A major Alzheimer’s risk gene may shrink brain cells years before symptoms

APOE4 Gene Drives Early Brain Cell Atrophy, Predicting Future Alzheimer’s Risk

Millions of individuals carry APOE4, the most significant inherited risk factor for Alzheimer’s disease. Recent studies indicate that this genetic variant can influence brain activity long before typical memory impairments manifest.

Scientists at Gladstone Institutes have mapped a molecular pathway that may clarify these preliminary effects, while also identifying a potential therapeutic avenue to counteract the underlying changes.

In a mouse-model investigation published in Nature Aging, the team discovered that APOE4 elevates expression of the protein Nell2. This upregulation prompts neurons to shrink and exhibit heightened excitability. Young mice displaying maximum brain hyperactivity subsequently developed the most pronounced memory deficits at older life stages.

To test causality, the researchers lowered Nell2 production in adult APOE4 mice. The intervention restored neuronal dimensions and normalized electrical behavior, suggesting that inhibitors of Nell2 might protect genetically susceptible individuals from progressive cognitive decline.

According to lead author Misha Zilberter, “Our work represents the first direct examination of how APOE4 impacts neuronal function across the lifespan. We uncovered fundamental circuit adjustments in juvenile mice that preserved normal learning yet set the groundwork for cognitive impairment later.”

Prior research had detected abnormal neural vigor in APOE4 carriers sometime before middle age—a pattern repeatedly linked to subsequent memory loss. The underlying mechanisms driving these age‑dependent changes, and their contribution to later‑life dysfunction, had remained uncertain.

To address this gap, investigators recorded brain activity in youthful mice and isolated individual hippocampal neurons. Juvenile APOE4 animals showed exaggerated firing rates within hippocampal regions that underpin memory functions.

Importantly, identical hippocampal zones harbor the hyperactive signature in humans with APOE4 as well.

“The magnitude of hyperactivity observed in young mice predicted how poorly they performed on spatial learning tasks later in life,” noted first author Dennis Tabuena.

The investigators further compared subject groups by introducing APOE3, a variant tied to lower Alzheimer’s risk.

Neuronal anatomy differed markedly between the two genotypes; APOE4 hippocampal neurons were notably smaller than their APOE3 counterparts. Smaller cells typically respond more readily to stimuli, rendering them prone to excessive firing.

While APOE3 hippocampal neurons also became more excitable with age, that shift did not emerge until maturity.

This pattern indicates that APOE4 accelerates a course analogous to normal aging, potentially explaining why carriers experience earlier onset of Alzheimer’s-related disease.

Although most APOE4 in a healthy brain originates from astrocytes, which support neurons, earlier speculation attributed the APOE4‑Alzheimer’s link primarily to astrocytic sources.

The latest findings diverge from that view. The hippocampal hyperactivity linked to APOE4 was driven solely by APOE4 synthesized within neurons themselves.

“Deleting APOE4 from astrocytes produced no change,” explained Zilberter. “Conversely, eliminating it from neurons led to cell growth restoration and normalization of function.”

The Molecular Target: Nell2

To identify the cellular cascade behind APOE4‑caused neuron shrinkage and hypersexuality, the team surveyed gene‑expression profiles across multiple cell types in the hippocampus.

The analysis singled out Nell2, a protein whose concentration spiked dramatically in neurons expressing APOE4.

Using CRISPR interference, researchers reduced Nell2 transcription in adult APOE4 hippocampal neurons. Lower Nell2 levels reversed cellular enlargement and decreased excitatory signaling, implicating this protein as the causal agent behind early hyperactivity.

Therapeutic Implications

“Nell2 is promising because we were able to reverse disease phenotypes in adult mice by reducing its burden. This implies that the pathological state is reversible, and that window of intervention exists even after disease processes have initiated.”

“This research marks a major breakthrough for Alzheimer’s science,” said Yadong Huang, MD, PhD, associate director of the Gladstone Institute of Neurological Disease. “It provides deeper insight into how APOE4 disrupts neuronal function at a young age, creating vulnerability to cognitive decline, and paves the way for therapies that could block the detrimental effects of APOE4 early.”

“What is encouraging is that lowering Nell2 in adult mice mitigated clinical‑like deficits. This demonstrates that the damage may be non‑irreversible, opening the possibility for treatment opportunities despite the presence of prodromal pathology.”

The research was supported by the National Institute on Aging (R01AG061150, R01AG087323, R01AG092390, R01AG085468, R01AG055682, R01AG071697, P01AG073082, F32AG0859612), the National Institute of Neurological Disorders and Stroke (K99NS134734), and the National Center for Research Resources (C06 RR018928).

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