164 - Diagnosing, preventing, & treating Alzheimer’s disease, & life lessons from dementia patients

KEYPOINTS

• 01

  Normal aging can be vibrant.

  Amanda Smith, a geriatric psychiatrist and director of clinical research at the University of South Florida's memory center in Tampa, grew up around grandparents and their friends who led active lives into their 70s and 80s, which shaped her sense of what normal aging looks like. She came to USF in 1997 as an intern, trained under Eric Pfeiffer, who founded the center in 1980, and took over as principal investigator on many trials when he retired in 2008.

• 02

  Dementia is a syndrome; Alzheimer's is one cause.

  Dementia means cognitive decline severe enough to impair daily function. In her clinic, roughly 50–60%+ of cases are Alzheimer's, about 20% vascular and about 20% Lewy body, with others such as frontotemporal dementia. Lewy body disease is often less protracted, while Alzheimer's averages 8–10 years from diagnosis and can last much longer.

• 03

  Amyloid builds for 10–20 years before symptoms.

  Amyloid PET imaging showed plaques accumulate 10, 15 or 20 years before clinical decline. Before 2011, the FDA's definition of Alzheimer's required dementia, leaving no room to study prodromal patients; the 2011 redefinition introduced mild cognitive impairment (MCI) and preclinical Alzheimer's, enabling earlier intervention.

• 04

  The amyloid pathway has clear genetic clues.

  People with Down syndrome have three copies of chromosome 21, where the amyloid precursor protein gene sits, make about a third more amyloid and almost inevitably develop Alzheimer's if they live long enough. Abnormal cleavage produces amyloid-beta peptides of 40 or 42 amino acids that clump; those fragments could theoretically be removed without consequence.

• 05

  APOE informs risk but isn't diagnostic.

  E4 raises risk substantially, but you can carry E4 and never develop Alzheimer's, or have E2/E3 and develop it. Smith tells E2/E3 patients they have only about a 10% risk reduction relative to E3/E3 and are 'not off the hook', and tells E3/E4 or E4/E4 patients that risk is modifiable. Attia compares waiting for dementia to waiting for a heart attack: intervene on risk early.

• 06

  Behavioral symptoms affect nearly everyone with dementia.

  About 90% of patients have a mood or behavioral issue at some point, such as depression, anxiety, agitation or psychosis, and caregivers need support too. Smith also spends a lot of time deprescribing: patients on 15–18 medications, like those still on three blood pressure drugs from age 50 who are now 90 and falling because their pressure is too low.

• 07

  The drug pipeline has shifted toward disease modification.

  Of about 120 drugs in the pipeline at the time, roughly 29 were in phase 3, and about 80% targeted disease modification rather than symptoms, which Smith calls a watershed made possible by the 2011 redefinition. Developing one drug takes 10–15 years and about $1.3–1.4 billion. Twelve agents targeted cognitive enhancement and 12 neuropsychiatric symptoms.

• 08

  Trial design is a major challenge.

  Alzheimer's trials traditionally run 18 months, because that's how long it takes for placebo patients to decline measurably; improvement rarely happens, so stability counts as success. Attia contrasts heart disease trials like FOURIER and ODYSSEY (PCSK9 inhibitors added to patients already at low LDL), arguing prevention trials in pre-symptomatic people are where the real wins will be.

• 09

  Anti-amyloid antibodies remove plaque.

  Aducanumab and similar drugs clearly clear amyloid on PET; one of Smith's patients, after an anti-amyloid trial, failed screening for another trial because her scan had become amyloid negative. The aducanumab trial gave APOE4 carriers lower doses initially because of ARIA (amyloid-related imaging abnormalities) risk, later amended to allow 10 mg/kg. The FDA decision was due June 7, 2021, and families were pressing after nearly 20 years without new treatments.

• 10

  Healthy aging should be measured by function.

  Smith argues outcomes should reflect what matters to patients and families, like independence and quality of life, not only test scores. She graduated from medical school in 1997, the year donepezil (Aricept) was approved, and has seen almost no new approved drugs since.