD.

After a controversial and tumultuous approval process (including a largely negative review from the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee in November of 2020), the drug finally received a green light from the FDA with a conditional approval.

Approval

Named by many “the biggest regulatory event of the year”, aducanumab’s PDUFA meeting yielded a positive decision to approve the drug for Alzheimer’s disease on 7 June 2021.

Below, we summarize the most important points from the FDA’s decision:

• The FDA emphasized the urgency for new AD treatments and the devastating effects of the disease affecting more than 6 million Americans.
• Aducanumab is the first treatment to show a reduction of amyloid beta plaques in the brain of AD patients. The drug was approved under the Accelerated Approval pathway, indicating aducanumab’s’ benefits for AD patients outweigh the risks of the therapy.
• The Agency acknowledged the exceptional circumstances and all the attention received by the drug due to the conflicting perspectives on trial results.
• Regulatory decision included a detailed analysis and review of clinical trial findings and all relevant data and input from the Peripheral and Central Nervous System Advisory Committee (most committee members were not convinced of the drug’s effectiveness) and patient communities.
• In all studies to date, aducanumab shows a consistent and convincing reduction of amyloid plaques in the brain, which is expected to reduce clinical decline and to provide patient benefit (in a dose- and time-dependent manner).
• The FDA will continue monitoring aducanumab’s journey to market and is requiring Biogen to conduct a phase 4 study to verify the drug’s clinical benefit with the conditional approval.

Interestingly, the FDA label^[12] does not contain any restrictions regarding the stage of the disease and it simply states the drug can be used “for the treatment of Alzheimer’s disease”. However, MRI scans prior to the initiation of treatment (as well as prior to the 7^th and 12^th infusions) are required.

Post-Approval Challenges

Aducanumab’s approval is accompanied by potential hurdles and bottlenecks in the healthcare system. The FDA label contains no restrictions regarding aducanumab’s administration to special groups of patients.  Therefore, a significantly higher than predicted patient pool will be eligible for the drug.  However, this comes with its own unique challenges.

An assessment conducted by the RAND corporation in 2017 speculates that there will be approximately 14.9 million Americans with mild cognitive impairment that would need to be evaluated, tested, and treated.  RAND highlights that the U.S. health care system is not prepared to handle the volume of patients.^[13]

The report outlines three factors which would affect distribution: the specialist workforce, diagnostics capabilities, and infusion centers to deliver the drug. Additionally, neurologists have historically not given many infusion drugs requiring education and market development.  Each of these factors would need to be addressed to help ready the U.S. healthcare system for the pent-up demand.

Luckily, Biogen seems to be well-prepared to start treating patients. The company anticipated that specialist and diagnostic capabilities will be a bottleneck and indicated that approximately 600 core facilities across the US will be ready to treat patients with aducanumab.^[14]

However, this does not address other very important questions such as: How much will payers decide to cover? How long should the drug be administered to patients? What will be FDA’s decision if the drug does not confirm its potential clinical benefit in the Phase 4 trial? All these will impact aducanumab’s uptake in clinical practice. The Institute for Clinical and Economic Review (ICER) issued a statement criticizing FDA’s decision and will hold an official public meeting on July 15^th to address some of these open questions.

On a different note, it is now speculated that FDA’s decision to approve aducanumab will set a negative precedent for other pharma companies. This could lead to companies pushing to get their drugs approved despite having mixed results, and this topic is likely to remain controversial.

Market Trends and Considerations

Development of Biomarkers

As mentioned briefly above, a large unmet need in AD is the lack of biomarkers that can definitively diagnose and track the disease. This is especially important due to the long prodromal phase of AD, making early diagnosis crucial to utilizing disease-modifying therapies.^[15]

Biomarkers for Aß and Tau

Both Aß and Tau detection currently rely on cerebrospinal fluid (CSF) analysis and positron emission tomography (PET) assays to measure their levels in the patient.

