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Key Points An imbalance between the production and clearance of amyloid-β (Aβ) is an early, often initiating, factor in Alzheimer disease (AD) Peripheral systems are suggested to be involved in Aβ production and clearance The central and peripheral pathways of Aβ metabolism communicate with each other, and work synergistically to clear Aβ from the brain Increasing experimental, epidemiologic and clinical evidence suggests that AD manifestations extend beyond the brain, and that AD pathogenesis is closely associated with systemic abnormalities The systemic abnormalities in patients with AD might not be secondary to the cerebral degeneration; instead, they might reflect underlying disease processes A systemic view of AD provides a novel perspective for understanding the role of Aβ in AD pathogenesis and offers opportunities for the development of new treatments and diagnostic biomarkers for AD Increasing evidence suggests that Alzheimer disease (AD) is not simply a CNS disorder, but involves interactions between systemic and brain-related factors. Wang and colleagues review the role of amyloid-β (Aβ) in AD, highlighting systemic abnormalities linked to Aβ metabolism and discussing how these abnormalities might influence central pathways of Aβ production and clearance. Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becoming more clearly defined. This Review focuses on amyloid-β (Aβ), a major hallmark of AD. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we propose that these abnormal systemic changes might not only develop secondary to brain dysfunction but might also affect AD progression, suggesting that the interactions between the brain and the periphery have a crucial role in the development and progression of AD. Such a systemic view of the molecular pathogenesis of AD could provide a novel perspective for understanding this disease and present new opportunities for its early diagnosis and treatment.

Alzheimer disease (AD) is the most common cause of dementia in older individuals. AD is characterized pathologically by amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain, with associated loss of synapses and neurons, which eventually results in dementia. Many of the early attempts to develop treatments for AD focused on Aβ, but a lack of efficacy of these treatments in terms of slowing disease progression led to a change of strategy towards targeting of tau pathology. Given that tau shows a stronger correlation with symptom severity than does Aβ, targeting of tau is more likely to be efficacious once cognitive decline begins. Anti-tau therapies initially focused on post-translational modifications, inhibition of tau aggregation and stabilization of microtubules. However, trials of many potential drugs were discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting agents in clinical trials are immunotherapies. In this Review, we provide an update on the results from the initial immunotherapy trials and an overview of new therapeutic candidates that are in clinical development, as well as considering future directions for tau-targeting therapies.The limited success of amyloid-β-targeting therapies for Alzheimer disease has led to a shift in focus towards the tau protein. This Review provides an update on the initial trials of tau-targeting therapies, focusing particularly on immunotherapies, and considers future directions for these therapies.

An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts ( n  = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast + ). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast + individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials. Cross-sectional and longitudinal analyses of tau pathology in preclinical Alzheimer’s disease reveal that tau tangles accumulate as a function of amyloid-β burden only in individuals positive for an astrocyte reactivity biomarker.

Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs that target Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD — Aβ plaques and tau neurofibrillary tangles — and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial.Many drugs that target amyloid-β in Alzheimer disease have failed in clinical trials. Karran and De Strooper analyse clinical trial data for these drugs in the light of drug properties that could affect their clinical performance. They propose that amyloid plaque would need to be reduced to a low level to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe such a benefit.

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.Accumulating evidence indicates that impaired glucose metabolism in the brain is involved in the cause and progression of neurodegenerative disorders of ageing such as Alzheimer disease. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by rescuing, protecting or normalizing brain energetics.

Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous community-based populations is unclear. We examined P-tau181 and P-tau217 ( n  = 1,329, aged 30–98 years), in the population-based Mayo Clinic Study of Aging. Continuous, unadjusted plasma P-tau181 and P-tau217 predicted abnormal amyloid positron-emission tomography (PET) (area under the receiver operating characteristic curve (AUROC) = 0.81–0.86) and tau PET entorhinal cortex (AUROC > 0.80), but was less predictive of a tau PET temporal region of interest (AUROC < 0.70). Multiple comorbidities were associated with higher plasma P-tau181 and P-tau217 levels; the difference between participants with and without chronic kidney disease (CKD) was similar to the difference between participants with and without elevated brain amyloid. The exclusion of participants with CKD and other comorbidities affected the establishment of a normal reference range and cutpoints. Understanding the effect of comorbidities on P-tau181 and P-tau217 levels is important for their future interpretation in the context of clinical screening, diagnosis or prognosis at the population level. Multiple comorbidities are associated with higher plasma P-tau181 and P-tau217 levels, and affects their normal reference ranges and cutpoints.

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer’s disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer’s Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments. The study on APOE4 homozygosity indicates a genetic variant of Alzheimer’s disease with early symptom onset and distinct biomarker progression, highlighting the need for specialized treatment approaches.

Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.The amyloid hypothesis has been the dominant model for the pathogenesis of Alzheimer disease for several decades. In this Perspective, Giovanni Frisoni and colleagues examine evidence for and against this hypothesis before outlining an alternative model, the probabilistic model of Alzheimer disease.

The hippocampus is one of the most affected areas in Alzheimer’s disease (AD)1. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life2. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry3,4. Nonetheless, direct evidence of AHN in humans has remained elusive. Thus, determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential. By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced. These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.Newborn neurons are continuously incorporated into the healthy adult human hippocampus up to the ninth decade of life. However, robust adult hippocampal neurogenesis sharply declines during the progression of Alzheimer’s disease.