In this episode of The Drive, host Dr. Peter Attia, founder of Early Medical, interviews Dr. Gaia Devi, a board-certified neurologist, psychiatrist, and clinical professor of neurology at Zucker Hofstra Northwell School of Medicine. Dr. Devi, the founder of New York Memory and Healthy Aging Services, specializes in memory disorders, cognitive neurology, and women's brain health.

The pair discuss why dementia should be viewed as a spectrum rather than a binary diagnosis, highlighting how high-functioning individuals compensate for underlying pathology. They explore the timeline of Alzheimer's biomarkers, noting that neuroinflammation may predate amyloid and tau deposition by decades.

Dr. Devi explains her clinical protocols for administering controversial anti-amyloid monoclonal therapies like lecanemab and donanumab, emphasizing a "low and slow" titration method to mitigate brain swelling and hemorrhage. Finally, they cover the intersection of menopause and cognitive decline, and the clinical overlap between vascular and Lewy body dementias.

Dementia as a Spectrum and the Role of Cognitive Reserve

Dr. Devi emphasizes that dementing conditions, particularly Alzheimer's, are spectrum disorders rather than binary diagnoses. "Pretty much all dementing conditions, and particularly Alzheimer's disease, can present variably depending on the person." - Gaia

High-functioning patients often possess significant cognitive reserve, allowing them to score 28 to 30 on standard MOCA or MMSE tests despite having moderate to severe pathology.

"Cognitive reserve" is defined as the brain's ability to maintain a large number of synaptic connections and remain resilient against pathological deterioration. - Gaia

The Pathological Timeline: Inflammation, Amyloid, and Tau

The traditional view that amyloid deposition is the first step in Alzheimer's is shifting. "Changes in the inflammatory pathways may predate amyloid deposition by quite some time." - Gaia

Neuroinflammation, driven by microglial and other glial cells, may begin decades before clinical symptoms, followed by amyloid plaques and eventually tau tangles.

Targeting early neuroinflammation through lifestyle, viral suppression (such as shingles vaccines or suppressive HSV treatment), and dental hygiene may prevent the pathological cascade entirely.

The Nuances of Biomarker Screening in Asymptomatic Patients

Dr. Devi expresses caution regarding blood-based biomarkers like A-beta 42/40 and p-Tau 217, noting they are primarily standardized against amyloid PET scans rather than clinical symptoms.

Amyloid deposition is highly prevalent in asymptomatic older populations: 25% of people in their 70s, 30% in their 80s, and 44% in their 90s have amyloid plaques without showing cognitive decline.

Screening asymptomatic individuals should be reserved for high-risk cases, such as patients carrying two copies of the APOE4 allele with a strong family history of early-onset disease.

A 'Low and Slow' Protocol for Monoclonal Antibody Therapies

Monoclonal antibodies like lecanemab and donanumab clear amyloid plaques but carry significant risks of Amyloid-Related Imaging Abnormalities (ARIA), including edema (ARIA-E) and hemorrhage (ARIA-H).

To mitigate these risks, especially in high-risk APOE 4/4 carriers, Dr. Devi developed a slow titration protocol. "There's no reason to go in and quickly accelerate the dosing. We could go at it slowly." - Gaia

While clinical trials show high rates of ARIA, Dr. Devi's slow titration protocol has achieved a low 4% incidence of ARIA, with only one symptomatic case over five years of clinical use.

A major clinical barrier is that insurance companies often refuse to reimburse patients if clinicians deviate from the standard, rapid FDA-approved titration schedules.

Menopause-Related Cognitive Impairment and Estrogen Therapy

Dr. Devi coined the term "Menopause-Related Cognitive Impairment" (MERCI) to describe the severe short-term memory and executive deficits that occur due to estrogen loss.

Estrogen receptors are highly localized in the hippocampus, where the hormone drives synaptic sprouting; its sudden withdrawal can mimic early-stage Alzheimer's disease.

"I have patients in my practice who've been misdiagnosed with Alzheimer's disease... who really only turned out to have menopause-related cognitive impairment." - Gaia

For women unable to take hormone replacement therapy, targeted brain exercises, transcranial magnetic stimulation (TMS), and cholinesterase inhibitors like donepezil can successfully recover cognitive function.

The Overlap of Vascular and Lewy Body Dementias

Pure forms of dementia are rare; autopsy studies show 98% to 99% of Alzheimer's patients have concomitant pathologies, most commonly cerebrovascular disease.

Approximately 40% of Alzheimer's patients eventually exhibit Lewy body pathology, and 30% to 40% of Lewy body patients have concomitant Alzheimer's pathology.

Lewy body disease is frequently misdiagnosed as Parkinson's disease, leading to the inappropriate prescription of dopamine agonists which can severely worsen confusion and trigger psychosis.

Unlike Parkinson's disease, Dr. Devi notes that she has "never seen a patient with Lewy body present initially with a rest tremor," which serves as a key clinical differentiator. - Gaia