Beyond the Amyloid Hypothesis of Dementia: Implications and Opportunities for the Field of Psychology

Abstract: The amyloid-cascade hypothesis (ACH) has dominated Alzheimer’s Disease (AD) research for more than thirty years. However, pharmaceutical interventions based on the ACH model have not produced consistently effective treatments during this time. Recent research suggests that a variety of lifestyle changes may reduce or prevent many forms of dementia from emerging or at least delay onset. Although psychologists have never been dominant in AD research or treatment, their unique training and depth of varied treatment expertise make them prime candidates to assume a leadership role.

Dementia* Is a condition characterized by a progressive decline in cognitive and adaptive abilities, affecting memory, thinking, personality, executive functions and the ability to perform activities of daily living. Alzheimer’s disease (AD) represents the most prevalent form, accounting for approximately 60 to 70 percent of all cases (Alzheimer’s Association, 2024). There are at least two major types of AD: familial or early onset (less than 65 years of age), which make up a very small percentage (<5%) of the total cases and sporadic or late onset, where the major risk factor is age (Dubois, et al, 2016) and gender. Women make up a far greater percentage of AD cases than men, but the differences do not appear to be due entirely to longevity (Alzheimer’s Association, 2024). For example, some studies suggest that estrogen may be related to the development of some types of AD (Pourhadi et al, 2023).

The familial type of AD is most likely due to mutations in several genes, including ones associated with the amyloid precursor protein (APP) and the presenilin (PSEN1, most common) or rarely PSEN 2 genes. These mutations seem to be inter-connected and are further discussed below.  On the other hand, despite many years of research, the etiology of the sporadic form of AD is not fully understood and likely involves a complex interplay of genetic, environmental and life-style factors. For example, APOE is a gene that provides instructions for making a protein that helps transport fats, including cholesterol, in the bloodstream and brain, and appears to influence both APP and pathogenic tau. The APOE4 (a variant of apolipoprotein E) is a major genetic risk factor for late onset (AD) and is sometimes called the “Alzheimer’s gene.” It is very common in the human population (about 25%; Wang, et al, 2021) and significantly increases the chances of developing AD after age 65. However, many carriers never develop AD (Wang, et al, 2021). Interestingly, another variant, APOE2 appears to reduce the risk of AD but is relatively rare (about 5% of the global population). Despite the various causes, after onset the clinical signs and course of both familial and sporadic AD appear to be essentially identical.

It is commonly accepted that dementia is not a singular entity but rather an umbrella term encompassing a range of conditions each with diverse underlying causes. These include vascular dementia, resulting from cerebrovascular damage; multi-infarct dementia; dementia with Lewy bodies; Parkinson Disease with dementia; frontotemporal dementia, involving degeneration of the frontal and temporal lobes; Alzheimer’s Disease; ALS with dementia and others.  Furthermore, cognitive impairment itself, can arise from various factors such as stroke, infections like HIV or Lymes Disease, chronic alcohol or substance abuse, repetitive traumatic brain injuries (e.g., from sports or military involvement), diabetes, nutritional deficiencies and other conditions. The etiology of dementia should therefore extend beyond a solitary focus on Alzheimer’s disease and encompass its multifaceted nature. Furthermore, the complexity of dementia or cognitive impairment itself can impede accurate diagnosis and timely intervention, underscoring the importance of expanding research into the diverse causes and mechanisms that contribute to cognitive decline itself.

* In DSM-5 (American Psychiatric Association, 2022), the term “dementia” is replaced with “major neurocognitive disorder” (NCD) and “mild neurocognitive disorder”. However, the more traditional terms are used in this report.

Table 1: A Simple Explanation of the Amyloid Hypothesis

Many scientists consider the model above, often called the amyloid cascade hypothesis (ACH) to be the overall cause of Alzheimer’s Disease. Although criticized from its onset, the amyloid-cascade hypothesis (Hardy and Higgins, 1992) has historically dominated Alzheimer’s research, and to some extent, continues to do so (see Behl, 2024 for an excellent review). However, it is becoming increasing evident that this restrictive range of research has not and probably will never fully explain the causes of all the major types of dementia, including Alzheimer’s disease.  Perhaps more importantly, it has not consistently led to effective treatments for most AD individuals. The multifactorial and probably multigenetic nature of age-related cognitive deterioration stands in contrast to the linear, one-dimensional amyloid cascade hypothesis. This author, as well as many others, suggest a much broader research outlook and focus that investigates alternative causes, mechanisms, and risk factors, potentially leading to more effective diagnostic, therapeutic and preventative strategies (Hunter, 2024; Behi, 2024; Granzotto and Sensi, 2024).

