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The Alzheimer’s-Cholesterol Connection

Elevated low density lipoprotein (LDL) cholesterol levels were tied to a higher probability of early-onset Alzheimer’s disease, a case series showed.

Early-onset Alzheimer’s patients had higher LDL cholesterol, total cholesterol, and apolipoprotein B (Apo B) levels, even after adjusting for the apolipoprotein E ε4 (APOE E4) allele — a genetic risk factor known to raise circulating cholesterol — reported Thomas Wingo, MD, of Emory University in Atlanta, and colleagues.

Moreover, early-onset Alzheimer’s cases were strongly associated with rare variants of APOB, which codes for the major protein of LDL cholesterol, they wrote in JAMA Neurology.

“A big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer’s risk,” Wingo told MedPage Today. “The existing data is murky on this point.”

“Our current work is focused on testing whether there is a causal link,” he continued. “If there is a causal link between Alzheimer’s disease and cholesterol, we might need to revise targets for LDL cholesterol to help reduce Alzheimer’s risk.”

Early-onset Alzheimer’s occurs before age 65 and has a large genetic basis with heritability of 91% to 100%. Mutations in three genes that cause Alzheimer’s — amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) — were discovered in families with early-onset disease, but most likely account for less than 10% of incident cases.

In this analysis, Wingo and colleagues studied three potential causes of early-onset Alzheimer’s: Alzheimer’s genetic variants, circulating plasma lipoproteins, and APOB, which is known to harbor rare variants with strong effects on raising or lowering LDL cholesterol.

To collect this data, they sequenced APOB, APP, PSEN1, and PSEN2 in samples from 2,125 early-onset cases and controls recruited from 29 Alzheimer’s disease research centers from 1984 through 2015. They also measured plasma cholesterol levels in 267 frozen samples collected from early-onset Alzheimer’s patients and controls from 2009 to 2014 at Emory University and the University of California San Francisco Alzheimer’s research centers.

Of the 2,125 samples that underwent genetic sequencing, 1,276 were from women (60.0%) and 654 (30.8%) were from patients with early-onset Alzheimer’s. The average age of early-onset patients was 55.6 and the average age of controls was 72.

In this group, only 3.4% carried APP, PSEN1, and PSEN2. The APOE E4 allele — the largest known genetic risk factor for late-onset Alzheimer’s — accounted for 10.1% of the variance. “These results collectively confirm that these four genes account for only a minority of the strong genetic predisposition seen in early onset Alzheimer’s disease, and additional genes are likely to be involved,” noted Makoto Ishii, MD, PhD, of Weill Cornell Medicine in New York City, in an accompanying editorial.

After controlling for APOE E4, early-onset cases had higher levels of total cholesterol (mean difference 21.9 mg/dL, P=2.9 × 10-5), LDL cholesterol (mean difference 22.0 mg/dL, P=1.8 × 10-6), and Apo B (mean difference 12.0 mg/dL, P=2.0 × 10-6) than controls in the 267 plasma samples. Adjusting for age showed similar results.

Deep resequencing showed that rare APOB coding variants were significantly more abundant in early-onset Alzheimer’s cases, after taking sex, APOE E4, genetic principal components, and study center into account (effect size 0.20; P = 4.20 × 10-4).

“Overall, this is an important study that provides the first evidence that rare genetic coding variants of APOB are strongly associated with early-onset Alzheimer’s disease,” Ishii observed. Consistent with these findings, a transgenic mouse model overexpressing APOB had significant memory impairment and increased beta-amyloid levels compared with wild-type mice, he noted.

“However, previous studies measuring circulating apolipoprotein B levels in humans have been inconclusive, with a large population study finding no association between circulating apolipoprotein B levels and incident dementia or Alzheimer’s disease,” he continued. “Therefore, whether these findings can be verified in individuals with late-onset Alzheimer’s disease remains to be determined.”

The study suggests other contributing factors — possibly rare variants in other genes involved directly in LDL cholesterol metabolism — may be involved, Ishii added. And while this analysis focused on cholesterol, “similar studies investigating other cerebrovascular risk factors, such as insulin resistance or type 2 diabetes mellitus in individuals with early-onset Alzheimer’s disease, may be equally enlightening,” he wrote.

The findings generate a number of questions, including whether APOB has protective and deleterious variants and what role APOB variants may play in late-onset Alzheimer’s disease, noted Wingo and colleagues.

The analysis also has several limitations, they noted. It does not infer causality and because of the rarities of the alleles tested, could not be analyzed using Mendelian randomization. Cholesterol data may be confounded by Alzheimer’s severity, smoking, or cholesterol-lowering drugs, but the genetic link between APOB and early-onset Alzheimer’s is unlikely to be affected by these variables, they added.

The study was supported by the Veterans Health Administration, the NIH, the Emory Integrated Genomics Core, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and the State of California Department of Health Services, Alzheimer’s Disease Research Center of California.

Researchers disclosed relevant relationships with the NIH, the NIA, the VA, Avid Radiopharmaceuticals, Eli Lilly, Piramal Imaging, GE Healthcare, Eisai, Axon Neuroscience, Merck, Genentech, Roche, Quest Diagnostics’ Dementia Pathway Collaboration, Cornell University, the Bluefield Project, Avanir Pharmaceuticals, AbbVie, Novartis, Biogen, Cognito Therapeutics, Future Health, and Takeda.

Editorialist Ishii was supported by the NIH and owns stock in Regeneron Pharmaceuticals.