The announcement that the NHS plans to introduce blood tests that reveal protein deposits said to be early signs of Alzheimer’s Disease (AD), raises more questions than answers. Would people diagnosed with preclinical Alzheimer’s modify their lifestyles to reduce their risk? What would be the effect of putting an AD label on someone knowing there is no cure for the disease, and on the over 30 percent of older people who have these brain deposits but never develop dementia? News of the blood tests coincide with trials that are under way with a new drug to treat people with no cognitive impairment who have the deposits, but eminent Professor Jason Karlawish warns that unless the FDA only approves drugs that actually improve cognition as well as remove plaques, physicians will have no evidence for prescribing them and there will be a mess that may cause collateral damage to science.

Jason Karlawish is a professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine and co-director of the Penn Memory Center. In the past three years, he has been a site co-investigator on clinical trials sponsored by Biogen, Eisai, and Lilly.

He explains that for much of the 20th century, Alzheimer’s disease has been defined by clinical features. The disease label follows from a clinician’s interview and examination of a person for the diagnostic signs and symptoms, such as memory loss and problems performing day-to-day activities.

Now, the focus on measures of amyloid and tau protein in the brain is redefining the disease – yet the hypothesis that has yet to be scientifically validated. Remembering the controversial FDA approval for Biogen’s Aduhelm that eroded trust in the Regulator, Professor Karlawish’s concern is that the FDA may approve drugs that are in the pipeline that remove the plaques, but do not improve cognition. (Aduhelm removed the plaques, but did not improve participants’ cognition and Biogen has since abandoned it.)

Results from the clinical trials of two new drugs, lecembi and donanemab show they removed brain deposits but only halted the progress of the disease and did not improve cognition. Dr Robert Howard, professor of old age psychiatry at University College London, said that the benefits are so modest as to be undetectable in an individual treated patient. ‘Although 27% slowing of disease course sounds impressive, this is not strictly what the analysis of the trial data showed. It’s important the results are discussed honestly, accurately and without spin.’ There are also concerns about the drug’s serious side effects, including brain swelling and bleeds and some deaths. It had questionable effects on participants’ cognition

Prof Karlawish says, ‘I’m one among many clinicians who look forward to diagnosing and treating a patient long before she has disabling cognitive impairments, but science, not corporate zeal to maximize profits, will lead me to that golden day. Hence the outcry over that first Aduhelm label.’

A report this month shows others share these concerns. Doctors and scientists are urging the FDA to convene a safety panel. Their worry that, prompted by its controversial approval of Biogen's Aduhelm, the FDA is cutting corners in evaluating Alzheimer's drugs. Biogen ignored the objections of an advisory panel and had no evidence showing that the drug actually slowed the decline of brain function.

Professor Karlawish worries the FDA will make the same mistake with Leqembi. ‘My colleagues and I are patiently waiting for the completion of trials testing lecanemab and donanemab in people who have elevated amyloid and are cognitively unimpaired. Especially since it’s reported that Eisai, the company jointly marketing the drug with Biogen, may seek FDA approval for the use of lecanemab in people who are cognitively unimpaired a year and a a half before the results of their clinical trials.

‘Eisai, like Biogen, is a company driven by a zeal for profits. (Remember Aduhelm’s initial price: $56,000 a year!) People are desperate to avoid dementia. Assembled together, these all-too-human sentiments could collectively precipitate a mess. The FDA must step in and serve the public interest. For a start, it should drop using amyloid lowering as a surrogate worthy of drug approval. It must demand rock-solid clinical data.’

Professor Karlawish envisages a situation where millions of cognitively unimpaired Americans worried about their risk of developing mild cognitive impairment or dementia will see TV commercials urging them to ‘talk to your doctor about Leqembi. ‘Their doctors will have thin — really no — evidence to write a prescription. Insurers such as Medicare and private plans (many of these people are under 65) will undoubtedly refuse to pay. Enter the patient advocates, the amyloid sceptics, the amyloid proponents, the anti-pharma crowd, the advocates for innovation. Behold the mess.’