Challenges to ACH:

Ongoing scientific research has increasingly questioned the exclusive role of amyloid-beta in the development of Alzheimer’s disease and other dementias (Hunter, 2024). The amyloid-cascade hypothesis is viewed by some within the field as a working framework, but its position as the definitive explanation for Alzheimer’s disease is no longer universally accepted. (Behl, 2024; Granzotto and Sensi, 2024; Yamashima, et al, 2023). The effectiveness of interventions aimed at removing amyloid-beta from the brain remains a subject of intense debate, with opinions divided on the salient improvements witnessed in actual daily living skills or other observable benefits.   Some researchers maintain that amyloid removal is central for treating AD. In contrast, others argue that amyloid deposition might be a late-stage consequence of other underlying pathological processes or even an incidental finding in aging brains (Yamashima, et al, 2023; Hunter, 2024).

The long-standing controversy surrounding the safety and effectiveness of anti-amyloid drugs (AADs) has increased recently (Granzotto and Sensi, 2024). The rejection of lecanemab by the European Medicines Agency (EMA) in July 2024, despite its approval in other major markets, including the United States, suggest a lack of a global agreement on the efficacy of these therapies and, by extension, the amyloid hypothesis itself.  The fundamental question is whether these drugs truly slow the underlying AD process or merely provide a limited reduction in some cognitive symptoms.  The repeated failures of numerous drugs targeting amyloid-beta over the past thirty years have also raised doubts on its prominence.  Furthermore, the frequent presence of amyloid-beta deposits in the brains of cognitively normal elderly individuals suggests that amyloid accumulation might be a common feature of aging rather than the primary driver of dementia.  In fact, some evidence indicates a much stronger correlation between the presence of tau tangles and degree of cognitive decline, as opposed to amyloid build-up in the disease process. The possibility that the production of amyloid-beta could be a protective response to various brain insults (at least initially), offers another perspective that challenges the traditional view (Onisiforou, Charalambous & Zanos, 2025).

Even with the recent regulatory approvals of AAD therapies like lecanemab, the clinical benefits associated with these treatments appear to be limited, and significant side effects often accompany them. While these drugs have shown the ability to slow cognitive decline in some patients, they also carry risks such as brain swelling and bleeding. Some experts view the clinical improvements observed as modest and potentially overinterpreted, especially when considering the substantial costs and the possibility of severe adverse events. The primary question surrounding these therapies is whether they truly modify the underlying disease process by slowing neurodegeneration and cognitive decline, or if they primarily address the progression of some symptoms (Granzotto and Sensi, 2024).

Tau Protein and Tangles.

While the amyloid cascade hypothesis has historically been central to Alzheimer’s disease research, the role of some forms of abnormal tau protein and the neurofibrillary tangles it forms within brain cells are increasingly recognized as essential factors in the progression and severity of dementia. In normal human brains, the tau protein is crucial for maintaining the neuron’s ability to function normally, including the neuron’s structural integrity and ability to communicate with other neurons.  In Alzheimer’s disease, some tau proteins undergo abnormal changes in their structure, leading them to aggregate and form neurofibrillary tangles. These tangles disrupt the internal support and transport system of neurons, which is crucial for carrying nutrients and other vital materials throughout the cell, thus ultimately leading to cellular damage and death. As previously mentioned, recent research suggests that the accumulation of tau tangles and the extent of neuronal loss in the brain show a stronger correlation with cognitive decline in individuals with AD than the degree of amyloid-beta deposits (Naseri, 2019). In this case, it appears that Aβ may play a role in initially starting the AD process. Still, the effects of the abnormal function of tau and the resulting neurofibrillary tangles are more responsible for the signs and severity of the overt symptoms (Naseri, 2019).

There is an obvious complex interplay between amyloid and tau, with studies showing that levels of different forms of tau protein increase in response to the proliferation of beta-amyloid plaques. However, these increases in tau can occur as early as two decades before the appearance of the neurofibrillary tangle’s characteristic of Alzheimer’s disease (Scharre, 2019; Morris, 2005). Even after neurofibrillary tangles start to form, there is often a long period of time before overt cognitive decline is recognized. The concept of cognitive reserve is sometimes used to explain this delay. For example, persons with a higher IQ, higher level of education, or who routinely engage in intellectually stimulating activities may have a greater ability to maintain their normal level of cognitive functioning for many years. In women, who tend to have a higher verbal IQ than men, this difference may mask the recognition of cognitive decline and thus delay accurate diagnosis. On the other hand, tau pathology may initially occur in parts of the brain that are less involved in normal activities, or a certain level of pathogenic tau accumulation is needed before overt symptoms occur or can be identified (Nasseri et al, 2019). There may also be other protective or resilience factors in the brain that are not yet recognized or fully understood that may explain the lengthy preclinical stage of AD and other dementias.