• Aß: Extracellular plaque-like deposition of Aß is thought to be a key feature in AD. As such, tools are being developed to measure Aß in CSF or imaging. Supporting the measurement of Aß in the CSF, patients with AD been found to have a ~50% decrease of Aß42 (the aggregation prone form of Aß) as these are thought to have aggregated in the brain and are no longer in the CSF.  Of note, this can be further refined by using the Aß42/ Aß40 ratio to account for interindividual differences in amyloid production.  Aß can also be measured through PET tracing and, in fact, it is the most widely used biomarker in current clinical trials. However, both CSF sampling and PET tracing have downsides of invasiveness and cost respectively, not to mention that the causative link between Aß and Alzheimer’s disease has not been completely proven.
• Tau: Similarly, with Aß, the patient’s CSF can be analyzed for total tau (T-tau) and phosphorylated tau (P-tau). These, together with Aß42/ Aß40 ratio have been proposed as biomarkers for AD.^[16] Tau imaging via PET has given researchers insight into AD but its development is still early, especially when compared to Aß. The same caveat exists with Tau as with Aß in that the causative link between these markers and AD are not yet completely proven.

Given the limitations of both CSF and PET tracing of Aß and Tau, blood-based biomarkers will be an important step forward in biomarker development in AD.  But this has been elusive and is considered the “Holy Grail” of AD diagnostics.^[17] A promising example of a blood-based biomarker is the measurement of P-tau217. An assay to do this is being developed by Lilly and in 2020, the company showed that it can be used to distinguish AD from other neurodegenerative diseases significantly better than other blood-based biomarkers or MRI.^18]

Tracking Neuronal Degradation

Outside of measuring Tau and Aß, there is a potential avenue of using biomarkers of neurodegeneration to track AD. These markers include synaptic dysfunction, glial activation and neuroinflammation, and co-pathologies like  α-synuclein and TDP-43.

Digital Biomarkers

Interestingly, digital biomarkers are being studied as a potential means of detecting AD in patients during the prodromal stage of their disease.  Increasing amounts of evidence suggest that cognitive, behavioural, sensory, and motor changes may precede clinical manifestations of AD by several years.  Early detection would, after all, increase the likelihood that a potential DMT could effectively prevent or delay full onset.

As mentioned, current tests designed to diagnose neurodegenerative diseases are not very effective in measuring the cognitive decline trajectory in the early stages of the disease.  So, there is significant interest in identifying digital biomarkers for AD that leverage the data generated by current day wearable devices.  These devices are mobile and wearable technologies that are attempting to assess movement, executive functions, speech and language, oculomotor, sleep patterns, heart rate, temperature, and/or cognitive decline.

An interesting example is that in January of 2021, Apple and Biogen announced a new research project attempting to understand if Apple’s devices can help monitor users for decline in cognitive health. This study will use Apple devices to track changes in the participant’s movements over time and see if this correlates with early signs of cognitive impairment.^[19]

Genetic Testing

Genetic tests are not widely used as the genetic basis of AD is still largely unexplained.^[20] Of note, genetic testing has shown to be useful in a limited population of patients, those with early-onset autosomal dominant AD (occurring in a patient’s 30s to mid-60s).  This limitation is not ideal, as the autosomal dominant variety of early onset AD potentially accounts for <1% of all cases.^[21]

Of note, the most common mutations associated with autosomal dominant AD are in PSEN1 on chromosome 14, PSEN2 on chromosome 1, APP on chromosome 21. Of these, PSEN1 mutations are the most common.^[22]

On the other hand, the genetic basis of sporadic AD is more complex and conferred by more common factors, each with less probability of causing AD than those associated with autosomal dominant early onset AD. The most popular gene is APOE on chromosome 19 with 3 alleles ε2-4.  Of these 3 APOE alleles, ε4 is thought to be a risk-factor gene as it increases the patient’s probability of developing AD, but this is not determinative, as some people with an APOE4 allele will not develop AD. Other genes of interest are being identified but the predictive value of these genes remain modest.^{[23] [24]}

Emerging Players and Treatments

The AD pipeline has been extremely competitive in the past few years. Multiple established pharmaceutical companies have focused their efforts on developing AD treatments, further demonstrating the high-unmet need in this neurodegenerative disease.  Other amyloid-based therapies in late stages of clinical development are:

• Eli Lilly’s solanezumab and donanemab – In January 2021, Lilly announced positive phase 2 results of donanemab with a slowing decline on the iADRS by 32% compared to placebo at 18 months. Additionally, the drug reduced A-beta plaques into normal ranges seen in healthy volunteers.^[25]  A larger phase 2 trial is currently ongoing.
• Roche’s gantenerumab: Currently studied in two phase 3 trials, the company plans to file for FDA approval in 2022.
• Biogen / Eisai’s lecanemab: Phase 3 trials in early-stage and pre-clinical AD patients are being conducted.
• Grifols’ Albutein: Includes periodic plasma exchanges with albumin and showed positive results in Phase 2b trial in July 2020.

