Q&A: Expert discusses Alzheimer’s disease knowledge gaps, effects of pandemic on research

Alzheimer’s disease remains a significant public health challenge, with as many as 5.8 million Americans having had the disease in 2020, according to estimates in a study published in Alzheimer’s & Dementia.

Researchers noted that this number may reach 14 million by 2060.

On World Alzheimer’s Day, Sept. 21, Healio reached out to William Hu, MD, PhD, FAAN, associate professor and chief of cognitive neurology at Rutgers-RWJ Medical School and Rutgers Institute for Health, Health Care Policy and Aging Research, to discuss the significant unmet research needs that exist for AD, the effects of the COVID-19 pandemic on AD research and more.

Healio: What significant unmet needs exist for AD research, and how might these begin to be addressed?

Hu: I see three major areas of knowledge gaps:

1.How do we translate findings from genetics into actionable plans? We now have more than 50 risk genes for AD, but we still can’t act on even the first one discovered decades ago (APOE) before or after someone develops AD. A lot of effort continues to go into discovering more risk genes, but understanding how to mitigate risks from the first 10 to 20 genes can yield much better personal and societal outcomes. We are focusing on a handful of genes related to inflammation, but many more need serious work. I see similar trends in identifying more protein or other targets through modern technology but looking at all the little pieces of something often is not enough to put it back together.

2.Is AD the most common cause of dementia around the world? Most research related to AD has focused on people of European ancestry, and we have assumed for a long time that what we learn in them is directly applicable to people of Asian, African or American ancestry. The frequency of risk genes differs between these major groups, and the impact of environment — diet, air pollution, other illnesses — is often under-appreciated.

3.Can we effectively treat AD just by tackling its parts? We now understand AD and related dementias to be more complex than the sum of their parts in terms of observable changes, but treatment programs still only focus on one part or another without giving much thought to the interaction between the individual parts. What will such a combination therapy look like, and how do we design trials to test them?

Healio: Amyloid, tau, inflammation and loss of brain cells all play a role in AD. Can you provide a brief breakdown of what real progress in addressing these areas might look like?

Hu: Research in amyloid and tau has revealed important new information on where and in what form abnormal forms of these proteins can impair normal brain functions. While we used to think in simple terms that amyloid plaques and tau tangles somehow directly injure brain cells, we now know various forms of amyloid and tau related and not related to plaques and tangles are involved in worsening, but also defending against, AD. Research in neuroinflammation has also come a long way. We once thought that immune cells did the same thing in the brain as they did in blood and other organs. We now have a much better understanding of how central these immune cells are in the onset of AD, potentially even before the appearance of tangles. Because scientists in autoimmune diseases and cancer have already come up with a suite of drugs targeting immune functions, these can all be potential tools in treating AD.

Healio: With the number of AD cases expected to significantly increase in the coming years, what can be done on the micro (eg, clinical) and macro (eg, systemic/governmental) levels to prepare for or possibly mitigate the effects of this expected increase?

Hu: At the personal level, I first say: “Listen to your mother.” Work hard in school; eat your fruits, vegetables and fish; exercise. Education, a healthy diet and regular physical exercise provide better protection for your brain than any supplement or computer game.

In the clinical setting, early and accurate diagnosis is important to match people with therapies that exactly — not just probably — match their disease. Even though most clinics and hospitals still rely on out-of-office referrals, very long testing and expensive scans to arrive at a diagnosis that is at most 70% accurate, we now have easy and affordable tests in neurologists’ offices that can answer whether someone has AD with more than 95% accuracy in under 2 hours. The only downside is that a doctor needs to put a tiny needle into someone’s low back to perform the test, and physicians in Europe are much more willing to do it than U.S. physicians because of low reimbursement here. Given the number of Baby Boomers approaching ages at higher risk for AD, it is not feasible to expect even a small proportion of them to drive to Boston or San Francisco for expensive testing. There may be blood tests good enough for clinical use in the future, but we certainly won’t have them for at least another 10 years. It seems to me that we can solve a major problem (ie, inaccurate diagnosis) which has plagued neurologists and psychiatrists for decades if we stop falling into the trap of needing more complicated or more expensive solutions.

Healio: How has the COVID-19 pandemic affected the lives of people with AD, and how has it impacted AD research?

Hu: I recently read a report from the U.K. that the pandemic set AD research back by at least 10 years. The disease itself killed many people with AD in nursing homes, and we have anecdotally observed the infection accelerated people’s dementia progression. The pandemic also significantly limited our ability to conduct in-person research visits due to campus shutdowns, illness among researchers and health of older study volunteers. Not only does this impact ongoing studies, but it also creates an urgent need to first restore us to the pre-pandemic level of research activity before even continuing our progress. Because infection and social isolation related to COVID-19 have the potential of worsening brain health, the puzzle of AD is made even more challenging if someone has long COVID or brain fog in addition to AD. While we have learned to do more with less during the pandemic, how we will manage the additional dimensions of an already complex disease will be a major challenge for the next decade.

Reference:

Matthews KA, et al. Alzheimers Dement. 2018;doi:10.1016/j.jalz.2018.06.3063.