Lifestyle and Other Modifiable Factors in Alzheimer’s Disease and Other Dementias

Because of the lack of consensus regarding the exact causes of AD, and the fact that highly effective pharmacological treatments are still lacking, scientists have been and still are actively looking for other potential causes and treatment modalities that may be used to treat or prevent various types of dementia.  Recently, the Lancet Commission (Livingston et al, 2020) published a groundbreaking report on novel ways to prevent and treat dementia. Numerous studies and meta-analyses supported this evidence-based report. The authors identified twelve lifestyle or potentially modifiable risk factors for dementia, including: low levels of education; hypertension; hearing impairment; obesity; smoking; depression; physical inactivity; social isolation; diabetes; excessive alcohol consumption; traumatic brain injury; and air pollution. Recently, these authors confirmed two new risk factors: high LDL cholesterol and untreated visual loss. These studies further suggested that by addressing these fourteen factors, up to 45% of all dementia cases may be preventable (Livingston et al, 2024) or at least delayed.  Similar studies have suggested additional modifiable factors such as sleep disorders, HIV infection, substance abuse, consuming high levels of fatty or deep-fried foods, and a lack of stimulating cognitive activities prior to AD onset.

Considering this report and similar research, specific lifestyle changes such as diet and exercise appear to be the easiest and most effective approaches to preventing and delaying dementia in normal populations (Livingston et al., 2020; Serrano-Pozo & Growdon, 2019). These two lifestyle changes also appear to directly or indirectly address many of the other factors identified by the Lancet Commission and thus will be further explored.

Diet and The Gut-Brain Axis

The connection between the gut and the brain, often referred to as the gut-brain axis or the “second brain”, is emerging as a critical area of research in understanding the development and progression of dementia (Nakhal et al, 2024). The gut microbiome (GM) is a complex community of microorganisms, including bacteria, fungi, viruses, and other microbes residing in the gastrointestinal tract, which communicate bidirectionally with the brain through neural, immune, endocrine, and metabolic pathways (Salami, 2021). This is important for many reasons, but especially because disruptions in this system may have both positive and negative effects on the brain’s protective mechanisms (Bano et al, 2024). Recent research suggests that alterations in the composition of this system may play a significant role in the development of Alzheimer’s disease and other dementias (Kowalski and Mulak, 2019). For example, it may prevent neuroinflammation and other brain changes leading to dementia or AD (Yang, et al, 2024; Onisiforou, Charalambous & Zanos, 2025). On the other hand, dysbiosis, or an imbalance in GM may have the opposite effect. After Japan’s nutrition transition from the traditional Japanese to the Western diet, AD rates rose from 1% in 1985 to 7% in 2008 (Grant, 2016). Similarly, a large-scale human study conducted in Australia and China has shown an obvious association between the health and diversity of gut bacteria and cognitive impairment (Wang et al, 2024). This research found that individuals with reduced diversity in their gut microbiota were more likely to exhibit cognitive impairment and develop some forms of dementia.  Notably, the study suggests simple interventions like increasing fruit intake and regular exercise can potentially prevent or reduce cognitive decline.

The Mediterranean-style diet (MSD), which includes high levels of whole grains, nuts, seeds, herbs, beans, fruit, leafy vegetables, olive oil and low levels of animal fat and red meat is positively correlated with a healthy microbiota (Merra et al 2020) and has also been shown to reduce the risk of Alzheimer’s and other dementias (Agarwal et al, 2023.) Similar diets such as DASH (Dietary Approaches to Stop Hypertension) and MIND, which combines the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) with the DASH diet, have also been shown to reduce cognitive decline (van den Brink et al, 2019) and possibly reduce or prevent certain dementias.  The reasons these diets are effective are not entirely clear, but may be singularly or in combination related to a number of influencing factors such as: 1) increasing levels of probiotics in the diet; 2) high levels of antioxidants in fruits and vegetables; 3) potentially reducing brain inflammation; 4) reduced risk of type II diabetes;  5) direct influence of the gut-brain interactions on the immune system, 6) reduction of low-density lipoprotein (LDL), 7) potentially lowering hypertension, and perhaps the diets themselves may directly or indirectly reduce the formation of Aβ or pathogenic tau accumulation in the brain (Dominguez, et al, 2021; Zhang, et al, 2024; Onisiforou, Charalambous & Zanos, 2025).

As we age, many of us get less active and more sedentary. Regular physical activity and a healthy diet may be the most efficient lifestyle changes for reducing the risk of some dementias and AD. Several studies have noted the importance of combining increased physical activity with diet modification for the prevention of dementia (Scarmeas, et al, 2009; Dominguez, et al, 2021). Even small amounts of moderate to vigorous physical activity have been linked to significant reductions in dementia risk (Iso-Markku, et al, 2022). In fact, it has been suggested that about 3% of all dementia cases could be prevented by increasing levels of physical activity (Dominguez, et al, 2021).

