HoldsUp

DavidPerlmutterMD · 2026-02-17 · David Perlmutter (host), Sarah Marzi

Why Some Brains Never Get Alzheimer’s | Dr. Sarah Marzi

37 research-tied claims examined: 4 overstated 1 context 30 supported 2 unverified

4

Overstated

0:03:42David Perlmutter (host)overstatedhigh

Genome-wide association studies (GWAS) have identified well over 100 genetic risk loci associated with Alzheimer's disease.

"and we'll talk about APOE, certainly that's an area that many of our listeners are familiar with, but you know there are well over a hundred when we look at these genome-wide association studies." (said at 0:03:42)

Large-scale genome-wide association studies (GWAS) and meta-analyses have greatly expanded the known genetic architecture of Alzheimer's disease (AD) beyond the well-known APOE locus. However, the number of confirmed genome-wide significant risk loci is approximately 75 to 91. The landmark 2022 GWAS meta-analysis by Bellenguez et al. identified 75 risk loci, and a subsequent consensus meta-analysis identified 91 risk loci (with an additional 18 loci noted as requiring external validation, totaling 109). Claiming that GWAS have identified 'well over 100' established risk loci somewhat overstates the number of definitively confirmed loci.

0:30:51Sarah Marzioverstatedlow

Vitamin D deficiency is a significant risk factor for Alzheimer's disease and accelerates disease progression in people who already have Alzheimer's.

"it's well known that vitamin D deficiency—so if you don't have enough vitamin D—is a powerful risk factor for Alzheimer's disease. And in fact, even once you already have Alzheimer's disease, vitamin D deficiency can make your course of disease faster and your progression worse." (said at 0:30:51)

While observational meta-analyses of prospective cohort studies link vitamin D deficiency to an increased risk of incident Alzheimer's disease (AD), describing it as a 'powerful risk factor' and asserting that it accelerates disease progression overstates the evidence. Meta-analyses typically report modest relative risk increases (hazard ratios around 1.34 to 1.57), and some studies show that this association is attenuated after adjusting for confounders. Furthermore, evidence linking vitamin D status to the rate of progression in established AD is primarily observational and subject to reverse causation, with randomized controlled trials of vitamin D supplementation generally failing to demonstrate substantial disease-modifying benefits.

0:48:25David Perlmutter (host)overstatedhigh

Men are twice as likely as women to develop Parkinson's disease.

"that's why men are two-to-one more likely to get Parkinson's." (said at 0:48:25)

Men are at higher risk of developing Parkinson's disease than women, but epidemiological meta-analyses show an overall male-to-female incidence and prevalence ratio of approximately 1.5 to 1 (1.48–1.49), rather than 2 to 1 (twice as likely).

1:10:00David Perlmutter (host)overstatedmoderate

Elevated blood sugar and systemic inflammation polarize microglia to an M1 phenotype that cannot phagocytize.

"when we are having issues with elevated blood sugar and inflammation in our bodies, that's tending to polarize these microglia to being that M1 phenotype that cannot phagocytize, as your work so elegantly demonstrated in the APOE study." (said at 1:10:00)

Hyperglycemia and inflammatory signals promote microglial activation toward pro-inflammatory states (historically categorized as the M1 phenotype) characterized by the release of inflammatory cytokines and reduced clearance of pathological debris compared to protective (M2 or early disease-associated microglial) phenotypes. However, asserting that M1 microglia categorically 'cannot phagocytize' overstates microglial biology; modern transcriptomic and functional studies demonstrate a complex spectrum of states rather than a strict binary, with altered or impaired clearance mechanisms rather than a complete absence of phagocytic capability.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.