Outlook on Promising Players in the Market:

• AC Immune (and strategic partner, Janssen Pharmaceuticals) announced^[26] positive results from their Phase 1b/2 trial evaluating ACI-35, an anti-phospho-Tau (pTau) vaccine for the treatment of AD. The vaccine is focused on reducing the spread and seeding of Tau pathology, which is believed to be a major hallmark of AD.
• Annovis Bio recently published positive results^[27] from their Phase 2 trial using Posiphen (ANVS-401) showing a 4.4 point improvement in cognitive symptoms in mild-to-moderate AD patients after only one month of treatment (Note: aducanumab claims to improve cognition by 1.4 points over 18 months^[28]). The drug is thought to reduce the production of amyloid precursor protein by blocking translation of its mRNA. It’s also important to note that Annovis’ data was based on the assessment of only 14 patients.  Data from the remaining 40 trial participants is expected in the near future.
• Cassava Sciences’ simufilam, focused on stabilizing altered filamin A in the brain of AD patients, showed positive interim results after 6 months of treatment.^[29] Patients showed a 10% improvement from baseline on ADAS-Cog11. Dementia-related behavior such as anxiety, delusion, and agitation, were also found to be improved by the drug (by 29%).
• Selphagy Therapeutic, a daughter company of Life Biosciences, designed a drug focused on restoring autophagy (i.e., the process through which toxic build-up of proteins are eliminated) for improving the symptoms of Alzheimer’s.^[30]  Although only preclinical data is available to date, the decline of chaperone-mediated autophagy activity observed in both mouse and human tissues suggests that their drug could have an anti-Alzheimer’s effect in people.^[31]
• Cognito, a start-up using visual and auditory stimulation, obtained positive results in their Phase 2 trial using gamma frequency neuromodulation therapy in mild-to-moderate AD patients.^[32] The stimulation slowed memory and cognition decline and additionally showed reduction in whole brain atrophy and volumetric loss. The company shared plans to start a larger pivotal trial of the neuromodulation therapy, which received a Breakthrough Device Designation from the FDA in January this year.
• Athira Pharma, which is focused on small molecule treatments that can halt or reserve the nerve damage causing Alzheimer’s disease (and other neurodegenerative diseases), is currently conducting phase 2 and phase 2/3 trials^[33] and is expecting results as early as next year.
• A new study using precision medicine to identify and target the drivers of Alzheimer’s or pre-Alzheimer’s in each patient has showed exciting results in both cognitive (improvement in MoCA scale) and MRI measurements (prevented brain shrinkage). The treatment protocols focused on a range of potential contributors to the disease including diet, exercise, sleep, stress, brain training, gastrointestinal health, inflammation, infectious agents, and toxins.^{[34] [35]}

Our Perspectives:  How We See the Market Evolving

It is difficult to give our opinion regarding the market outlook of Alzheimer’s disease without first discussing the recent approval of aducanumab. This is potentially one of the most important drug approvals in CNS in years. For patients and caregivers, this means that there is new hope in facing their diagnosis.  For doctors, this gives them a new tool with which to combat Alzheimer’s disease and help their patients. For scientists, this approval provides further evidence for the amyloid hypothesis. For the pharmaceutical industry, it potentially heralds a new era in Alzheimer’s disease treatments, one where disease modifying therapies are approved largely due to patient need and despite mixed phase 3 data and disapproval from the FDA advisory board. There will likely be increased investment and development in Alzheimer’s moving forward.

Now that the drug has been approved, it will be interesting to see if Biogen and Eisai find aducanumab to be effective in helping patients and, if not, how this is handled by both companies and the FDA.  It is not an exaggeration to say that this approval will leave an indelible mark in the AD field.