While studies evaluating the effects of exercise on AD symptoms and prevention are mixed, some generalizations are possible. Regular physical activity can improve heart health and blood flow to the brain; improve coordination and balance (thus reduce the risk of falling); reduce the risk of strokes and Type II diabetes; improve sleep quality; increase energy, improve mood, and possibly reduce depression; reduce brain inflammation, and perhaps may even slow down the accumulation of Aβ or pathogenic tau in the brain (Toman, Klímová, & Vališ  2018; Tussing-Humphreyset al, 2017).  Physical activity may be more effective in delaying progression if used in the early stages of cognitive decline. Similarly, physical activity may be of greatest benefit for preventing AD if started early in life and continued throughout the person’s lifespan. Further, physical activity combined with social interaction (e.g. dancing or walking with others) appears to offer the greatest potential for improvement (Toman, Klímová, & Vališ, 2018).

Psychological and Psycho-social Interventions

Aside from assessment, it would be fair to say that psychologists as a whole and even geropsychologists have not been at the forefront of research or treatment of AD and other dementias. There may be several reasons for this. One, as this article has discussed, the prevailing view of AD is that it is a neurodegenerative biological disorder, and a popular perception is that dementias require medical or pharmacological interventions. Second, a major treatment modality of clinical psychology is psychotherapy, which, for obvious reasons, may not be effective, particularly in the later stages of these disorders. Third, and perhaps more important, there is a shortage of psychologists specializing in geropsychology or dementia care, limiting the availability of these professionals to contribute to research and clinical practice (Merz et al, 2017).  These authors point out that only 3% of licensed psychologists in the United States identify professional geropsychology as their primary or secondary specialty.

Despite these limitations, psychologists have and continue to make many contributions to AD care and research beyond cognitive assessment. They are instrumental in developing and implementing evidence-based interventions to manage the behavioral and psychological symptoms of dementia (BPSD), such as agitation, wandering, and aggression (Logsdon, McCurry, & Teri, 2007). Psychologists also play a key role in training caregivers and direct care staff in effectively using behavioral management techniques, such as reminiscence therapy, cognitive behavioral therapy (CBT), and environmental modifications that enhance safety and reduce confusion (Beata, et al, 2023). Further, psychologists provide crucial support for family and caregivers, who often experience significant stress and burnout related to living with or caring for their loved ones (Alzheimer’s Society, 2011).

The ongoing awareness of AD as a multifaceted disorder and psychology’s emphasis on the bio-psychosocial model presents a perfect opportunity to expand their research and treatment contributions. For example, the National Institute on Aging (NIA) supports 495 active clinical trials on AD and related dementias. Of these, the vast majority are non-amyloid theory-related topic areas, many of which are lifestyle changes addressed above, such as diet and exercise, stress reduction, cognitive training, caregiving, sleep disorders, and others. Less than 15% of these clinical trials were related to pharmacology (National Institute on Aging, 2024). Interestingly, the recent focus on lifestyle changes for preventing some forms of AD seems to be paying off.  Current research suggests that the incidence of AD in high-income Western countries has decreased significantly over the past 25 years for both men and women (Wolters et al, 2020). Although the definitive reason for this decline is not totally established, it appears to be related to various lifestyle changes that prevent AD. However, given the risk factors of AD, such as obesity and diabetes, are rapidly increasing in our younger generations, this positive trend is not likely to continue without a focused intervention.

Psychologists are well-positioned to address lifestyle factors, such as physical inactivity, smoking, obesity, and depression, and modify these through behavioral interventions. Similarly, the task of early detection and prevention of AD also creates significant opportunities for psychologists to contribute their expertise in risk assessment, lifestyle interventions, and cognitive training programs aimed at delaying or preventing the onset of the disease. Advancements in technology, such as the use of virtual reality in cognitive rehabilitation and assessment, are also opening new avenues for psychological interventions and research (Clay, et al, 2020). The recognition that AD is not solely a late-stage development but rather a progressive disorder with preclinical and prodromal phases opens opportunities for psychologists in early detection, risk prediction, and the development of preventative strategies. For example, research into the early signs of AD, such as spatial disorientation, may provide useful non-invasive early detection methods (Berkowitz, Harvey, & Clark, 2020). The concept of cognitive reserve described above suggests that factors like education and cognitive engagement can delay the signs of AD pathology, presenting opportunities for psychological investigation and the development of targeted interventions. Finally, because of their research training, extensive history of treatment as well as long-established ethical codes, psychologists are well prepared to promote the autonomy and human rights of individuals with dementia and their loved ones to ensure their active involvement in decisions regarding their care and treatment.

In conclusion, we appear to be on the verge of a paradigm shift related to the causes, treatment, and prevention of AD. As such, the field of psychology and psychologists themselves are well prepared to be at the forefront of this movement and should take the opportunity to do so.