Outside of the aducanumab approval we see that the AD market is poised to grow.  Therapeutically, due to the large pent-up demand for a disease modifying therapy, we believe there is still space for new therapies to come onto the market minimally affected by Biogen’s first mover advantage. After all, there are a few promising therapeutics in the pipeline including those targeting Tau tangles, the other half to the amyloid beta part of the Alzheimer’s disease equation. All in all, it will be interesting to see the effect of the how the AD market shapes up in the wake of the aducanumab and how new therapies adjust to this new treatment landscape.

End Notes

[1] World Health Organization (WHO), Dementia, https://www.who.int/news-room/fact-sheets/detail/dementia, accessed 7 June 2021.

[2] Kourtis, Lampros C., et al, Digital biomarkers for Alzheimer’s disease: the mobile/wearable devices opportunity, npj Digital Medicine, 21 February 2019, https://www.nature.com/articles/s41746-019-0084-2

[3] David A Wolk, MD and Bradford C Dickerson, MD, Clinical features and diagnosis of Alzheimer disease, UpToDate, Accessed 7 June 2021, https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-alzheimer-disease?search=Alzheimers%20disease&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H29

[4] Ibid.

[5] Company Press Release, Eli Lilly and Co., Lilly Receives U.S. FDA Approval of TAUVID™ (flortaucipir F 18 injection) for Use in Patients Being Evaluated for Alzheimer’s Disease, 28 May 2020, https://investor.lilly.com/news-releases/news-release-details/lilly-receives-us-fda-approval-tauvidtm-flortaucipir-f-18

[6] Alzheimer’s Association, Stages of Alzheimer’s, https://www.alz.org/alzheimers-dementia/stages, accessed 7 June 2021

[7] ALZForum, Of Four Aβ Antibodies, Only Aducanumab Stems Tide of Toxic Oligomers, 28 September 2020, https://www.alzforum.org/news/research-news/four-av-antibodies-only-aducanumab-stems-tide-toxic-oligomers

[8] GlobalData, https://pharma.globaldata.com/Deals/Facts/biogen-idec-enters-into-co-development-agreement-with-neurimmune-therapeutics_gd_835895

[9] GlobalData, https://pharma.globaldata.com/Deals/Facts/biogen-and-neurimmune-announce-option-exercise-for-alzheimers-disease-investigational-treatment-aducanumab_1759674

[10] GlobalData, https://pharma.globaldata.com/Deals/Facts/eisai-enters-into-co-development-agreement-with-biogen-idec-for-alzheimers-disease_gd_898278

[11] McDermid, Riley, Investors Cheer as Biogen’s BIIB037 Skips To Phase 3 For Alzheimer’s, BioSpace, 04 December 2014, https://www.biospace.com/article/investors-cheer-as-biogen-s-biib037-skips-to-phase-3-for-alzheimer-s-/

[12] Aduhelm™ label information, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s000lbl.pdf

[13] Jodi L. Liu, Jakub P. Hlavka, Richard Hillestad, and Soeren Mattke, Assessing the Preparedness of the U.S. Health Care System Infrastructure for an Alzheimer’s Treatment, RAND Corporation, 2017, https://www.rand.org/pubs/research_reports/RR2272.html

[14]Biogen CEO Earnings Call Transcript, Seeking Alpha, 22 April 2021, https://seekingalpha.com/article/4420630-biogen-inc-biib-ceo-michel-vounatsos-on-q1-2021-results-earnings-call-transcript

[15] Lee, J.C., Kim, S.J., Hong, S. et al. Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers. Exp Mol Med 51, 1–10 (2019). https://doi.org/10.1038/s12276-019-0250-2

[16] Zetterberg, H., Bendlin, B.B. Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies. Mol Psychiatry 26, 296–308 (2021). https://doi.org/10.1038/s41380-020-0721-9

[17] Schindler, S.E., Bateman, R.J. Combining blood-based biomarkers to predict risk for Alzheimer’s disease dementia. Nat Aging 1, 26–28 (2021). https://doi.org/10.1038/s43587-020-00008-0

[18] Company Press Release, Eli Lilly & Co., Lilly’s P-tau217 Blood Test Shows High Accuracy in Diagnosis of Alzheimer’s Disease in Data Published in JAMA, https://investor.lilly.com/news-releases/news-release-details/lillys-p-tau217-blood-test-shows-high-accuracy-diagnosis

[19] Hale, Conor, JPM: Biogen teams up with Apple to see whether iPhones can spot cognitive decline, Fierce Biotech, 12 January 2021, https://www.fiercebiotech.com/medtech/jpm-biogen-teams-up-apple-to-see-if-iphones-can-spot-cognitive-decline

[20] Rick Sherva, Ph.D. and Neil W Kowall, M.D., Genetics of Alzheimer disease, UpToDate, https://www.uptodate.com/contents/genetics-of-alzheimer-disease

[21] Koriath, C.A.M., Kenny, J., Ryan, N.S. et al. Genetic testing in dementia — utility and clinical strategies. Nat Rev Neurol 17, 23–36 (2021). https://doi.org/10.1038/s41582-020-00416-1

[22]National Institute on Aging, Alzheimer’s Disease Genetics Fact Sheet, https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet, accessed 7 June 21

[23] Ibid.

[24] Sherva and Kowall

[25] ALZ Forum, In Phase 2, Donanemab Curbs Cognitive Decline in Early Alzheimer’s, 12 January 2021, https://www.alzforum.org/news/research-news/phase-2-donanemab-curbs-cognitive-decline-early-alzheimers

[26] AC Immune Press Release, AC Immune’s Alzheimer’s Vaccine Generates Potent Anti-pTau Antibody Response in a Phase 1b/2a Study, 11 February 2021, https://ir.acimmune.com/news-releases/news-release-details/ac-immunes-alzheimers-vaccine-generates-potent-anti-ptau

[27] Newsfile, 21 May 2021, https://www.newsfilecorp.com/release/84812/Annovis-Bio-Announces-Positive-Phase-2-Data-ANVS401-Improves-Cognition-in-Alzheimers-Disease-Patients-Cognition-Improved-3.3-Points-on-ADASCog11

[28] Biogen Corporate Presentation, https://investors.biogen.com/static-files/6ccd60d6-29e3-4b97-b8ab-cffc5124c275, March 2021

[29] Cassava Sciences Press Release, Cassava Sciences’ Simufilam Improves Cognition and Behavior in Alzheimer’s Disease in Interim Analysis of Open-label Study, 2 Feb 2021, https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-simufilam-improves-cognition-and-behavior

[30] Liu, Angus, Startup aims to treat Alzheimer’s by invigorating neurons’ garbage-disposal abilities, Fierce Biotech, 22 April 2021, https://www.fiercebiotech.com/research/treating-alzheimer-s-disease-by-invigorating-cell-s-specialized-garbage-cleaning-system?mkt_tok=Mjk0LU1RRi0wNTYAAAF8mW3CVt6f0vnoFYpdEKrDD0XGfL0m1zeF-b49B9-Z-gvwT6aG0bwlbqvV1AQlad3scTqxBkY_WhpdcgDIvElRmNqpJMCf39wHUhuqWnCMxcfAPSkl&mrkid=1005935

[31] Bourdenx, et al, Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome, Cell, vol. 184, issue 10, 22 Aril 2021, https://www.cell.com/cell/fulltext/S0092-8674(21)00379-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867421003792%3Fshowall%3Dtrue

[32] Muoio, Dave, Cognito Therapeutics touts positive Phase 2 results for device-delivered Alzheimer’s treatment, MobileHealthNews, 10 March 2021, https://www.mobihealthnews.com/news/cognito-therapeutics-touts-positive-phase-2-results-device-delivered-alzheimers-treatment

[33] Athira company website, https://www.athira.com/our-approach-2/#pipeline, accessed 08 June 2021

[34] Kat Toups, Ann Hathaway, Deborah Gordon, Henrianna Chung, Cyrus Raji, Alan Boyd, Benjamin D. Hill, Sharon Hausman-Cohen, Mouna Attarha, Won Jong Chwa, Michael Jarrett, Dale E. Bredesen, Precision Medicine Approach to Alzheimer’s Disease: Successful Proof-of-Concept Trial, https://www.medrxiv.org/content/10.1101/2021.05.10.21256982v1

[35] Trial First to Show Improvements in Alzheimer’s Patients, BioSpace, 13 May 2021, https://www.biospace.com/article/releases/trial-first-to-show-improvements-in-alzheimer-s-patients/